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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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Dean, sorry that you think this is a silly question from me. It is just a lot easier to get a short straight answer from you than going through your longer review and the Cool Fat Burner website with a lot of information most of which I don't care about for now. Thank you for answering my question.

 

I have a few more questions about your cool vest. How long does it stay cool -- half an hour, one hour, or longer? And how long does it take to get recharged in the freezer? Does one order of the original include spare cold packs, or do I need to buy the spare packs separately? Can you help me with those questions, or I have to find out about them on my own?

==

Quote Dean:

 

Grace, you've been hanging out here long enough, and I know you have a thick enough skin, so I'm not afraid to tell you this is a silly question you should be able to answer for yourself based on my Cool Fat Burner review and the Cool Fat Burner website. Think independently Grace, and save your questions for the really tough ones, which I'm happy to try to answer.

 

But to answer your current question, I consider the original Cool Fat Burner as better at targeting the areas where the most BAT is located, but the "Gut Buster" model a good addition to the original to increase overall body cooling and to target the abdominal region with localized cooling in order to encourage the subcutaneous fat in that region to turn from white to brown.

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Grace,

 

Dean, sorry that you think this is a silly question from me. It is just a lot easier to get a short straight answer from you than going through your longer review and the Cool Fat Burner website with a lot of information most of which I don't care about for now. Thank you for answering my question.

 

Sorry Grace, that doesn't cut it. Public forums, and especially unsupported ones like this, can only flourish if people give and take. As a very new person, you've been mostly in "taking" mode - which is fine, up to a point.

 

But now that you've been here a while and know the ropes, it's time to start standing on your own feet, and (hopefully) eventually giving something back to the rest of us as well. So when you ask a flurry of questions like this:

 

How long does it stay cool -- half an hour, one hour, or longer? And how long does it take to get recharged in the freezer? Does one order of the original include spare cold packs, or do I need to buy the spare packs separately? Can you help me with those questions, or I have to find out about them on my own?

 

which I've answered already in the Cool Fat Burner review post I've pointed you to, rather than feed your laziness and promote your dependence on others, I'll have to go with your latter answer - i.e. you'll have to find out about them on your own.

 

It is a hackneyed expression, but that doesn't make it any less true. Give someone a fish and they eats for a day, teach someone to fish and they eat for a lifetime.  Please don't take this as an endorsement for eating fish...

 

--Dean

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Question to Dean, Gordo, anyone else experimenting with CE: in regards to improved glucose readings, have you found that CE primarily is improving the postprandial readings, or is it also improving fasting readings? 

 

Hi Brian, good to see some new people in this thread!  In my personal experience I am seeing improvements in both fasting and postprandial readings.  I've been seeing fasting readings in the 50's which I never saw before I started CE, and I didn't even think numbers like that were possible without hypoglycemic symptoms (which I have NEVER had while doing CE by the way!).  I don't think there has been much published about this yet.  Also as Dean's experience suggests -- I'm not sure how universal these results will be.  Some people seem to be able to "amp up" their BAT activity more readily than others.  For example I just stumbled upon Wim Hof, AKA "The Ice Man":

Opmerkelijk-resultaat-in-onderzoek-naar-

He is able to do amazing things and to me it seems he likely has special genetics that somehow give him incredible BAT activity and circulation that I doubt very many people in the world could ever duplicate even with a lot of training.

 

I had recently been raving to my wife about cold showers because they make me feel spectacular, some people compare the feeling to "runner's high".  I finally talked her into giving it a try, and her response was "they don't do for me what they do for you" ;)    I don't know if there is something unusual about me, or if my results are just the culmination of many factors - I've stated before how it seems every time Dean adds to his list of things that activate BAT, almost all of them turn out to be things I've been doing for years, for example even in his most recent post of this nature he mentioned limonene/citrus fruit, I've been eating 1-2 lemons or limes a day for more than a year.  I've been eating most of the things on his list on a regular basis for more than a year, and when I started cold exposure, I quickly ramped up to pretty serious/challenging levels of CE.  So I guess the jury is still out on how much is genetics, vs. how much is hard core training/practice.  

 

One difference between Dean and I might be that he exercises all day, to me this seems counter-productive, the cooling he is doing might be offset by the warming caused from continuous exercise.  By contrast, I do "HIIT" style exercise of minimal duration, and cooling mostly while sedentary - maximizing the impact of CE on my body.

 

Another difference between us is muscle & fat mass.  Having more muscle and fat is highly likely to be an advantage when it comes to extraordinary BAT activity (in comparison to extremely low muscle and fat levels).  However too much fat has been shown to also be counter-productive, I'm not exactly sure where the sweet spot is.

 

I like the homemade cooling solutions.  Note: If you have an Aldi near you, just last week they started selling their own brand version of this:

http://www.amazon.com/AZMED-Ice-Bag-Reusable-Color/dp/B00YBASCB4/

for $5.  The amazon reviewers seem to love these things.  I thought it might be useful so I picked one up, now I'm thinking about getting a couple more since they are cheap (and they may not be stocked for much longer).

 

Regards,

Gordo

Edited by Gordo

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I agree. ==

Quote Dean:

Sorry Grace, that doesn't cut it. Public forums, and especially unsupported ones like this, can only flourish if people give and take. As a very new person, you've been mostly in "taking" mode - which is fine, up to a point.

 

 

Sorry, I don’t feel that I have known enough ropes to stand on my own feet. I am still learning. I had felt greatly supported until I got a bump like this from you, which is fine. When I have anything to give, I will give for sure. But again right now I am still in the learning mode, and will probably be in that mode for a while.

==

Quote Dean:

But now that you've been here a while and know the ropes, it's time to start standing on your own feet, and (hopefully) eventually giving something back to the rest of us as well. So when you ask a flurry of questions like this:

 

 

I spent more than half an hour trying to locate your cool fat burner review post, and failed. That is very strange. I typed three times “cool fat burner” in the search box and got nothing. Right now my post is on page 16. I went back to Page No. 15, 14 and 13, three times and could not find it. I remember I saw it two days ago shortly before Todd’s first post. But I cannot find it. Could you tell me the right way to search it?

==

Quote Dean:

which I've answered already in the Cool Fat Burner review post I've pointed you to, rather than feed your laziness and promote your dependence on others, I'll have to go with your latter answer - i.e. you'll have to find out about them on your own.

 

 

Again I appreciate tremendously your example and support! But I do not agree with you on the fish analogy. First, you don’t give me any “fish”. I happen to like the kind of “fish” you have, and will get it on my own. Also the “fish” is reusable and I want to learn how to reuse it. You already shared how, don’t want to waste your time saying that again, and want me to read your previous sharing post. Now I have spent a good amount of time trying to find it, and am not successful, as I stated above.  Please let me know what you think. Thanks!

==

Quote Dean:

It is a hackneyed expression, but that doesn't make it any less true. Give someone a fish and they eats for a day, teach someone to fish and they eat for a lifetime.  Please don't take this as an endorsement for eating fish...

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Also I am here to add that on Page No. 15, in my post #299, I saw in my quote of you on  “full review of the Cool Fat Burner vest.” I clicked on that link and it turned out to be  “404 not found.”

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Grace,

 

 I do not agree with you on the fish analogy. First, you don’t give me any “fish”. I happen to like the kind of “fish” you have, and will get it on my own.

 

That is a good attitude. I'm glad, because in your previous post, when you said:

 

Dean, sorry that you think this is a silly question from me. It is just a lot easier to get a short straight answer from you than going through your longer review and the Cool Fat Burner website with a lot of information most of which I don't care about for now. Thank you for answering my question.

 

It sounded to me like you wanted to be lazy and have me tell you the answers rather than search out the information for yourself. I guess I must have misinterpreted your words.

 

Also I am here to add that on Page No. 15, in my post #299, I saw in my quote of you on  “full review of the Cool Fat Burner vest.” I clicked on that link and it turned out to be  “404 not found.”

 

Sorry - that link back in post #299 seemed to be missing the obligatory ":" after the "https" in the URL for some bizarre reason. I've corrected it there, but to save you and others the trouble, here is the correct and working link to my full review of the Cool Fat Burner.

 

I have no idea why simply typing "cool fat burner" into the search box at the top of the page didn't work for you. It works fine for me although it brings up quite a few pages where the three words are mentioned. The review is about 3/4 of the way down the page. You'll do better to put the phrase "Cool Fat Burner" in quotes when conducting a search, and even better, search on "Cool Fat Burner Review".

 

One other suggestion Grace - could you try using the quote button to quote parts of my (or other people's) posts? I answered your question about how to use it yesterday in this post. It would make your posts much easier to read.

 

Thanks,

 

--Dean

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Here's a clinical study investigating "Energy Expenditure Responses to Different Temperatures" that I thought might interest you, Dean:

 

https://clinicaltrials.gov/ct2/show/NCT01568671?term=12-dk-0097&rank=1

 

"Background:

 

- The way that the body burns calories is known as energy expenditure. Some studies show that when we are cold, we burn more calories to keep our bodies warm. Brown fat is a special kind of fat that can use energy to keep the body warm. Small animals and infants have been known to have brown fat for many years. Recently, it has been suggested that adult humans also have brown fat. If brown fat becomes active (burns calories) in adult humans when exposed to cold, then these people would tend to burn off more calories and might not gain weight easily. Learning more about the relationship between energy expenditure, brown fat, environmental temperature, and body temperature may help explain why some people become obese and other people do not.

 

"Objectives:

 

* To better understand how the body burns calories when exposed to different temperatures.

* To study brown fat and how it burns calories in cold temperatures."

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BAT and Thermogenesis in Athletic vs. Sedentary Women

 

Here's a clinical study investigating "Energy Expenditure Responses to Different Temperatures" that I thought might interest you, Dean:

https://clinicaltrials.gov/ct2/show/NCT01568671?term=12-dk-0097&rank=1

 

Neat clinical trial - I wish I could participate! There really is a lot of interest in brown fat and thermogenesis these days in the medical community - particularly as a way to fight obesity.

 

Which reminds me, here is a new study [1] I came across a couple days ago by researchers at Harvard that is similar in many respects to the clinical trial you pointed to. It looked at 24 women, 16 of whom were pretty serious athletes (~11 hours of exercise per week) and 8 of whom were sedentary.  The two groups were identical in age (~21) and close in BMI (~22). Not surprisingly, the athletes had a lot less fat mass and a lot more lean mass. So what about BAT and BAT activity? To find out, researchers had the women avoid exercise for at least 12 hours, and then wear a cold vest in the lab for a two hours before scanning them for BAT and BAT activity.

 

What they found was that the lean, athletic women had less BAT than the sedentary women. In fact, BAT mass and BAT activity was inversely correlated with lean mass and positively correlated with total fat mass across all the women. Here is the distribution of BAT mass in athletes (left) vs. sedentary women (right):

 

Jx9uqt9.png

 

and here is a typical PET image showing the BAT deposits (dark regions) around the collarbone area in a typical sedentary women (left) and the lack of corresponding BAT deposits in a typical athletic woman (right):

 

6T7nSNF.png

 

 

It goes without saying that it's unlikely that any of the women in the study were intentionally exposing themselves to cold to increase BAT or thermogenic capacity.  It would be interesting to see if athletes whose sport is swimming have more BAT. Swim training (up to 2h per day) definitely builds BAT in both old and young rodents [2-5] and I expect it would do the same in humans.

 

Interestingly, the athletic women had a somewhat higher resting energy expenditure than the sedentary ladies, suggesting that even at rest their extra muscle mass was burning calories and generating heat in lieu of BAT. The mechanism? It could be uncoupling proteins in muscle mitochondria, but I think it more likely to be a result of either sarcolipin-induced futile cycling of calcium ions or futile creatine cycling. Both occur in skeletal muscles and both expend ATP (and calories) to generate heat. In fact, the former will be the topic of my next post, which will basically show that BAT and sarcolipin-induced futile cycling are complementary, non-overlapping ways that rodents generate heat.

 

What this and other studies of thermogenesis in rodents and humans say to me is that there are several alternative methods to burn calories "cleanly" to generate heat, either in BAT or in skeletal muscles. But obviously to do either you need enough "meat on your bones" in the form of adipose tissue or muscle mass to serve as the substrate for thermogenesis. The last sentence of the abstract of [1] is quite relevant in this regard:

 
Brown fat may undergo adaptive reductions with increasing energy deficit.

 

Or looked at the other way around, it may be that a really low BMI (and correspondingly low calorie intake) is not that beneficial (also see here) relative to a BMI in the "sweet spot" around 22-24 like these women had (and like the long-lived vegan Adventists with a BMI of ~24), since the extra "meat on your bones" at a 22-24 BMI enables you to burn calories cleanly to generate heat in either BAT or muscle tissue without negative consequences for health or longevity. In contrast, most really skinny women have virtually no BAT and very little muscle mass, unless they are "constitutionally lean" and therefore have a genetic tendency to express BAT, burn lots of calories, and be able to eat as much as they want without gaining weight.

 

This ability to eat lots of calories without gaining weight and without negative metabolic consequences by upregulating thermogenesis will be the topic of my next post.

 

--Dean

 

----------------

[1] 1. PLoS One. 2016 May 31;11(5):e0156353. doi: 10.1371/journal.pone.0156353.

 
Effect of Chronic Athletic Activity on Brown Fat in Young Women.
 
Singhal V(1,)(2), Maffazioli GD(2), Ackerman KE(2,)(3), Lee H(4), Elia EF(5),
Woolley R(2), Kolodny G(5), Cypess AM(6), Misra M(1,)(2).
 
 
BACKGROUND: The effect of chronic exercise activity on brown adipose tissue (BAT)
is not clear, with some studies showing positive and others showing negative
associations. Chronic exercise is associated with increased resting energy
expenditure (REE) secondary to increased lean mass and a probable increase in
BAT. Many athletes are in a state of relative energy deficit suggested by lower
fat mass and hypothalamic amenorrhea. States of severe energy deficit such as
anorexia nervosa are associated with reduced BAT. There are no data regarding the
impact of chronic exercise activity on BAT volume or activity in young women and 
it is unclear whether relative energy deficiency modifies the effects of exercise
on BAT.
PURPOSE: We assessed cold induced BAT volume and activity in young female
athletes compared with non-athletes, and further evaluated associations of BAT
with measures of REE, body composition and menstrual status.
METHODS: The protocol was approved by our Institutional Review Board. Written
informed consent was obtained from all participants prior to study initiation.
This was a cross-sectional study of 24 women (16 athletes and8 non-athletes)
between 18-25 years of age. Athletes were either oligo-amenorrheic (n = 8) or
eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity,
VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body
composition.
RESULTS: Athletes and non-athletes did not differ for age or BMI. Compared with
non-athletes, athletes had lower percent body fat (p = 0.002), higher percent
lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and
activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07,
respectively). We found negative associations of BAT activity with duration of
amenorrhea (r = -0.46, p = 0.02).BAT volume correlated inversely with lean mass
(r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid
hormones.
CONCLUSIONS: Our study shows a trend for lower BAT in young female athletes
compared with non-athletes, and shows associations of brown fat with menstrual
status and body composition. Brown fat may undergo adaptive reductions with
increasing energy deficit.
 
PMID: 27243823  [PubMed - as supplied by publisher]
 
 
------------
2. Res Commun Mol Pathol Pharmacol. 1997 Jan;95(1):92-104.
 
Effects of swimming training on brown-adipose-tissue activity in obese ob/ob
mice: GDP binding and UCP m-RNA expression.
 
Ueno N(1), Oh-ishi S, Kizaki T, Nishida M, Ohno H.
 
Author information: 
(1)Department of Public Health, Juntendo University, School of Medicine, Tokyo,
Japan.
 
Brown adipose tissue (BAT) of obese animals is generally in a relatively
atrophied and thermogenically quiescent state. The aim of the current study was
to investigate the effect of swimming training on BAT activity in lean and obese 
(ob/ob) mice. The trained mice underwent a 6-week endurance swimming training (1 
h/day, 5 days/week) in water at 35-36 degrees C. The swimming training
significantly increased BAT mass and its protein content in both the lean and
obese mice, suggesting hypertrophy. After swimming training, the amounts of
protein and guanosine 5'-diphosphate binding in the mitochondria recovered from
BAT of both mice increased significantly as compared with the respective
sedentary groups, whereas the uncoupling protein (UCP) content increased
significantly only in lean mice. After swimming training, the level of UCP mRNA
expression did not change substantially in lean mice but appeared to increase in 
obese mice. The results obtained here suggest that swimming training leads to an 
increase in the nonshivering thermogenesis of obese mice in addition to lean
mice.
 
PMID: 9055352  [PubMed - indexed for MEDLINE]
 
---------------------
3. Mech Ageing Dev. 1996 Aug 15;89(2):67-78.
 
Swimming training improves brown-adipose-tissue activity in young and old mice.
 
Oh-ishi S(1), Kizaki T, Toshinai K, Haga S, Fukuda K, Nagata N, Ohno H.
 
Author information: 
(1)Department of Hygiene, National Defense Medical College, Tokorozawa, Japan.
 
The impairment of brown adipose tissue (BAT) thermogenic activity with aging has 
been well documented. The current study investigated the effect of swimming
training on BAT activity in 2-month-old (young) and 26-month-old (old) male mice.
The trained mice underwent a 6-week swimming program (1 h/day, 5 days/week) in
water at 35-36 degrees C. Compared with young sedentary mice, the BAT-to-body
mass ratio was markedly smaller in old sedentary mice, accompanied by the
decreased amount of protein, whereas there was no significant difference in
uncoupling protein (UCP) content, UCP mRNA expression, or guanosine
5'-diphosphate (GDP) binding (an index of UCP activity) between young and old
mice. Meanwhile, the swimming training definitely increased BAT mass and its
protein content in both the young and old mice, suggesting hypertrophy and
hyperplasia. In addition, after the swimming training, the amounts of protein,
UCP antigen, and GDP binding in the mitochondria recovered from BAT of both mice 
increased significantly as compared with the respective sedentary groups, while
the expression of UCP mRNA did not vary substantially. These findings suggest
that, irrespective of age, swimming training enhances the thermogenic activity
and capacity in BAT of mice.
 
PMID: 8844640  [PubMed - indexed for MEDLINE]
 
--------------------
4. Jpn J Physiol. 1982;32(4):647-53.
 
Enhanced calorigenesis in brown adipose tissue in physically trained rats.
 
Hirata K.
 
The calorigenesis occurring in brown adipose tissues (BAT) in response to infused
norepinephrine [NE: 4 micrograms/(kg . min)] was estimated from the arteriovenous
O2 difference across the interscapular brown adipose tissue and the rate of blood
flow to BAT in physically trained (TR) and control (CT) rats. TR rats were
trained by 2-hr daily swimming in agitated water at 36 degrees C for 18 weeks.
The colonic temperature was maintained at approximately 37.5 degrees C throughout
the training period. With NE infusion, the O2 content of arterial blood was
unchanged, but that from Sulzer's vein significantly decreased from 12.5 to 2.5
vol% in TR and from 15.7 to 4.3 vol% in CT rats. The increase in O2 consumption
in BAT with NE was estimated as 1.60 ml/min in TR and 0.83 ml/min in CT rats. The
increase in the whole body O2 consumption with NE was 3.19 ml/min in TR and 2.29 
ml/min in CT rats. The contribution of calorigenesis in BAT to the whole body
calorigenic response to NE was estimated at 50% in TR and 36% in CT rats. These
results directly demonstrated that physical training per se causes an enhancement
of the calorigenic response of brown adipose tissues to norepinephrine in rats.
 
PMID: 7176210  [PubMed - indexed for MEDLINE]
 
-------
5. Horm Metab Res. 2012 Oct;44(11):797-803. doi: 10.1055/s-0032-1314875. Epub 2012
Jul 16.
 
Blunted response of pituitary type 1 and brown adipose tissue type 2 deiodinases 
to swimming training in ovariectomized rats.
 
Ignacio DL(1), Fortunato RS, Neto RA, da Silva Silvestre DH, Nigro M, Frankenfeld
TG, Werneck-de-Castro JP, Carvalho DP.
 
Author information: 
(1)Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica
Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro,
Brazil.
 
Ovariectomy leads to significant increase in body weight, but the possible
peripheral mechanisms involved in weight gain are still unknown. Since exercise
and thyroid hormones modulate energy balance, we aimed to study the effect of
swimming training on body weight gain and brown adipose tissue (BAT) type 2
iodothyronine deiodinase responses in ovariectomized (Ox) or sham-operated (Sh)
rats. Rats were submitted to a period of 8-week training, 5 days per week with
progressive higher duration of exercise protocol. Swimming training program did
not totally prevent the higher body mass gain that follows ovariectomy in rats
(16.5% decrease in body mass gain in Ox trained rats compared to 22% decrease in 
sham operated trained animals, in relation to the respective sedentary groups),
but training of Ox animals impaired the accumulation of subcutaneous fat pads.
Interestingly, swimming training upregulates pituitary type 1 (p<0.001 vs. all
groups) and BAT type 2 iodothyronine deiodinases (p<0.05 vs. ShS and OxS) in sham
operated but not in Ox rats, indicating an impaired pituitary and peripheral
response to exercise in Ox rats. However, BAT mitochondrial O2 consumption
significantly increased by swimming training in both sham and Ox groups,
indicating that Ox BAT mitochondria responds normally to exercise stimulus, but
does not result in a significant reduction of body weight. In conclusion,
increased body mass gain produced by Ox is not completely impaired by 8 weeks of 
high intensity physical training, showing that these animals sustain higher rate 
of body mass gain independent of being submitted to higher energy expenditure.
 
© Georg Thieme Verlag KG Stuttgart · New York.
 
PMID: 22815055  [PubMed - indexed for MEDLINE]
 

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Sarcolipin in Muscles and UCP-1 in Fat - Independent Contributors to Diet-Induced Thermogenesis

 

As I promised in my last post, here is an update on the sarcolipin story.

 

Recall from this post, a calcium gradient across the sarcoplasmic reticulum (SR) in muscle cells is critically for their ability to contract. Sarcolipin (SLN) reduces the gradient by allowing calcium to leak through the membrane of the SR exactly analogous to the way UCP-1 lets protons leak through the mitochondrial inner membrane (MIM) to reduce the electrical gradient across the MIM. In both instances, ATP has to be expended to maintain/restore the gradient, burning calories and generating heat in the process. UCP-1 is a protein expressed in the mitochondria of brown and beige fat cells, while SLN is a protein expressed in the cytoplasm of muscle cells. 

 

This new study [1], used mice that were missing either the gene that produces  SLN (SLN-/-) , UCP1 (UCP1-/-) or both. They kept the mice at thermoneutral temperature (29 °C) and fed them a high fat diet (45% of calories from fat) for 12 weeks to investigate how much weight gain happened in mice with and without SLN, UCP1 or both - figuring even without cold exposure the body will naturally engage in diet-induced thermogenesis (DIT) via the two pathways (if available) to avoid gaining so much weight.

 

They especially wanted to see if mice missing one thermogenic pathway would upregulate the other pathway in order to compensate, and avoid getting obese on a high fat diet. In a previous study [2] by this same group, they investigate cold-induced thermogenesis (as opposed to diet-induced thermogenesis in [1]), and found that indeed, mice missing UPC1 upregulated SLN futile cycling to stay warm, and visa versa. In [2] the double knockout mice nearly died from the severe cold conditions.

 

The same group found in [3] that in similar conditions to [1], high-fat feeding in thermoneutral conditions resulted in SLN-knockout mice gaining more weight than wild-type mice, and mice that overexpressed SLN in skeletal muscles:

 

consumed more calories but gained less weight and maintained a normal metabolic profile in comparison with WT and Sln(-/-) mice.

 

Here is a fascinating series of graphs from [3] comparing normal (i.e. wild-type or WT) mice (red) with sarcolipin-overexpressing mice (blue), showing just how potent sarcolipin is at preventing weight and fat gain, reducing cholesterol and triglycerides, improving glucose tolerance in the face of an ad lib, high fat diet. As you can see, the sarcolipin overexpressing mice ate more calories but gained a lot less weight and fat mass, had lower total cholesterol triglycerides and better postprandial glucose control than the normal mice:

 

i8GqoWq.png

 

In short, sarcolipin allows mammals to burn more calories by generating more heat through futile Ca++ ion cycling in muscles either when challenged with cold or extra calories, improving many metabolic parameters in the process. I would really like to see a lifespan study in these sarcolipin-overexpressing mice...

 

But back to [1]. What they found was that unlike with cold-induced thermogenesis, the two thermogenic pathways (UCP1 and SLN) didn't substitute for one another in the single knockout mice:

 

Loss of either SLN or UCP1 alone was sufficient to cause diet-induced
obesity. No compensatory upregulation of UCP1 in SLN(-/-) mice or vice versa was 
found. Paradoxically, loss of both mechanisms failed to exacerbate the obesity phenotype. 

 

So mice missing either UCP1 or SLN got fat on a high fat diet, but mice missing both UPC1 and SLN didn't get any fatter than the single-knockout mice. The authors conclude that both thermogenic pathways are required to maximize diet-induced thermogenesis and to prevent excessive weight gain when fed a high fat diet, but that some other, less efficient thermogenic pathway is likely kicking in to prevent the double-knockout mice from gaining even more weight than either of the single-knockout mice strains. One candidate for the third thermogenic pathway is futile creatine cycling in skeletal muscles.

 

What I found most interesting was that the bodies of these mice were burning off the extra calories they were consuming from the high fat diet even at thermoneutral temperatures - showing that UPC1 and sarcolipin aren't just employed to defend body temperature in the face of cold exposure. Instead, they are critically important for diet-induced thermogenesis as well - burning extra calories to avoid weight gain.

 

Of course, the ability to burn off extra calories via cold- or diet-induced thermogenesis depends on having enough brown/beige fat and/or skeletal muscle mass to support them, and to really kick thermogenic capacity/activity up a notch, cold-exposure is obviously very helpful.

 

--Dean (who has finally resorted to wearing both his cold vests simultaneously as summer has arrived in Pittsburgh)

 

-----------

[1] Obesity (Silver Spring). 2016 May 30. doi: 10.1002/oby.21542. [Epub ahead of

print]
 
Sarcolipin and uncoupling protein 1 play distinct roles in diet-induced
thermogenesis and do not compensate for one another.
 
Rowland LA(1), Maurya SK(2), Bal NC(1,)(2), Kozak L(3), Periasamy M(1,)(2).
 
Author information: 
(1)Department of Physiology and Cell Biology, The Ohio State University, College 
of Medicine, Columbus, Ohio, USA. (2)Sanford Burnham Prebys Medical Discovery
Institute, Lake Nona, Orlando, Florida, USA. (3)Institute of Animal Reproduction 
and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
 
OBJECTIVE: It is well known that uncoupling protein 1 (UCP1) in brown adipose
tissue plays an important role in diet-induced thermogenesis. In this study,
whether sarcolipin (SLN), a regulator of sarco/endoplasmic reticulum Ca(2+)
-ATPase pump in muscle, is also an important player of diet-induced thermogenesis
was investigated, as well as whether loss of SLN could be compensated by
increased UCP1 expression and vice versa.
METHODS: Age- and sex-matched UCP1(-/-) , SLN(-/-) , and double knockout for both
UCP1 and SLN mice maintained in C57Bl/6J background were challenged to high-fat
diet for 12 weeks and then analyzed for weight gain, alterations in serum
metabolites, and changes in thermogenic protein expression.
RESULTS: Loss of either SLN or UCP1 alone was sufficient to cause diet-induced
obesity. No compensatory upregulation of UCP1 in SLN(-/-) mice or vice versa was 
found. Paradoxically, loss of both mechanisms failed to exacerbate the obesity
phenotype.
CONCLUSIONS: Data suggest that both SLN- and UCP1-based adaptive thermogenic
mechanisms were essential for achieving maximal diet-induced thermogenesis. When 
both mechanisms were absent, less efficient thermogenic mechanisms were activated
to counter energy imbalance.
 
© 2016 The Obesity Society.
 
PMID: 27238087
 
------------
[2] J Biol Chem. 2015 May 8;290(19):12282-9. doi: 10.1074/jbc.M115.637603. Epub 2015 
Mar 30.
 
Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal
Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold
Stress.
 
Rowland LA(1), Bal NC(1), Kozak LP(2), Periasamy M(3).
 
Author information: 
(1)From the Department of Physiology and Cell Biology, College of Medicine, The
Ohio State University, Columbus, Ohio 43210 and. (2)the Institute of Animal
Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn,
Poland. (3)From the Department of Physiology and Cell Biology, College of
Medicine, The Ohio State University, Columbus, Ohio 43210 and
periasamy.1@osu.edu.
 
The importance of brown adipose tissue as a site of nonshivering thermogenesis
has been well documented. Emerging studies suggest that skeletal muscle is also
an important site of thermogenesis especially when brown adipose tissue function 
is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the
sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) pump, could contribute to heat
production in skeletal muscle. In this study, we sought to understand how loss of
UCP1 or SLN is compensated during cold exposure and whether they are both
necessary for thermogenesis. Toward this goal, we generated a UCP1;SLN double
knock-out (DKO) mouse model and challenged the single and DKO mice to acute and
long-term cold exposures. Results from this study show that there is
up-regulation of SLN expression in UCP1-KO mice, and loss of SLN is compensated
by increased expression of UCP1 and browning of white adipose tissue. We found
that the DKO mice were viable when reared at thermoneutrality. When challenged to
acute cold, the DKO were extremely cold-sensitive and became hypothermic.
Paradoxically, the DKO mice were able to survive gradual cold challenge, but
these mice lost significant weight and depleted their fat stores, despite having 
higher caloric intake. These studies suggest that UCP1 and SLN are required to
maintain optimal thermogenesis and that loss of both systems compromises survival
of mice under cold stress.
 
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
 
PMCID: PMC4424359
PMID: 25825499
 
------------
[3] J Biol Chem. 2015 Apr 24;290(17):10840-9. doi: 10.1074/jbc.M115.636878. Epub 2015
Feb 24.
 
Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its
Overexpression Enhances Energy Expenditure and Resistance against Diet-induced
Obesity.
 
Maurya SK(1), Bal NC(2), Sopariwala DH(2), Pant M(2), Rowland LA(2), Shaikh
SA(2), Periasamy M(3).
 
Author information: 
(1)the Sanford Burnham Medical Research Institute at Lake Nona, Orlando, Florida 
32827. (2)From the Department of Physiology and Cell Biology, The Ohio State
University, Columbus, Ohio 43210 and. (3)the Sanford Burnham Medical Research
Institute at Lake Nona, Orlando, Florida 32827 periasamy.1@osu.edu
mperiasamy@sanfordburnham.org.
 
Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca(2+) ATPase
(SERCA) in muscle. SLN binding to SERCA uncouples Ca(2+) transport from ATP
hydrolysis. By this mechanism, SLN promotes the futile cycling of SERCA,
contributing to muscle heat production. We recently showed that SLN plays an
important role in cold- and diet-induced thermogenesis. However, the detailed
mechanism of how SLN regulates muscle metabolism remains unclear. In this study, 
we used both SLN knockout (Sln(-/-)) and skeletal muscle-specific SLN
overexpression (Sln(OE)) mice to explore energy metabolism by pair feeding (fixed
calories) and high-fat diet feeding (ad libitum). Our results show that, upon
pair feeding, Sln(OE) mice lost weight compared with the WT, but Sln(-/-) mice
gained weight. Interestingly, when fed with a high-fat diet, Sln(OE) mice
consumed more calories but gained less weight and maintained a normal metabolic
profile in comparison with WT and Sln(-/-) mice. We found that oxygen consumption
and fatty acid oxidation were increased markedly in Sln(OE) mice. There was also 
an increase in both mitochondrial number and size in Sln(OE) muscle, together
with increased expression of peroxisome proliferator-activated receptor δ (PPARδ)
and PPAR γ coactivator 1 α (PGC1α), key transcriptional activators of
mitochondrial biogenesis and enzymes involved in oxidative metabolism. These
results, taken together, establish an important role for SLN in muscle metabolism
and energy expenditure. On the basis of these data we propose that SLN is a novel
target for enhancing whole-body energy expenditure.
 
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
 
PMCID: PMC4409248
PMID: 25713078

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Extended Fasting Results in the Whitening of Beige Fat

 

Two posts back, I discussed PMID 27243823 which found muscular, athletic women who have very little fat (not surprisingly) also have very little Brown Adipose Tissue (BAT). The authors of that study concluded:

 

Brown fat may undergo adaptive reductions with increasing energy deficit.

 

This new study [1] looks into that mechanism, in the context of fasting. It found that in mice, 24 hours of fasting resulted in the 'whitening' of beige subcutaneous fat, and a shift in the subcutaneous fat to a gene expression profile that makes it look more like visceral fat. The authors conclude:

 

These results indicate that in addition to the capacity of 'browning' to defend against hypothermia during cold exposure, the
subcutaneous adipose depot is also capable of 'whitening' to preserve energy during fasting, presumably to maintain energy balance.
 

This result isn't too surprising. Once again we see the body tries to defend energy balance - avoiding too much weight loss during a fast by turning brown fat to white, just like we saw the opposite effect the the post immediately preceding this one - the boosting of thermogenesis to prevent too much weight gain when extra calories are consumed. 

 

Since mice have such a high metabolic rate, 24h of fasting in a mouse is probably the equivalent of several days of fasting in people. So this whitening of brown fat as a result of fasting probably isn't an issue for people who engage in time-restricted feeding - i.e. who eat daily within a narrow window of time. But for people (like Sthira) who engage in extended water fasts, it seems likely they are sacrificing some of their brown/beige fat to conserve calories, if they had any to start with.

 

Of course there very well may be other benefits of extended fasts (e.g. increased autophagy) that are health-promoting. I don't want to make it seem like I'm bashing on extended fasts, just pointing out one potential downside if you are interested in increasing BAT & thermogenesis.

 

--Dean

 

-------------

[1] Nat Commun. 2016 May 31;7:11533. doi: 10.1038/ncomms11533.

 
Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p
and suppression of PRDM16.
 
Ding H(1), Zheng S(1), Garcia-Ruiz D(1), Hou D(1), Wei Z(1), Liao Z(1), Li L(1), 
Zhang Y(1), Han X(2), Zen K(1), Zhang CY(1), Li J(1), Jiang X(1).
 
Author information: 
(1)State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation
Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for
MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences
(NAILS), School of life sciences, Nanjing University, 163 Xianlin Road, Nanjing, 
Jiangsu 210046, China. (2)Key Laboratory of Human Functional Genomics of Jiangsu 
Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
 
Visceral adiposity is strongly associated with metabolic disease risk, whereas
subcutaneous adiposity is comparatively benign. However, their relative
physiological importance in energy homeostasis remains unclear. Here, we show
that after 24-h fasting, the subcutaneous adipose tissue of mice acquires key
properties of visceral fat. During this fast-induced 'visceralization',
upregulation of miR-149-3p directly targets PR domain containing 16 (PRDM16), a
key coregulatory protein required for the 'browning' of white fat. In cultured
inguinal preadipocytes, overexpression of miR-149-3p promotes a visceral-like
switch during cell differentiation. Mice deficient in miR-149-3p display an
increase in whole-body energy expenditure, with enhanced thermogenesis of
inguinal fat. However, a visceral-like adipose phenotype is observed in inguinal 
depots overexpressing miR-149-3p. These results indicate that in addition to the 
capacity of 'browning' to defend against hypothermia during cold exposure, the
subcutaneous adipose depot is also capable of 'whitening' to preserve energy
during fasting, presumably to maintain energy balance, via miR-149-3p-mediated
regulation of PRDM16.
 
PMID: 27240637 

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Might be of interest in regards to amino acid restriction, specifically leucine this time. Note however that soy is quite high in leucine, so it might need to be somewhat reduced in any CE-focused diet? FWIW, I have found through experimentation that if I eat a couple of vegan high protein bars (15 g soy protein isolate each), it reliably will bump my next morning's fasting glucose a bit.

 

 

Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling.
PMID:26643647

Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of fibroblast growth factor 21 into the blood stream, and enhanced insulin-dependent activation of Akt in liver. However, LR had no effect on hepatic lipid levels and failed to lower lipogenic gene expression in the liver. LR did affect remodeling of white and brown adipose tissues, increasing expression of both thermogenic and lipogenic genes.

 

http://www.ncbi.nlm.nih.gov/pubmed/26643647

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BrianA,

 

Thanks for the leucine restriction (LR) reference. Here is the full reference [1]. Unfortunately the full text of the paper doesn't seem to be available through Sci-hub or anywhere else I can find. That's too bad, because it looks really interesting. But I was able to get ahold of the figures from the paper from (evil - according to Michael) ResearchGate, via this link. Here are some of the cool results of LR.

 

The LR mice ate more and were more active that the mice fed standard chow (graph not shown). They exhibited improved insulin sensitivity and postprandial glucose control (graph not shown). Their white adipose tissue (iWAT) turned much more 'beige', expressing many of the thermogenic genes. Especially apparent was an upregulation in  UCP1 gene expression and UCP1 protein synthesis, which were increased 4x and 6x in iWAT relative to controls, respectively (see left graphs below). UPC-1 gene expression and protein synthesis was also upregulated in BAT (see right graphs below).

 

 

RBIlr1L.png   x9C32rC.png

As you mentioned, FGF21 was upregulated dramatically by LR in both serum (3x) and liver (2x):

 

0xzUHYA.png

 

That increase in FGF21 is very impressive and potentially important, since FGF21 appears to extend lifespan in mice, improve immunocompetence and is upregulated by cold in humans

 

In short, it looks like leucine restriction can be added to the list of dietary manipulations of individual amino acids that can increase BAT and thermogenesis - a list which currently includes methionine restriction and increased arginine intake. I've added LR to the master list of thermogenic agents below. It should come as no surprise by now that leucine is high in animal products - walrus meat is highest (so best to cut back ☺), followed by beef, fish, eggs, cheese and soy.

 

--Dean

 

----------------

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Healthy Fats - Olive Oil / MUFA-rich diet, DHA / EPA / fish-oil
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Drugs / Supplements - metformin, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

-------------

[1] Biofactors. 2015 Nov-Dec;41(6):391-402. doi: 10.1002/biof.1240. Epub 2015 Dec 8.

 
Metabolic responses to dietary leucine restriction involve remodeling of adipose 
tissue and enhanced hepatic insulin signaling.
 
Wanders D(1), Stone KP(2), Dille K(2), Simon J(2), Pierse A(2), Gettys TW(2).
 
Author information: 
(1)Department of Nutrition, Georgia State University, Atlanta, GA, USA.
(2)Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical 
Research Center, Baton Rouge, LA, USA.
 
Dietary leucine was incrementally restricted to test whether limiting this
essential amino acid (EAA) would fully reproduce the beneficial responses
produced by dietary methionine restriction. Restricting leucine by 85% increased 
energy intake and expenditure within 5 to 7 days of its introduction and reduced 
overall accumulation of adipose tissue. Leucine restriction (LR) also improved
glucose tolerance, increased hepatic release of fibroblast growth factor 21 into 
the blood stream, and enhanced insulin-dependent activation of Akt in liver.
However, LR had no effect on hepatic lipid levels and failed to lower lipogenic
gene expression in the liver. LR did affect remodeling of white and brown adipose
tissues, increasing expression of both thermogenic and lipogenic genes. These
findings illustrate that dietary LR reproduces many but not all of the
physiological responses of methionine restriction. The primary differences occur 
in the liver, where methionine and LR cause opposite effects on tissue lipid
levels and expression of lipogenic genes. Altogether, these findings suggest that
the sensing systems which detect and respond to dietary restriction of EAAs act
through mechanisms that both leucine and methionine are able to engage, and in
the case of hepatic lipid metabolism, may be unique to specific EAAs such as
methionine.
 
© 2015 International Union of Biochemistry and Molecular Biology.
 
PMCID: PMC4715699 [Available on 2016-12-08]
PMID: 26643647

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Unfortunately the full text of the paper doesn't seem to be available ...I was able to get ahold of the figures from the paper from (evil - according to Michael) ResearchGate

 

I don't know what I may have said that you've misinterpreteed/misremembered in this way, but I'm all for RG, and use it regularly — amongst other things, to avoid use of sci-hob, which I do regard as a highly problematic (tho' well-intentioned at some level) workaround in a problematic (but not meriting abolition) situation.

 

NB: reducing animal protein will not lead to leucine restriction, but leucine moderation. Here, and in other leucine restriction studies, the restricted animals got 15% or the rodent RDA for leucine, or the human equivalent of 430 mg/d for a 150 lb human: if you got 100% of the RDA for protein from 700 g firm tofu, that's already eleven times that amount. If you ate nothing but 1800 Cal of potatoes a day, that's stil >2300 mg/d, or more than fivefold what leucine restricted mice are given.

 

The life extension community is suffering from widespread confusion on this point that comes from — and is certainly perpetuated by — overly-loose use of language (and what I suspect is willful ignorance at best on the part of vegan propagandists (I mean the ignominious Greger and possibly Mark McCarty, not you, Dean — honest). I have begged people over and over and over again to please, please, please, stop muddying the water by referring to limiting one's intake of some nutrient to RDAish levels as "restriction" of that nutrient. Biogerontological studies of protein-, Met + Cys-, Leu-, Trp-, or Calorie restriction involve restricting consumption of these nutrients to levels far below the animals' "RDA" intake; with the exception of the Calories in CR, I don't practice or endorse that, and neither does anyone I know of (including a few folks who do, unfortunately, refer to what they do as "restriction" of that nutrient).

 

However, there may be some value for moderation of leucine and other BCAAs by humans on CR: see my previous comments on BCAAs, particularly leucine (see this and this for more recent studies on health effects of high intake of leucine; we were discussing this study and this one).

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Michael,

 
[Admin note: stuff about ResearchGate deleted and moved to this thread about accessing papers]
 
Thanks for the links to the discussions on Longecity.org. It appears your are (or were) pretty active over there. I'm very curious about your overall impression of LongeCity.org vs our forums as discussed in this thread. I hope you can respond.
 
But back to the topic of leucine - One of those Longecity threads contains a link to another study [1], which also found that leucine restriction upregulates BAT. Good to see a confirmation. Overall, it looks like you think both methionine and leucine moderation (as opposed to restriction or elimination, which is ill-advised and not possible anyway) may be a pretty reasonable idea:
Methionine restriction is impossible,* unless you're going to stop eating actual food. However, Met moderation is entirely doable, and happily largely via the same strategy as leucine moderation. "More effective" doesn't play into it: the pathways involved are completely unrelated, and the benefits of moderation (and, in mice on a synthetic diet, of actual restriction of Met + Cys) distinct.
 
But contra to what you suggestion, it appears that beneficial methionine moderation and leucine moderation do share at least one common metabolic pathway - they both upregulate UPC1 expression and thermogenic activity in BAT and WAT.
 
Coincidence? You know my perspective by now...
 
--Dean
 
-----------------------
[1] Diabetes. 2010 Jan;59(1):17-25. doi: 10.2337/db09-0929. Epub 2009 Oct 15.
 
Leucine deprivation decreases fat mass by stimulation of lipolysis in white
adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose
tissue.
 
Cheng Y(1), Meng Q, Wang C, Li H, Huang Z, Chen S, Xiao F, Guo F.
 
 
OBJECTIVE: White adipose tissue (WAT) and brown adipose tissue (BAT) play
distinct roles in adaptation to changes in nutrient availability, with WAT
serving as an energy store and BAT regulating thermogenesis. We previously showed
that mice maintained on a leucine-deficient diet unexpectedly experienced a
dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for
this loss, however, are unclear. The goal of current study is to investigate
possible mechanisms.
RESEARCH DESIGN AND METHODS: Male C57BL/6J mice were fed either control,
leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters 
and expression of genes and proteins related to lipid metabolism were analyzed in
WAT and BAT.
RESULTS: We found that leucine deprivation for 7 days increases oxygen
consumption, suggesting increased energy expenditure. We also observed increases 
in lipolysis and expression of beta-oxidation genes and decreases in expression
of lipogenic genes and activity of fatty acid synthase in WAT, consistent with
increased use and decreased synthesis of fatty acids, respectively. Furthermore, 
we observed that leucine deprivation increases expression of uncoupling protein
(UCP)-1 in BAT, suggesting increased thermogenesis.
CONCLUSIONS: We show for the first time that elimination of dietary leucine
produces significant metabolic changes in WAT and BAT. The effect of leucine
deprivation on UCP1 expression is a novel and unexpected observation and suggests
that the observed increase in energy expenditure may reflect an increase in
thermogenesis in BAT. Further investigation will be required to determine the
relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine
deprivation-stimulated fat loss.
 
PMCID: PMC2797918
PMID: 19833890

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All:
 
(Dean: we should maybe move this first bit about RG and sci-hüb to the thread on the latter — whad'yer think?).
 

Michael,
 

I don't know what I may have said that you've misinterpreted/misremembered in this way, but I'm all for RG, and use it regularly — amongst other things, to avoid use of sci-hob, which I do regard as a highly problematic (tho' well-intentioned at some level) workaround in a problematic (but not meriting abolition) situation.


Sorry Michael. My bad. I did misremember. I attributed an off-forum email exchange I had with a former colleague and co-author of mine ...

ResearchGate is the worst of the worst because not only do they spam me with robot-generated requests like Academia.edu, but they actually forge my colleagues' names in the From line so it looks like the mail is coming from them.

 


I have never had this happen, and don't believe that they do it. What I suspect s/he's misinterpreted/misremembered in this way ;) is that if you come across a paper for which there is a record in RG but no available full-text, you have the option of clicking to email the authors to request that they do so. And, if they don't already have an email for the authors, they'll ask  if you have it and use it to send the request. I don't do the latter, regarding it as a violation of the authors' privacy, but I certainly routinely use their system to send either personalized or generic requests for reprints and uploads to people who are already members or whose contact info has already been submitted by some other user.
 
This is of course intended to bring in more members and expand their content, which both improves the network and makes them more viable as a platform. But it's not like the true bottery of scraping all the contacts in your email account and sending out bot requests to join that look like they've come personally from the user, as happens routinely with eg. LinkedIn (which is one of the reasons I've never joined the latter).
 

 

Another issue I have with ResearchGate is that they pollute the search engines with links to THEIR copies of papers which can only be read if you join up and sign in.

 


I don't believe this is true: I've downloaded papers I've come across via Google while not signed in with no problem, and sent others links to same without being told that the recipient can't use the link (tho' of course my recipient may not have tried, out of blind trust ;) or lack of time or concern, or may not have troubled me about any problem they encountered). In any case, I would actually regard this as a good policy, making it closer to a genuine network for scholarly exchange instead of just another way to get around journal paywalls for anyone who uses Google and hits one of their links. (I am aware that this is problematically elitist. But there is a long tradition — accpeted by all journal publishers — of scholars sending each other reprints, and  I can't condone outright just breaking down the walls and eroding their ability to keep the lights on).
 

 

I think Sci-Hub.io's approach is like stealing groceries to feed the hungry. Sure, hungry people need food right now. But it's still theft,
and if done on a large scale, the grocery store goes out of business.

 


Right. And, like the sale of groceries, there is a valuable service being provided by the journals, which the critics tend to grossly downplay.
 

As you can see, his tone and his beliefs resemble yours (at least in my mind and as I understand them - especially about Sci-hub) - hence my conflation of you two. Sorry about that.


Totally understandable. I've done worse :"-).
 

contra to what you suggestion, it appears that beneficial methionine moderation and leucine moderation do share at least one common metabolic pathway - they both upregulate UPC1 expression and thermogenic activity in BAT and WAT.


I'm sure they share many metabolic pathways, as indeed we were privileged to hear in detail at Richard Miller's tour de force presentation at the Ninth Calorie Restriction Society Conference (and I didn't mean to say they don't, tho' I can see that my comment could very easily have been taken that way). But at root, they start at different places, even if they both affect thermogenesis downstream: leucine/BCAA restriction is a supply-side approach to inhibiting mTOR (like rapamycin, the first and most well-documented case of a drug that retards aging in mammals), whereas
 

There is, for example, little overlap in patterns of changed hepatic gene expression, and Meth-R mice do not show the increase in p38 and pERK kinase activation and decline in mTOR function seen in liver of CR mice (Sun et al., 2009).(1)

 
By contrast:
 

New data now show elevated ATF4 levels, and elevation of ATF4-dependent proteins and mRNAs, in liver of mice treated with acarbose or rapamycin, calorically restricted mice, methionine-restricted mice, and mice subjected to litter crowding. Elevation of ATF4, at least in liver, thus seems to be a shared feature of diets, drugs, genes, and developmental alterations that extend maximum lifespan in mice.(1)

 
... and cf. (2), and unpublished data cited by Miller in the aforementioned presentation.
 
References
1: Li W, Li X, Miller RA. ATF4 activity: a common feature shared by many kinds of slow-aging mice. Aging Cell. 2014 Dec;13(6):1012-8. doi: 10.1111/acel.12264. Epub 2014 Aug 26. PubMed PMID: 25156122; PubMed Central PMCID: PMC4326926.

2: Li W, Miller RA. Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J Gerontol A Biol Sci Med Sci. 2015 Mar;70(3):263-72. doi: 10.1093/gerona/glu040. Epub 2014 Apr 1. PubMed PMID: 24691093; PubMed Central PMCID: PMC4351389.

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For new folks stumbling upon this thread...  I have started a new BAT/cold exposure discussion over at LongeCity that you may be interested in checking out, the very first post in the thread includes a brief summary of the benefits of cold exposure / BAT activation / thermogenesis with various references to the science, as gleaned from this now slightly unwieldy thread here at CRSociety.org.  I also reposted a bunch of my little experiments with CE and glucose control, as well as the "Dean's List" of BAT activators.  In short, if you want to get up to speed quickly, that might be a decent place to start, then if you want to really dig in, you can read the whole book as it appears here   B)xyz

 

Regards,

Gordo

Edited by Gordo

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Gordo,

 

As I said over on LongeCity - that is a great series of posts on CE you put together. Hopefully it will pique the interest of the smart folks over there, and we'll get a discussion going. But regardless, you've done a great service pulling together all that information, along with your own personal experiments, into a fascinating and coherent summary.  Thanks so much for doing it. 

 

It looks like CE is getting more attention. Just today I received a heads up about a new interview with Wim Hof (aka the Iceman) by one of my favorite podcasters, Rich Roll. It has the provocative subtitle "Cold is God", so it has got to be good ☺. The topics Rich covers with Wim include not just cold exposure, but many of the other extreme practices and endeavors Wim has accomplished, including (as summarized by Rich):

  • how to awaken inner dormant ability
  • how to control metabolic pathways
  • the science behind the Wim Hof Method [cold exposure and special breathing technique]
  • surviving grief — catalyst for change & exploration
  • delving deeper into consciousness
  • furthering the message with 26 world records
  • being of service and in tune with nature
  • voluntary activation of the sympathetic nervous system
  • breathing & extreme cold
  • pH levels: acidosis vs. alkalosis
  • voluntary E. coli endotoxin injection
  • Mount Kilimanjaro ascent
  • pain management & inflammation studies
  • reversing chronic conditions
  • combatting depression, grief & addiction
  • intermittent hypoxic training
  • spiritual, environmental, ethical, and health crises
  • the primal path
  • typical day with Wim Hof

I haven't listened to this interview yet (I plan to tomorrow). But having watched Wim's TEDx Talk (embedded below), I'm really looking forward to hearing more details about his approach to cold exposure, as well as other ways of challenging himself and pushing the envelope of human potential.

 

--Dean

 

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All,

 

I listened to Rich Roll's interview with Wim Hof (aka the Iceman). I just have to say, while I admire the man's passion to inspire himself and other people to 'push the envelope' of human potential, I wasn't very impressed with his ability to communicate either his method or the science behind it. I felt the same thing with his TedxAmsterdam talk. He tends to ramble, and jump around a lot. Overall he's an impressive guy because of what he's done (and can do) related to cold exposure and human endurance - e.g swimming underwater in a frozen lake between two holes in the ice cut 50m apart - that's nuts...

 

But for me his actions and abilities speak much louder than his words, which I don't find especially informative or convincing. I think Ray Cronise, or even Eric from Cool Fat Burner, provide much more convincing motivation and science-based justification for cold exposure, at least for left-brain folks like me.

 

--Dean

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More Evidence for the Importance of Sarcolin-mediated Thermogenesis in Muscle Cells

 

Recall in several previous posts (here and here) I described in detail the  recent evidence that a different form of "futile cycling" (burning energy/ATP to generate heat) involving sarcolipin and Ca++ ions in muscle cells (rather than electron transport in the mitochondria) is likely to be involved in thermogenesis, particularly in humans, since we have only modest amounts of BAT.

 

Well, this new study [1] further confirms this sarcolipin-mediated thermogenesis story. It found mice who'd had their BAT surgically removed can maintain their body temperature when subjected to prolonged cold exposure (4 °C for 9 days!).

 

For the first four days, they shivered to keep warm (poor mice...). But after 4 days they stopped shivering and relied on non-shivering thermogenesis (NST) to keep warm. What the researchers found was that the BAT-ablated mice boosted their sarcolipin levels in muscle cells to induce thermogenesis via futile calcium ion pumping across the membrane of the sarcoplasmic reticulum. Put more simply, their muscles burned calories without contracting, in order to generate heat.

 

As discussed in those two previous posts, this independent muscle-based thermogenic pathway seems likely to be important for humans, since we, like BAT-ablated mice, have relatively little brown adipose tissue to support thermogenesis.

 

--Dean

 

---------

[1] J. Biol. Chem. jbc.M116.728188. doi:10.1074/jbc.M116.728188

 

Increased reliance on muscle based thermogenesis upon acute minimization of brown adipose tissue function

 
Naresh C. Bal1*, Santosh K. Maurya1, Sushant Singh1, Xander H.T. Wehrens2 and Muthu Periasamy1
 
Abstract
 
Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides Brown Adipose Tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle based NST. However, the muscle-based-NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum (SER) Ca2+-cycling and its regulation by sarcolipin (SLN) can be the basis for muscle-NST. Due to the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study we investigated if muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT; constitute ~70% of total BAT) and exposed the mice to prolonged cold (4 deg C) for 9 day. The iBAT-ablated mice were able to maintain optimal body temperature (~35-37 deg C) during the entire period of cold exposure. After 4 days in cold, both sham controls and iBAT-ablated mice stopped shivering, resumed routine physical activity indicating that they are cold adapted. The iBAT-ablated mice showed higher oxygen consumption, decreased body-weight and fat-mass suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both SR and mitochondria including alteration in the expression of key components of Ca2+-handling, and mitochondrial metabolism. These changes along with increased SLN expression provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST, when BAT activity is minimized.
 
Keywords: calcium transport mitochondria mitochondrial metabolism sarcoplasmic reticulum (SR) skeletal muscle Cold adaptation Core body temperature Mitochondrial dynamics brown adipose tissue
 
PMID: 27298322

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Hey Dean, I just listened to that Rich Roll interview with Wim Hof today also and I was going to post very similar thoughts to yours.  While I did find it somewhat intriguing and a little entertaining, I came away thinking "Is this guy inspirational, or just a whimsical psychobabbling circus side show?  Honestly, the most interesting thing I found from that interview was a quick blub that I bet the majority of listeners might not have even caught, and I wish that Rich would have latched onto it and delved deeper but he didn't almost like he subconsciously knows Wim is full of it but consciously refuses to admit it, haha.  The precise item of interest to me was that Wim claims he can actually tap into and control the release of his own body's DMT stores to the point of being able to actually have psychedelic visual hallucinations, all on demand and without consuming or smoking any questionable substances.  I've never heard anyone make such a claim before.  

 

Also despite having plenty of time to do so, they didn't describe AT ALL what his methods are exactly.  While I'm impressed by Wim's amazing world records, he comes across as a snake oil salesman to me.  The good news is that they did mention several teams of scientists supposedly studying various offshoots of his alleged practices and how they might have practical applications.

 

It was nice that he admitted to having frozen his own retinas to the point of blindness (from cold water exposure), and to giving himself severe frostbite with long term damage (from running a half marathon on snow in bare feet in -6F degree temps) so people at least know they shouldn't expect to be able to do stupid things without consequences   :rolleyes:

Edited by Gordo

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Myostatin Inhibition Turns White fat to Brown/Beige Fat

 

Here is another tantalizing connection between BAT and a longevity-promoting intervention. It appears from [1] and [2] that inhibiting myostatin signalling not only boosts muscle mass, but also dramatically increases the conversion of white fat to thermogenic brown/beige fat. This is interesting because one of the two gene therapy treatments Liz Parrish underwent in hopes of living a longer and healthier life was a myostatin inhibitor. Ms. Parrish probably chose myostatin inhibition as one of the first interventions to try based on lifespan studies of myostatin knockout/knockdown mice like those used in [1] and [2]. In particular, genetically modified mice partially missing the gene for myostatin live 15% longer [3] than wild-type mice.

 

This is also very interesting because myostatin inhibition is an anabolic intervention, which we CR folks normally think will result in reduced lifespan. Not in this case however. Since Michael never posts here anymore ☹, I'll quote him from elsewhere on [3] instead. As you might anticipate, Michael is skeptical about the life-extension potential of myostatin reduction. Here is what he said in the FightAging.org comment section discussing [3]: 

 

 

This appears to be the usual case of partially making up for poor animal husbandry, rather than a true extension of the normal, healthy lifespan. Per their survivorship data, their WT controls have mean and maximal survivorships of 782 and 1037 days, vs. 858 and 1201 days for their -/+ mice; for comparison, the numbers for normal, healthy, nonobese, non-genetically-messed-up, non-toxin-fed mice should be ≈900 and ≈1100 d, respectively. That does still leave at least a suggestion of an effect on max LS, but I have seen Weindruch/Walford control groups with max LS this long. IAC, the main effect is against short-living controls.

 
It's not the genetics -- "The background strain of the mice was C57BL/6" (Supplementary Data S1 Experimental procedures) -- but I'd say there's good reason to think it's the classic "fat rats" problem: all they say about food intake is "standard Lab Diet 5001 chow (Purina Lab Diet, St. Louis, MO) ad libidum", which absent additional precaution means the animals spent all day snacking their way into metabolic morbidity. And the authors say (evidently not thinking of this confounder):
 
The mechanism behind the increased longevity of MSTN+/− mice is not known, but inhibition of myostatin can reduce systemic inflammatory proteins and body fat (Gumucio & Mendias, 2013 [PMID: 22815045])".
 
Quickly skimming & "Find"-ing through the latter, I don't actually see where this is documented, but it's consistent with PMIDs 21197386, 20877574, and 19208906, and also with studies reviewed in the last of these citations:
 
Knockout of the Mstn gene (Mstn [for myostatin]) from agouti lethal yellow (Ay) and obese (Lepob/ob) mice [two genetic models of extreme obesity, the latter being knockout of the leptin receptor -MR] improves glucose tolerance, increases muscle mass, and decreases adiposity (6). Obesity-prone Ay and Lepob/ob Mstn null mice have body sizes roughly equal to those of their littermate controls due to a diametrical change in muscle and fat characterized by fewer adipocytes that are reduced in size and hyperplasia and hypertrophy of individual muscle fibers. In addition, Mstn knockout mice exhibit an ability to fend off age-related expansion of adipose tissue mass by keeping their fat cells small, unlike wild types, which have enlarged adipocytes contributing to increasing adiposity with age. Evidently, knockout mice experience continued protection against obesity over the later part of their lifespan as they age compared with wild-type mice, yet they have similar total and resting metabolic rates.
Of course, this is what you'd expect from a mutation that drives fuel into muscle building. So I'm going to guess that the mutation kept their -/+ animals at normal leanness, leading to normal LS, while their controls became obese and metabolically morbid, and accordingly short-lived.
 
Posted by: Michael at March 27th, 2015 11:28 AM

 

 

Michael may be right here. Cutting down on myostatin activity may improve the metabolic health of ad lib fed myostatin knockdown mice, enabling them to live longer than the ad lib fed WT controls by avoiding the negative effects of obesity. Michael suggests the benefits the myostatin knockdown mice enjoyed was likely a result of the mutation "driving fuel into muscle building" and keeping them lean.

 

But we see from [1] and [2] that improved glucose tolerance, reduced inflammation and decreased adiposity enjoyed by the low-myostatin mice is also likely in (large?) part the result of increased thermogenesis due to the browning of their white fat. And fortunately for us, this is benefit that we all can enjoy without the expensive gene therapy Liz Parrish underwent. You guessed it, via cold exposure.

 

--Dean

 

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[1]  FASEB J. 2013 May;27(5):1981-9. doi: 10.1096/fj.12-225755. Epub 2013 Jan 29.

 
Myostatin knockout drives browning of white adipose tissue through activating the
AMPK-PGC1α-Fndc5 pathway in muscle.
 
Shan T(1), Liang X, Bi P, Kuang S.
 
Author information: 
(1)Department of Animal Science, Purdue University, West Lafayette, IN 47907,
USA.
 
Myostatin (Mstn) is predominantly expressed in skeletal muscles and plays
important roles in regulating muscle growth and development, as well as fat
deposition. Mstn-knockout (Mstn(-/-)) mice exhibit increased muscle mass due to
both hypertrophy and hyperplasia, and leaner body composition due to reduced fat 
mass. Here, we show that white adipose tissue (WAT) of Mstn(-/-) develops
characteristics of brown adipose tissue (BAT) with dramatically increased
expression of BAT signature genes, including Ucp1 and Pgc1α, and beige adipocyte 
markers Tmem26 and CD137. Strikingly, the observed browning phenotype is non-cell
autonomous and is instead driven by the newly defined myokine irisin (Fndc5)
secreted from Mstn(-/-) skeletal muscle. Within the muscle, Mstn(-/-) leads to
increased expression of AMPK and its phosphorylation, which subsequently
activates PGC1α and Fndc5. Together, our study defines a paradigm of muscle-fat
crosstalk mediated by Fndc5, which is up-regulated and secreted from muscle to
induce beige cell markers and the browning of WAT in Mstn(-/-) mice. These
results suggest that targeting muscle Mstn and its downstream signaling
represents a therapeutic approach to treat obesity and type 2 diabetes.
 
PMCID: PMC3633817
PMID: 23362117
 
--------
[1] Int J Obes (Lond). 2016 Jun 14. doi: 10.1038/ijo.2016.110. [Epub ahead of print]
 
Myostatin signals through miR-34a to regulate Fndc5 expression and browning of
white adipocytes.
 
Ge X(1), Sathiakumar D(1), Lua BJ(2), Kukreti H(2), Lee M(1), McFarlane C(1).
 
Author information: 
(1)Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for
Molecular Medicine, Singapore, Singapore. (2)School of Biological Sciences,
Nanyang Technological University, Singapore, Singapore.
 
Background/ObjectivesMyostatin (Mstn) plays a pivotal role in glucose and lipid
metabolism. Mstn deficiency leads to increased browning of white adipose tissue, 
which results in increased energy expenditure and protection against diet-induced
obesity and insulin resistance. In this study we investigated the molecular
mechanism(s) through which Mstn regulates browning of white
adipocytes.MethodsQuantitative molecular analyses were performed to assess Mstn
regulation of miR-34a and Fndc5 expression. miR-34a was overexpressed and
repressed to investigate miR-34a regulation of Fndc5. Luciferase reporter
analysis verified direct binding between miR-34a and the Fndc5 3'UTR. The
browning phenotype of Mstn(-/-) adipocytes was assessed through analysis of brown
fat marker gene expression, mitochondrial function and Infrared thermography. The
role of miR-34a and Fndc5 in this browning phenotype was verified through
antibody-mediated neutralization of FNDC5, knockdown of Fndc5 by siRNA and
through miR-34a gain-of- and loss-of-function experiments.ResultsMstn treatment
of myoblasts inhibited Fndc5 expression, while loss of Mstn increased Fndc5
levels in muscles and in circulation. Mstn inhibition of Fndc5 is
miR-34a-dependent. Mstn treatment of C2C12 myoblasts upregulated miR-34a
expression, while reduced miR-34a expression was noted in Mstn(-/-) muscle and
WAT. Subsequent overexpression of miR-34a inhibited Fndc5 expression, while
blockade of miR-34a increased Fndc5 expression in myoblasts. Reporter analysis
revealed that miR-34a directly suppresses Fndc5 expression through a
miR-34a-specific binding site within the Fndc5 3'UTR. Importantly, Mstn-mediated 
inhibition of Fndc5 was blocked upon miR-34a inhibition. Mstn(-/-) adipocytes
showed reduced miR-34a, enhanced Fndc5 expression and increased thermogenic gene 
expression, which was reversed upon either neutralization of Fndc5 or Fndc5
knockdown. In agreement, Mstn(-/-) adipocytes have increased mitochondria,
improved mitochondrial function and increased heat production.ConclusionsMstn
regulates Fndc5/Irisin expression and secretion through a novel miR-34a-dependent
post-transcriptional mechanism. Loss of Mstn in mice leads to increased
Fndc5/Irisin expression, which contributes to the browning of white
adipocytes.International Journal of Obesity accepted article preview online, 14
June 2016. doi:10.1038/ijo.2016.110.
 
PMID: 27297797
 
------------
[3] Aging Cell. 2015 Aug;14(4):704-6. doi: 10.1111/acel.12339. Epub 2015 Mar 24.
 
Haploinsufficiency of myostatin protects against aging-related declines in muscle
function and enhances the longevity of mice.
 
Mendias CL(1,)(2), Bakhurin KI(2), Gumucio JP(1,)(2), Shallal-Ayzin MV(2), Davis 
CS(2), Faulkner JA(2).
 
Author information: 
(1)Department of Orthopaedic Surgery, University of Michigan Medical School, Ann 
Arbor, MI, USA. (2)Department of Molecular & Integrative Physiology, University
of Michigan Medical School, Ann Arbor, MI, USA.
 
The molecular mechanisms behind aging-related declines in muscle function are not
well understood, but the growth factor myostatin (MSTN) appears to play an
important role in this process. Additionally, epidemiological studies have
identified a positive correlation between skeletal muscle mass and longevity.
Given the role of myostatin in regulating muscle size, and the correlation
between muscle mass and longevity, we tested the hypotheses that the deficiency
of myostatin would protect oldest-old mice (28-30 months old) from an
aging-related loss in muscle size and contractility, and would extend the maximum
lifespan of mice. We found that MSTN(+/-) and MSTN(-/-) mice were protected from 
aging-related declines in muscle mass and contractility. While no differences
were detected between MSTN(+/+) and MSTN(-/-) mice, MSTN(+/-) mice had an
approximately 15% increase in maximal lifespan. These results suggest that
targeting myostatin may protect against aging-related changes in skeletal muscle 
and contribute to enhanced longevity.
 
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley
& Sons Ltd.
 
PMCID: PMC4531085
PMID: 25808276 

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More on the Beneficial Gut Microbiome Changes Induced by Cold Exposure

 

Months ago, way earlier on Page 3 of this thread, in this post and this one too, I discussed a study [2] that probably most of us have forgotten. In it, researchers transplanted the gut microbes from cold-housed and warm-housed mice to mice housed at normal temperatures. The mice that received the fecal transplant from the cold-housed mice exhibited the browning of white fat, increased thermogenesis, improved insulin sensitivity and improved nutrient absorption & gut function.

 

This new study [1] did some of the same experiments but more, with some very interesting results. In this study, standard C57BL/6J mice were housed at either a temperature close to thermal neutrality (29 °C = 84 °F) or two colder temperatures (17 °C or 12 °C, or 63 °F and 54 °F, respectively). They were fed ad lib either standard rodent chow (CHD) or high-fat rodent chow (HFD).

 

Both sets of cold-housed mice ate dramatically more, but gained a lot less weight than the warm-housed mice, especially on the obesogenic high-fat diet. As expected BAT volume and UCP1 expression in both BAT and inguinal white fat increased dramatically as a result of cold exposure.

 

In accordance with Gordo's remarkable glucose results, the cold-housed mice were much better at regulating glucose, as well exhibiting improved insulin sensitivity (data not shown) in a glucose tolerance test, as illustrated in this graph from the full text:

 

w2kvEsO.png

 

Here is a dramatic and potentially important result:

 

FGF21 was 7- and 2.5-fold upregulated in iBAT at 12°C on a HFD and CHD, respectively
 
 
Here is another interesting result from [1], suggesting it doesn't take long for the benefits of cold exposure to kick in, at least in mice:
 
[in] mice that were fed HFD for 4 weeks at 29C and then transferred to 12C for 6 days... cold exposure
induced Ucp1 expression 5-fold in iBAT after 1 day at 12 °C.
 

These researchers did a much more detailed analysis of changes in the gut microbiota of mice housed at the different temperatures than did [2]. There was a clear difference in the gut microbes of cold- vs. warm-housed mice. Their results were the standard alphabet soup of various specific bacteria species, some increased and some decreased by cool temperatures, and most of which I'd never heard of. Unexpectedly (for me anyway), getting transferred from warm-housing to cold-housing increased  the ratio of Bacteroidetes to Firmicutes:

 

qupgGPA.png

 

in apparent contradiction to the results of [2], which found cold-exposed mice became enriched with Firmicutes relative to Bacteroidetes. So it remains unclear exactly what microbial changes contributed to the improved metabolic health of the mice. Here are the species that the authors of [1] suggest might account for the difference:

 

Bacteria belonging to Bacilli and Erysipelotrichaceae, usually associated with obesity (Turnbaugh
et al., 2009), were enriched in mice at 29C, whereas Adlercreutzia and Desulfovibrio, associated
with leanness (Caesar et al., 2015; Goodrich et al., 2014), were increased at 12C....
Consistent with the study of Chevalier et al. [study [2] below - DP], we identified a decreased abundance of
Verrucomicrobia and an increased abundance of Deferribacteres when mice were exposed to cold,
suggesting that altered abundance of members in these phyla contribute to the cold-induced phenotype.

 

So there was some (but not complete) overlap between [1] and [2] in the gut microbiome changes induced by cold exposure.

 

But one thing is abundantly clear from [1], like it was in [2] - namely that it was some sort of changes to the mice's gut microbiome that caused at least a large part of the metabolic improvements associated with cold exposure.

 

How is this clear you ask?

 

Because like [2], the researchers in [1] did fecal transplants from warm-housed and cold-housed mice to other mice and looked at their metabolism both 1 day and 6 weeks after the transplant, during which they were housed at normal lab temperature. Here are some dramatic graphs of the results. In all of them, the black bars represent the mice who received fecal transplants from the cold-housed mice (cold-recipients), and the light grey bars are for the mice who got the transplant from the warm-housed mice (warm-recipients):

 

xIibH2W.png

 

As you can see, the cold-recipients gained a lot less fat, had 3x as much UPC1 expression in BAT, and showed dramatically better glucose response to a glucose challenge than the warm-recipients.

 

Tests showed that the cold exposed mice in this study had increased levels of circulating bile acids (BAs) generated by the altered gut microbe population. The authors believe this change in bile acid synthesis and metabolism may explain the increased BAT thermogenesis and improved metabolic health of both cold-exposed and cold-recipient mice:

 

Our investigations suggest that changes in the gut microbiota in response to the cold exposure mediate BA metabolism,
possibly through changes in AMPK and FXR signaling, to complement sympathetic signaling in the regulation of
thermogenesis in iBAT and resistance to [diet-induced obesity].

 

In other words, cold exposure changes the gut microbiome in such a way so as to increased production of bile acids which serve as is a signal to BAT to boost thermogenesis.

 

But wait a minute, you might be saying. Don't I remember from a Dr. Greger video that higher levels of certain bile acids (resulting from a diet high in animals products) are associated with cancer? Yup, but fortunately the camcer-causing bile acids Dr. Greger mentions, like DCA, are dramatically downregulated in favor of other, beneficial bile acids, by cold exposure. In fact, mice that received the fecal transplant from cold-exposed mice had a 10x lower level of the carcinogenic bile acid DCA compared with recipients from warm-housed mice. So chalk up another one in the win column for cold exposure. 

 

But whether the mechanism involves changes in bile acid metabolism or something else, it looks like it's possible to gain many of the metabolic benefits of cold exposure via a fecal transplant from previously cold-exposed individuals. In the words of the authors:

 

These results suggest that functional differences between microbiota of mice
kept at 12C and 29C can be transferred to recipient mice kept at 23C.
 

Of course fecal transplants can get pretty messy, and aren't commonly done these days in humans except in extreme circumstances. I'm inclined to stick with directly exposing myself to cold...

 

--Dean

 

----------

[1] Cell Metab. 2016 Jun 14;23(6):1216-1223. doi: 10.1016/j.cmet.2016.05.001.

 
Altered Microbiota Contributes to Reduced Diet-Induced Obesity upon Cold
Exposure.
 
Ziętak M(1), Kovatcheva-Datchary P(2), Markiewicz LH(1), Ståhlman M(2), Kozak
LP(3), Bäckhed F(4).
 
 
Maintenance of body temperature in cold-exposed animals requires induction of
thermogenesis and management of fuel. Here, we demonstrated that reducing ambient
temperature attenuated diet-induced obesity (DIO), which was associated with
increased iBAT thermogenesis and a plasma bile acid profile similar to that of
germ-free mice. We observed a marked shift in the microbiome composition at the
phylum and family levels within 1 day of acute cold exposure and after 4 weeks at
12°C. Gut microbiota was characterized by increased levels of Adlercreutzia,
Mogibacteriaceae, Ruminococcaceae, and Desulfovibrio and reduced levels of
Bacilli, Erysipelotrichaceae, and the genus rc4-4. These genera have been
associated with leanness and obesity, respectively. Germ-free mice fed a high-fat
diet at room temperature gained less adiposity and improved glucose tolerance
when transplanted with caecal microbiota of mice housed at 12°C compared to mice 
transplanted with microbiota from 29°C. Thus, a microbiota-liver-BAT axis may
mediate protection against obesity at reduced temperature.
 
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
 
PMID: 27304513
 
-------
[2]  Cell. 2015 Dec 3;163(6):1360-74. doi: 10.1016/j.cell.2015.11.004.
 
Gut Microbiota Orchestrates Energy Homeostasis during Cold.
 
Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S, Montet X, Seimbille Y, Zamboni N, Hapfelmeier S, Trajkovski M.
 
 
Highlights
 
Cold exposure leads to marked changes in the gut microbiota composition
 
Cold microbiota transplantation increases insulin sensitivity and WAT browning
 
Cold exposure or cold transplantation increase the gut size and absorptive capacity
 
Reconstitution of cold-suppressed A. muciniphila reverts the increased caloric uptake
 
Abstract
 
Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.
 
PMID: 26638070

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Olive (Oil) Polyphenols Turn Fat Cells Brown/Beige

 

Here is yet another example of  what I've come to call the "BAT Rule" - the observation most interventions known to promote health and/or longevity also seem to boost BAT activity, white fat browning, and/or thermogenesis. 

 

In this case, it's is the polyphenol compounds in olives, high-quality extra-virgin olive oil (EVOO) and olive leaf extract (OLE).

 

This new study [1], found human subcutaneous fat cells (in a petri dish) treated with a polyphenol-rich OLE (produced via a procedure I'll detail in a moment) differentiated into brown/beige adipose tissue, and expressed high levels of heat-producing UPC1 in their mitochondria compared with fat cells cultured without exposure to OLE. And we're not talking about a small effect here. Here are the graphs of UPC1 gene expression (left) and protein expression (right) in undifferentiated adipose stem cells at the start of the experiment (UNDIFF), and fat cells at the end of the experiment after differentiation in the absence or presence of olive leaf extract (DIFF and DIFF+OLE, respectively). How about that for a big difference - no doubt about the significance of the UPC1 increase!

 

D500TZz.png

 

And UCP1 wasn't the only interesting gene/protein upregulated by OLE. I won't show the graphs for these, but simply report approximately how much they changed (by eyeballing the graphs) in the DIFF+OLE cells vs the DIFF cells:

  • IRS-1 - The expression of insulin receptor gene IRS-1 was upregulated by a factor of 10x in the DIFF+OLE cells. This likely explains the increased insulin sensitivity seen with cold-induced browning of white fat, and the association of olive oil with improved insulin sensitivity and reduced (or at least not increased) diabetes risk compared with other fat sources.
  • SIRT1 - Expression of the SIRT1 gene was upregulated by a factor of 2.7x in the DIFF+OLE cells. Cold-exposure is also known to increase SIRT1 levels, as I've documented before, and so does CR. This post on CR and CE Synergy has a discussion of the role elevated SIRT1 and AMPK (see next bullet) play in the metabolic effects of the two interventions. Both are well known components of health- and longevity-promoting metabolic pathways.
  • AMPK - Expression of the AMPK protein was increased by at least a factor of 10x in the DIFF+OLE cells, but possibly more since AMPK protein was basically undetectable in the DIFF cells not exposed to OLE. In this post and in the post about CR/CE synergy mentioned above I discuss evidence that cold exposure increases AMPK.

In short, exposure to olive leaf extract causes baby fat cells to grow up to become brown/beige fat cells rather than 'evil' white fat cells, and as a result express the health-promoting proteins associated with brown/beige fat.

 

So just what is in olive leaf extract, and how does it compare with what is in the kind of high quality EVOO that folks around here (esp. Michael) make such a big deal about?

 

The authors of [1] did HPLC analysis of their OLE extract, and found it contained the following polyphenols:

 

Oleuropein (46.25 mg/g of dried leaves) is the most abundant antioxidant compound, followed by hydroxytyrosol glucoside and ligstroside (15 and 9.7 mg/g of dried leaves, respectively). The extract contained also luteolin-7-O-glucoside, verbascoside, rutin, and hydroxytyrosol, and caffeic acid, chlorogenic acid (data not shown).

 

The above list appears to include most of the polyphenols used by reputable olive oil vendors and industry watchdogs to evaluate the quality of top-notch EVOO to separate the scam EVOO from the good stuff - which is a big problem.  First off, from this list on website of the olive oil industry group website "Olive Oil Times", we see that the OLE contains virtually all the same polyphenols as high quality EVOOs.

 

How about polyphenol concentrations on the OLE vs. EVOO?  From Michael's epic Quotidian Diet Post to LongeCity.org, we see that Michael insists his EVOO contain "high (≥ 350mg/kg) total phenolics, assayed using caffeic acid equivalents." This "caffeic acid equivalent" metric is the same method the authors of [1] used to measure the concentration of polyphenols in their OLE, which is convenient. What did they find? Their OLE contained 40mg of total phenolics per gram. That equates to 40,000mg/kg (40g/kg) of polyphenols, or two orders of magnitude higher concentration of polyphenols in the OLE than in Michael's top-notch olive oils. 

 

So the OLE used in [1] was pretty potent stuff - which isn't surprising since it was distilled from dried leaves, and hence doesn't contain much if any fat. But obviously exactly how potent a dose the cells in [1] received depends on how much of it they dripped onto the fat cells. And besides, there is really no easy way to calculate any sort of equivalence between the concentration of polyphenols you get in your body as a result of eating EVOO vs. directly dripping OLE onto cells. 

 

Fortunately, [1] isn't the only study investigating olive oil polyphenols and brown adipose tissue. In fact, this post from back in March (which I'd forgotten about) goes into depth about study [3], which found UPC1 expression in BAT was ~40% higher in rats fed a diet rich in olive oil for four weeks relative to diets rich in either safflower oil, palm oil or beef tallow. 

 

Further evidence that EVOO boosts BAT & thermogenesis comes from [4], which I stumbled across in preparing this post. The researchers in [4] did something similar to [3], feeding rats three different relatively high fat (for rats) diets (30% of calories from fat) containing corn oil, refined OO, or EVOO. They basically found the same thing as [3], that EVOO (but not refined OO or corn oil) upregulated UPC1 in BAT, and dramatically increasing the metabolic health of the EVOO-fed rats relative to the other two groups:

 

After 28 days of feeding, the final body weight, weight gain, energy efficiency, perirenal adipose tissue and epididymal fat pad and plasma triglyceride concentrations were the lowest in the rats fed the EV-olive oil diet. The content of uncoupling protein 1 (UCP1) in IBAT and the rates of urinary noradrenaline and adrenaline excretions were the highest in the rats fed the EV-olive oil diet.

 

So it looks like in vivo studies [3][4] feeding rodents extra virgin olive oil support the same thing found in vitro in [1], namely that the polyphenols in EVOO upregulate UPC1 and thermogenesis. Interestingly, the researchers in [4] conducted a second experiment halfway between the petri dish experiment in [1] and the feeding experiments in [3] (and the first experiment of [4]). What they did was inject EVOO polyphenols into the bloodstream of rats. Here is what they found: 

 

The intravenous administration of the extract of the phenolic fraction from EV-olive oil significantly increased plasma noradrenaline and adrenaline concentrations, whereas that of hydroxytyrosol [a specific polyphenol in EVOO and OLE - DP] had no effect. These results suggest that phenols except hydroxytyrosol in EV-olive oil enhance thermogenesis by increasing the UCP1 content in IBAT and enhancing noradrenaline and adrenaline secretions in rats.

 

So that's cool. But for those of us who are happier eating nuts than shelling out for super-expensive, hard-to-evaluate and (IMO) not-as-tasty EVOO, how did they make the olive oil/leaf polyphenol extracts? That's where it gets interesting... 

 

In the methods section of the free full text of [1], here is what they did to make their OLE:

 

Samples of olive leaves (Olea europaea L.) from four sicilian varieties namely ‘Biancolilla’, ‘Coratina’, ‘Nocellara’, and ‘San Benedettese’ were employed. The leaves were collected at the same time, during pruning period, from Sicilian organic farming.
 
The extract was obtained in accordance to Lee-Huang et al. [2] method with some modifications. Briefly, sicilian olive leaves, previously dehydrated at 40°C, were extracted by an aqueous solvent, 100 mL of hot water was employed for the extraction of 5 g of leaves. 
 
And in more detail, from the free full text of the above referenced [2]:
 
 Dried olive leaves (Olea europea) were rinsed thoroughly with sterile distilled water to remove dust,
insecticides, and contaminating material. The leaves were ground into small pieces and extracted twice
with sterile distilled water for 12 h at 80 C, at a ratio of 40ml water to 1 g leaf. Insoluble material was
removed by centrifugation at 20,000g for 30min. The clear supernatant was concentrated by lyophilization,
reconstituted with water to 0.1 g starting material per ml, sterilized by Millipore filtration with a 0.45
micron filter, and stored at 20 C until use.
 

In other words, they picked leaves from various varieties of olive trees, and then dried them in a dehydrator. Then they soaked the dried leaves in hot water twice for 12 hours each time to extract the polyphenols. Then they strained and concentrated the resulting liquid (via freezing and sublimation to remove most of the water) to create the OLE extract they used to drip on the fat cells in culture.

 

In short, they made olive leaf tea.

 

Which got me thinking... So Why Don't We Brew Our Olive Oil?

 

But to finish off this post, it appears there is pretty compelling evidence that the polyphenols in EVOO (and OLE) that Michael is always touting as wonderful are potent stimulators of BAT and thermogenesis. What's more, many of the metabolic benefits of EVOO compared to other fat sources are likely the result of these effects, at least in part.

 

Once again we see the "BAT Rule" prevailing - healthy foods and interventions almost invariably stimulate BAT and thermogenesis. This time the healthy food is EVOO and olive leaf extract.

 

EVOO was already on the master list of BAT & thermogenesis stimulators, but I've added olive leaf extract, and olive leaf tea to the list below, both of which I plan to address in the new thread I alluded to above. And yes, in that thread I also plan to address the question "Why don't we just eat olives?"

 

--Dean

 

----------------

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Drugs / Supplements - metformin, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 

--------------

[1] Front Pharmacol. 2016 May 31;7:143. doi: 10.3389/fphar.2016.00143. eCollection

2016.
 
Olive Leaf Extract from Sicilian Cultivar Reduced Lipid Accumulation by Inducing 
Thermogenic Pathway during Adipogenesis.
 
Palmeri R(1), Monteleone JI(1), Spagna G(1), Restuccia C(1), Raffaele M(2),
Vanella L(2), Li Volti G(3), Barbagallo I(4).
 
Author information: 
(1)Department of Agricultural, Food and Environment, University of Catania
Catania, Italy. (2)Biochemistry Section, Department of Drug Sciences, University 
of Catania Catania, Italy. (3)Department of Biomedical and Biotechnological
Sciences, University of CataniaCatania, Italy; Euro-Mediterranean Institute of
Science and TechnologyPalermo, Italy. (4)Biochemistry Section, Department of Drug
Sciences, University of CataniaCatania, Italy; Euro-Mediterranean Institute of
Science and TechnologyPalermo, Italy.
 
Olive leaves contain a wide variety of phenolic compounds belonging to phenolic
acids, phenolic alcohols, flavonoids, and secoiridoids, and include also many
other pharmacological active compounds. They could play an important role in
human diet and health because of their ability to lower blood pressure, increase 
coronary arteries blood flow and decrease the risk of cardiovascular diseases.
The aim of this study was to investigate the effect of olive leaf extract (OLE)
from Sicilian cultivar on adipogenic differentiation of human adipose derived
mesenchymal stem cells and its impact on lipid metabolism. We showed that OLE
treatment during adipogenic differentiation reduces inflammation, lipid
accumulation and induces thermogenesis by activation of uncoupling protein
uncoupling protein 1, sirtuin 1, peroxisome proliferator-activated receptor
alpha, and coactivator 1 alpha. Furthermore, OLE significantly decreases the
expression of molecules involved in adipogenesis and upregulates the expression
of mediators involved in thermogenesis and lipid metabolism. Taken together, our 
results suggest that OLE may promote the brown remodeling of white adipose tissue
inducing thermogenesis and improving metabolic homeostasis.
 
PMID: 27303302
 
------------
[2] Biochem. Biophys. Res. Commun. 2003, 307, 1029–1037. doi: 10.1016/S0006-291X(03)01292-0
 
 Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. 
 
Lee-Huang, S., Zhang, L., Huang, P. L., Chang, Y. T., and Huang, P. L.
 
Abstract
 
We investigated the antiviral activity of olive leaf extract (OLE) preparations standardized by liquid chromatography coupled
mass spectrometry (LC MS) against HIV 1 infection and replication. We find that OLE inhibits acute infection and cell to cell
transmission of HIV 1 as assayed by syncytia formation using uninfected MT2 cells co cultured with HIV 1 infected H9 T lym
phocytes. OLE also inhibits HIV 1 replication as assayed by p24 expression in infected H9 cells. These anti HIV effects of OLE are
dose dependent, with EC50s of around 0.2 lg/ml. In the effective dose range, no cytotoxicity on uninfected target cells was detected.
The therapeutic index of OLE is above 5000. To identify viral and host targets for OLE, we characterized gene expression profiles
associated with HIV 1 infection and OLE treatment using cDNA microarrays. HIV 1 infection modulates the expression patterns of
cellular genes involved in apoptosis, stress, cytokine, protein kinase C, and hedgehog signaling. HIV 1 infection up regulates the
expression of the heat shock proteins hsp27 and hsp90, the DNA damage inducible transcript 1 gadd45, the p53 binding protein
mdm2, and the hedgehog signal protein patched 1, while it down regulates the expression of the anti apoptotic BCL2 associated X
protein Bax. Treatment with OLE reverses many of these HIV 1 infection associated changes. Treatment of HIV 1 infected cells
with OLE also up regulates the expression of the apoptosis inhibitor proteins IAP1 and 2, as well as the calcium and protein kinase
C pathway signaling molecules IL 2, IL 2Ra, and ornithine decarboxylase ODC1.
 
Keywords: Anti HIV agent; Olive leaf extract; Antiviral; cDNA microarray; Gene expression profile; LC MS
 
PMID: 12878215
 
-----------
[3] Am J Clin Nutr. 2002 Feb;75(2):213-20.
 
Olive oil feeding up-regulates uncoupling protein genes in rat brown adipose
tissue and skeletal muscle.
 
Rodríguez VM(1), Portillo MP, Picó C, Macarulla MT, Palou A.
 
Author information: 
(1)Department of Nutrition and Food Science, the University of País Vasco,
Vitoria, Spain.
 
 
BACKGROUND: Some nutrients, such as carotenoids, retinoic acid, and certain types
of fatty acids, increase thermogenic capacity.
OBJECTIVE: The influence of 4 dietary lipid sources (olive oil, sunflower oil,
palm oil, and beef tallow) on the content of uncoupling proteins 1, 2, and 3
(UCP1, UCP2, and UCP3) and their messenger RNA (mRNA) expression in several
tissues of rats was compared.
DESIGN: Wistar rats were randomly divided into 4 groups and fed ad libitum diets 
containing 40% of energy as fat. UCP1, UCP2, and UCP3 mRNA and protein were
assessed by Northern blot and Western blot, respectively. Oxygen consumption in
tissues was measured by polarography. Total-body oxygen consumption was assessed 
in an open-circuit chamber system. Circulating fuels (fatty acids and glucose)
and hormones (triiodothyronine, thyroxine, corticosterone, and insulin) were
measured.
RESULTS: Olive oil feeding induced the highest UCP1, UCP2, and UCP3 mRNA
expression in interscapular brown adipose tissue. An analogous effect was
observed in gastrocnemius muscle UCP3 mRNA. No significant differences were
observed in perirenal white adipose tissue UCP2 mRNA. Changes in mRNAs were not
accompanied by close changes in the protein content of UCPs and were not
associated with changes in adipose tissue oxygen consumption. Nevertheless,
total-body oxygen consumption was higher in rats fed olive oil than in those fed 
the other 3 diets. No significant differences were found in body and tissue
weights or in serum indexes.
CONCLUSION: Olive oil induced an up-regulating effect on UCP mRNA that was
probably not mediated by systemic metabolic changes, but rather related to a
local effect on interscapular brown adipose tissue and skeletal muscle.
 
PMID: 11815310
 
----------
[4] J Nutr Biochem. 2007 Oct;18(10):685-92. Epub 2007 Apr 5.
 
Extra virgin olive oil increases uncoupling protein 1 content in brown adipose
tissue and enhances noradrenaline and adrenaline secretions in rats.
 
Oi-Kano Y(1), Kawada T, Watanabe T, Koyama F, Watanabe K, Senbongi R, Iwai K.
 
Author information: 
(1)Laboratory of Nutrition Chemistry, Faculty of Home Economics, Kobe Women's
University, 2-1 Aoyama, Higashisuma, Suma-ku, Kobe 654-8585, Japan.
oi@suma.kobe-wu.ac.jp
 
The effects of extra virgin olive oil (EV-olive oil) on triglyceride metabolism
were investigated by measuring the degree of thermogenesis in interscapular brown
adipose tissue (IBAT) and the rates of noradrenaline and adrenaline secretions in
rats, both in vivo and in situ. In Experiment 1 (in vivo), rats were given an
isoenergetic high-fat diet (30% fat diet) containing corn oil, refined olive oil,
or EV-olive oil. After 28 days of feeding, the final body weight, weight gain,
energy efficiency, perirenal adipose tissue and epididymal fat pad and plasma
triglyceride concentrations were the lowest in the rats fed the EV-olive oil
diet. The content of uncoupling protein 1 (UCP1) in IBAT and the rates of urinary
noradrenaline and adrenaline excretions were the highest in the rats fed the
EV-olive oil diet. In Experiment 2 (in situ), the effects of the extract of the
phenolic fraction from EV-olive oil and a compound having excellent
characteristics as components of EV-olive oil, hydroxytyrosol, on noradrenaline
and adrenaline secretions were evaluated. The intravenous administration of the
extract of the phenolic fraction from EV-olive oil significantly increased plasma
noradrenaline and adrenaline concentrations, whereas that of hydroxytyrosol had
no effect. These results suggest that phenols except hydroxytyrosol in EV-olive
oil enhance thermogenesis by increasing the UCP1 content in IBAT and enhancing
noradrenaline and adrenaline secretions in rats.
 
PMID: 17418557

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Score another one for Gordo? On page 8 of this recent Longo paper it's mentioned that TRF (time restricted feeding) increases BAT activity and metabolic rate ("TRF also increases activity levels of brown adipose tissue"). Didn't have time to track down the original work, we need Detective Dean! http://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30250-9.pdf

 

I was wondering if Gordo might perhaps have fasting glucose data (as a sort of proxy for BAT activity?) from before he started TRF-style eating and afterwards, and whether it caused any noticeable difference in fasting numbers?

 

I also was wondering in regards to the recent microbiome info, has anyone seen evidence that pre/probiotics might play a factor? I noticed in one of Gordo's lunches that he's taking Jarrow Inulin FOS for example.

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Ketogenic Diets, Fasting, and Time Restricted Feeding DON'T Activate BAT

 

BrianA,

 

Here is the entire sentence in the Longo paper you reference that makes the claim that time restricted feeding (TRF) increases BAT activity:

 

TRF also increases activity levels of brown adipose
tissue (thereby increasing metabolic rate), increases fatty acid
b-oxidation, and reduces hepatic glucose production (Froy,
2011; Froy et al., 2006; Froy and Miskin, 2010).
 

I tracked down the three Froy references Longo claims supports this idea [1-3].. They all talk about the influence of TRF on circadian rhythms. I took at look at the full text of two of them (here and here), and nowhere does phrase "brown adipose tissue" or the word "BAT" occur in either of them. From the abstract, the third looks like pretty much a carbon copy of the other two. Disappointing when you find an author like Longo fudging or making mistakes about references like that...

 

But in my searching, I did find [4], which found that being in a state of ketosis (in this case, as a result of a high-fat, low-carb ketogenic diet) results in increased BAT mitochondrial size, and UCP1 expression in BAT, at least in mice. But quite unexpectedly (at least to me, and perhaps the authors as well), BAT activity (as measured by radioactively labelled glucose uptake) was actually decreased by about 50% in mice on the ketogenic diet. Here is the PET image of mice fed a regular chow diet (left) vs. a ketogenic diet (KD - right):

 

JTJXjAV.png

 

According to the authors, the likely mechanism is somewhat troubling - insulin resistance in BAT. Here is what they say in [4] (my emphasis):

 

18F-FDG uptake in IBAT of the KD group was about half of the chow group...

 

Mice on the KD had significantly reduced uptake of 18F-FDG in their BAT. This result is in agreement with a previous study by Jornayvaz et al. (ref) which found significantly reduced labeled glucose uptake during hyperinsulinemic euglycemic clamp in BAT of mice fed the KD. These results suggest that the KD causes insulin resistance in this tissue, although the mechanism is unclear. 

 

I'd like to point out how sleazy the authors' treatment of this seems to me to be.  When I see a title like [4]'s, "A ketogenic diet increases brown adipose tissue mitochondrial proteins and UCP1 levels in mice", I naturally assume these changes would have resulted in increased BAT activity and thermogenesis. It's not even in the abstract that this is not the case - you need to dig into the full text before you see the truth - that BAT activity was actually decreased by the KD diet, and BAT appeared to become insulin resistant on a KD diet to boot. It seems to me these authors may have an agenda, despite working at the NIH (and not for the Atkins Foundation).

 

Since I've never thought a ketogenic diet was a very good idea in the first place, I'm not counting this as a violation of the BAT Rule - the observation that healthy diet or lifestyle factors almost always seem to also increase BAT and/or thermogenesis. In fact, I interpret the fact that a KD doesn't increase BAT activity or thermogenesis as a (further) indication that a KD is probably not a bad idea long-term, given how consistent the BAT Rule seems to be. 

 

So despite a KD increasing BAT mitochondria size and UCP expression, I'm not going to add a KD to the master list of BAT activity / thermogenesis inducers - since it doesn't appear to trigger either of those. 

 

Similarly, while I initially though fasting and time restrictive feeding could be classified as BAT / thermogenesis inducers because they can result in a state of ketosis (a modest example of which Saul recently observed in his own blood work), I'm not going to add them to the master list either, since ketosis doesn't activate BAT or thermogenesis.

 

Fasting is already on the list, but looking back at evidence in the post that got it on the list, I'm going to remove even fasting from the list. Here's why. The evidence was based on a single study showing fasting increased UPC3 (not UCP1) in muscle tissue (not BAT). UPC3 doesn't seem to be involved in thermogenesis, a fact which that post even acknowledged. So it looks like I was a little overzealous putting fasting on the list of BAT / thermogenesis inducers in the first place (sorry Sthira).

 

If someone else can find evidence that Longo has (but failed to cite) about TRF activating BAT, I'll be happy to reconsider. But for now they both stay off, along with a ketogenic diet.

 

--Dean

 

----------------

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Drugs / Supplements - metformin, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

-----------------

[1] Froy, O. (2011). Circadian rhythms, aging, and life span in mammals. Physiology
(Bethesda) 26, 225–235.
 
--------
[2] Froy, O., and Miskin, R. (2010). Effect of feeding regimens on circadian
rhythms: implications for aging and longevity. Aging (Albany, N.Y.) 2, 7–27.
 
---------
[3] Froy, O., Chapnik, N., and Miskin, R. (2006). Long-lived alphaMUPA transgenic
mice exhibit pronounced circadian rhythms. Am. J. Physiol. Endocrinol.
Metab. 291, E1017–E1024.
 
--------
[4] IUBMB Life. 2013 Jan;65(1):58-66. doi: 10.1002/iub.1102. Epub 2012 Dec 10.
 
A ketogenic diet increases brown adipose tissue mitochondrial proteins and UCP1
levels in mice.
 
Srivastava S(1), Baxa U, Niu G, Chen X, Veech RL.
 
(1)Laboratory of Metabolic Control, National Institute on Alcohol Abuse and
Alcoholism, National Institutes of Health, Rockville, MD, USA.
 
 
We evaluated the effects of feeding a ketogenic diet (KD) for a month on general 
physiology with emphasis on brown adipose tissue (BAT) in mice. KD did not reduce
the caloric intake, or weight or lipid content of BAT. Relative epididymal fat
pads were 40% greater in the mice fed the KD (P = 0.06) while leptin was lower (P
< 0.05). Blood glucose levels were 30% lower while D-β-hydroxybutyrate levels
were about 3.5-fold higher in the KD group. Plasma insulin and leptin levels in
the KD group were about half of that of the mice fed NIH-31 pellets (chow group).
Median mitochondrial size in the interscapular BAT (IBAT) of the KD group was
about 60% greater, whereas the median lipid droplet size was about half of that
in the chow group. Mitochondrial oxidative phosphorylation proteins were
increased (1.5-3-fold) and the uncoupling protein 1 levels were increased by
threefold in mice fed the KD. The levels of PPARγ, PGC-1α, and Sirt1 in KD group 
were 1.5-3-fold while level of Sirt3 was about half of that in the chow-fed
group. IBAT cyclic AMP levels were 60% higher in the KD group and cAMP response
element binding protein was 2.5-fold higher, suggesting increased sympathetic
system activity. These results demonstrate that a KD can also increase BAT
mitochondrial size and protein levels.
 
PMCID: PMC3821007
PMID: 23233333

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