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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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So it looks like I was a little overzealous putting fasting on the list of BAT / thermogenesis inducers in the first place (sorry Sthira).

 

:-(

 

I'll fast anyway. I'm actually looking very forward to my next fast! It's a little bit addictive, prolonged water-only fasting, so I have to be careful and watch that I don't overdo it.

 

"If it's worth doing," she said, "then it's worth overdoing." And I looked at her, those wondering brown eyes, and so I said yes let's overdo it, let's overdo us some thermogenic induction right about now. Welcome Summer Equinox, be careful with all that heat you've built around us.

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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?

 

First -- Great new info about cold exposure's potential impact on the microbiome (I saw the same study Dean posted a few posts up, that was just published, when running a google scholar search, and was ready to post only to find Dean had already analyzed it out the wazoo here, haha).

 

Regarding time restricted feeding (tRF), that is also an interesting idea.  I will have to see how many readings my meter actually saves, and cross reference that will my old food journal entries (MyFitnessPal) to see what I can come up with for you there, but I'm not too optimistic that I have that data (I wonder if there are any relevant published studies that would be more controlled anyway?).

 

Dean, in regard to the Longo comments/doubts -- do you have a way to contact him about this?  It would be interesting to see how he responds.  I kind of suspect there may be something to the idea of tRF and BAT activity being connected in some way, but it would be nice to see some real data.  Perhaps he could dig it up.  Here is one reference that may indirectly support the idea (emphasis mine): 

 

"Recent experimental studies have elucidated some of the metabolic mechanisms involved with IF. Animal models have shown positive changes in glucose (lower plasma glucose and insulin levels) and in lipid metabolism (reduced visceral fat tissue and increased plasma adiponectin level)...

 

"Despite the limited number of samples studied, positive results have been reported on the impact of IF for human health. IF is reported to improve the lipid profile; to decrease inflammatory responses, reflected by changes in serum adipokine levels; and to change the expression of genes related to inflammatory response and other factors. Studies on obese individuals have shown that patient compliance was greater for IF than other traditional nutritional approaches (calorie restriction), and IF was found to be associated with low oxidative stress. Recent reports suggest that IF exerts a positive impact on the metabolic derangements commonly associated with cardiovascular diseases... Results from these and other studies on similar populations have shown improvements in the lipid profile, with higher HDL-cholesterol levels in women and lower triglyceride levels in men, and increased muscular expression of Sirt 1 (40) -a gene involved with the regulation of food intake, fat metabolism, cell differentiation, apoptosis, and prevention of aging...

 

"The authors also found that IF causes oscillation of triglyceride metabolism between anabolism (gluconeogenesis and de novo lipogenesis) and catabolism (lipolysis). The same group later reported that female C57BL/6J mice subjected to four-week IF showed significantly reduced visceral fat percentage, increased subcutaneous fat percentage, increased plasma adiponectin levels, and unchanged amount of fat tissue."

 

 

Regarding pre/pro biotics:

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.

 We already know there is a pathway between cold exposure and the microbiome, so its not a great leap to think that modifications you make to your gut biome could have an impact on BAT activity.  Mike Lustgarten wrote an article I'll paraphrase from:  Butyrate stimulates expression of fibroblast growth factor 21 (Liet al. 2012), whose overexpression extends both average and maximal lifespan in mice (Zhang et al. 2012).  Data suggest that increasing gut bacterial species that produce butyrate may be important for increasing lifespan in both lower organisms and, in mammals. How can we boost butyrate-producing bacteria? Prebiotics, food ingredients that stimulate the growth and/or activity of bacteria in the digestive system may be the best option. Two such food components are inulin and fructooligosaccharides (FOS), which in vitro, stimulate growth of the butyrate producers F. prausnitziiE.rectaleE. hallii and R. intestinalis 4-15 fold above basal levels (Scott et al. 2014). In vivo, consumption of 10g/day of inulin for 16 days in healthy, middle aged humans (BMI 25 kg*m-2, avg. age 38) significantly stimulated growth of F. prausnitzii (Ramirez-Farias et al. 2009). Therefore, consumption of foods rich in inulin and FOS may be a valid strategy for boosting levels of butyrate-producing bacteria in our intestines.

Foods containing inulin and fructoligosaccharides:

fos-inulin.png

(Probably best to get it from real foods, but that supplement I take is likely a good alternative, you will know for sure its feeding some bacteria when you start taking it due to the copious amounts of gas, haha.  The supplement is inexpensive, but I also eat plenty of dandelion's from my organic lawn  :unsure: plus onions daily)

 
Edited by Gordo

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Interesting that Longo goofed apparently on that reference, but perhaps he is correct about that idea and just gave the wrong ref by mistake? Running low on time tonight, but I did a quick google scholar search for "time restricted feeding" combined with "brown adipose tissue" and this was the first hit:

 

http://www.sciencedirect.com/science/article/pii/S1550413112001891

 

Seems to discuss in TRF high-fat fed mice, they expend more BAT energy and are protected against obesity.

 

There may be some other interesting studies in that google scholar search... I have a feeling that the whole circadian angle "should" tie into BAT, just because animals naturally evolved to modify their body temp in a rhythmic fashion each day, which I expect would often be driven in part by BAT. I remember seeing that "bat waking up" video on youtube... So if TRF tends to enhance/strengthen the body's circadian systems then you might expect it to also strengthen BAT activity?

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Time Restricted Feeding Boosts BAT UCP1 Expression and Energy Metabolism

BrianA,

Great find! I can't believe I missed this paper [1]. I swear I did a search for "Time restricted feed" AND "brown adipose tissue", but apparently I missed it. Thanks for spotting it. It's a real goldmine. In fact it is interesting enough to deserve a title, detailed analysis, and an update to the master list of BAT activity & thermogenesis inducers.

First off, what they did was divide mice into four groups based on diet, Normal (13% of calorie from fat) chow who had continuous Ad lib access to food (NA), Normal chow fed in a Time restricted window (8h during the dark period) (NT) , high Fat chow (61% of calories from fat) fed continuously and Ad lib (FA) and high Fat chow fed in an 8h Time restricted window (FT). During their 8h feeding window, the Time Restricted Feeding (TRF) mice, groups NT and FT, were allowed to eat as much as they wanted. All mice were housed 3-5 to a cage at an unspecified temperature, which was probably normal (cold for mice) lab temperature of 21-22 °C. The experiment lasted 12 weeks.

As you might imagine, the FA mice got really fat. Here is a photo of representative mice from the four groups (from the supplemental material), along with pictures of their abdominal cavity (middle row) and liver (bottom row). First thing to note is the author's labeling convention - the normal chow data is always in blue, and the high-fat diet data is always in red. The dark colors correspond to the time restricted feeding animals (think "they were fed during the dark period") and the light colors correspond to animals that were fed continuously ad lib.

r9kCDS8.png

Notice from the pictures, the NA and NT mice appear pretty similar in size, but the FA mouse looks a whole lot fatter than the FT mouse. You'll see this throughout my discussions - benefits of TRF were much more dramatic in the high-fat diet animals, relative to the normal (low-fat) chow animals.

But you can see on both diets the TRF mice (NT and FT groups) had dramatically less visceral fat that the corresponding, continuously fed mice. And notice the huge distinction in the liver between the FA and all three other groups - the FA mouse had developed a severe case of 'fatty liver'. More quantitatively, the weight trajectories of the four groups is illustrated in the leftmost graph below. As you can see, the other three groups gained weight slowly, but the high-fat ad lib mice (FA) really packed on the pounds (er, grams), topping out at nearly 50g, which is huge for mice. 

guWboce.png

But here is where things really get interesting, and surprising.

All four groups of mice ate virtually the same number of calories! The second graph above is the cumulative food consumption of the four groups over the course of the experiment, yes, measured in calories. Nor was their level of physical activity much different, although the distribution of activity across the day was different for the four groups (third graph above). It appears (from the fourth graph) that the difference was in total daily energy expenditure, as quantified by total daily oxygen consumption, with the two TRF groups expending more oxygen than their continuously-fed counterparts, with a really large difference apparent between the FT and FA mice.

In short, time restricted feeding mice ate as much as the continuously-fed AL mice and weren't more physically active, but nonetheless burned more calories over the course of the day, particularly when fed a high fat diet.

How were the TRF animals burning more calories, particularly on a high-fat diet? In part it was better metabolism of glucose by the liver, as the paper painstakingly documents, but which isn't the focus here. A large part of the metabolic improvement as a result of TRF appears to come from increased BAT thermogenesis, particularly in the high-fat (FT) group. Here are three graphs comparing the temporal variation in the three uncoupling proteins UPC[1-3] in BAT of the FA and FT groups over two days, with light and dark bars along the bottom of the graphs representing 12h light and dark periods. 

jqaKFMw.png

As you can see from the two peaks, the TRF mice fed a high fat diet had a tremendous increase in the expression of uncoupling proteins in BAT. In fact, this UCP1 peak in the BAT of the FT group was about 7x the level of UCP1 expression in the continuously-fed high-fat mice (FA group).

Notice the peak occurs during the latter portion of the dark period, which was shortly after they'd finished gobbling down there food (a graph I'll show later).  The timing of the peak corresponds to the time of day during which the FT mice were burning a lot more calories than the FA mice, as seen in this graph of temporal variations in oxygen consumption (which shows just a single day):

GwJ0f3m.png

What's really interesting is to look at the circadian variation in the BAT UCP expression of the two groups of mice feed normal chow (from the supplemental material):

POCIWeD.png

Notice than both groups show a noticeable but much more modest circadian rhythm to their BAT UCP1 expression, corresponding to a rise in UCP1 expression in the latter half of the dark period, stretching into the light period. But neither group shows the dramatic spike in UCP protein expression (and therefore, presumably thermogenesis) that the FT group did. Notice the difference in scales on the two UPC1 graphs - peak UCP1 expression in the FT group was 4x as large as any of the other groups, including the time-restricted low-fat (NT) group. Basically, TRF seems to restore and amplify the normal circadian rhythm of UCP1 expression in BAT, that is otherwise obliterated by a high-fat continuously-fed ad lib diet.

The paper documents all kinds of other improvements including better glucose control after an a glucose challenge (left graph below), lower insulin level after an overnight fast (-) or 1h after a glucose challenge (+) in the middle graph below, and much improved coordination (right graph):

c0b3Cud.png

These effects were quite dramatic - notice the glucose responses were indistinguishable between the three non-FA groups in the graph on the left, and that the FT group has a low fasting and post-glucose challenge insulin levels as the other two, normal-chow fed groups (middle graph), and most impressive of all, the FT group exhibited the best motor coordination performance of any of the four groups (right graph).

Finally, proinflammatory cytokines, including TNFα Interleukin-6 (IL6), Interleukin-1 (IL1) and CXCL2, were dramatically reduced in both NT and FT mice relative to their corresponding continuous-fed counterparts:

uWD9HWr.png

 

The rest of the paper documents in a lot more detail the positive effects TRF had on liver function, but you get the picture. 

Here are a few good quotes from the discussion section to give you a flavor of the authors' interpretation of their results:

Although it has long been assumed that the cause of adiposity associated with mouse models of diet-induced obesity is nutritional, there is an emerging suggestion that the temporal spreading of calorie intake could be contributing as well... Therefore, mice fed HFD ad lib have a short fasting period and a long feeding window. This feeding pattern perturbs metabolic pathways entrained by both circadian and feeding rhythms. The temporal disruption in cellular metabolic processes, in combination with the nutrient quality, predisposes the organism to obesity and metabolic diseases.

The TRF regimen entrained the circadian clock and metabolic regulators to fixed feeding times and prevented high-fat-diet-induced disruption of the normal cellular metabolic program... thus highlighting that both nutrient quality and the daily feeding pattern are important determinants of the liver metabolic homeostasis...

Implicit in our findings is that the control of energy metabolism is a finely tuned process that involves an intricate network of signaling pathways and transcriptional effectors, including nutrient-sensing mechanisms and the circadian system. TRF acted on these interwoven networks and moved their state toward that of a normal feeding rhythm...

Although a number of clinical studies have shown that the perturbation of light:dark or sleep:wake cycle (e.g., shiftwork) has adverse metabolic consequences in humans, there is very little information on the perturbation of eating rhythms in the participants of these studies. Hence, the contribution of frequent feeding and reduced daily fasting period to obesity, type 2 diabetes, and other adult-onset metabolic diseases is unclear. 

So it looks like you're right on several counts BrianA.

 

Time restricted feeding appears to restore a normal, natural circadian rhythm to many of the body's metabolic processes, thereby preventing obesity, metabolic syndrome, and fatty liver disease, particularly when consuming an obesogenic, high-fat diet. And a major way it helps prevent obesity and improve metabolic health is by increasing BAT activity. Here is a handy graphical abstract of these results, for anyone who does better with pictures than words:

QcImBVl.png

One final observation. As you can see from the two graphs below, the time-restricted feeding mice on both diets ate the vast majority of the food within a couple hours of onset of the dark period - the equivalent of their "morning" since they are nocturnal. So the human equivalent would be to eat the almost all of one's calories at breakfast in order to get these sorts of benefits.

f6RBBQt.png

Basically what all this data is suggesting is that you can eat a high-fat diet ad lib and not experience adverse health consequences as long as you limit your food intake to a narrow time window shortly after waking, at least if you're a mouse ☺.

In conclusion, it looks like the BAT Rule1 wins again - something many of us have long thought to be healthy (and practiced ourselves), namely eating within a narrow window of time during the day, especially in the morning, turns out to boost BAT activity as well. I'm added "Time Restricted Feeding - most calories at breakfast" to the master list below of BAT activity and thermogenesis inducers.

Thanks again BrianA!

 

--Dean

----

1BAT Rule - Virtually every dietary or lifestyle intervention that is known to be healthy is also associated with an increase in BAT activity or thermogenesis.

 

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

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
  • Time Restricted Feeding - most calories at breakfast
  • 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] Cell Metab. 2012 Jun 6;15(6):848-60. doi: 10.1016/j.cmet.2012.04.019. Epub 2012

May 17.
 
Time-restricted feeding without reducing caloric intake prevents metabolic
diseases in mice fed a high-fat diet.
 
Hatori M(1), Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M,
Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S.
 
Author information: 
(1)Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
 
 
While diet-induced obesity has been exclusively attributed to increased caloric
intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat
frequently throughout day and night, disrupting the normal feeding cycle. To test
whether obesity and metabolic diseases result from HFD or disruption of metabolic
cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a 
HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as
those with ad lib access yet are protected against obesity, hyperinsulinemia,
hepatic steatosis, and inflammation and have improved motor coordination. The tRF
regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the
circadian clock and their target genes' expression. These changes in catabolic
and anabolic pathways altered liver metabolome and improved nutrient utilization 
and energy expenditure. We demonstrate in mice that tRF regimen is a
nonpharmacological strategy against obesity and associated diseases.
 
Copyright © 2012 Elsevier Inc. All rights reserved.
 
PMCID: PMC3491655
PMID: 22608008
Edited by Michael R
http:-->https

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Dean, in regard to the Longo comments/doubts -- do you have a way to contact him about this?  It would be interesting to see how he responds.  I kind of suspect there may be something to the idea of tRF and BAT activity being connected in some way, but it would be nice to see some real data.  Perhaps he could dig it up.  Here is one reference that may indirectly support the idea (emphasis mine): 

 

 

 

 

Good idea! Dean could contact Longo, his email is on the USC page  He responded to an email that I sent him months ago

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Cloud,

 

I'm not sure if you saw my most recent post about the study BrianA dug up, but it now appears to me Longo may be right about the BAT-inducing potential of time-restricted feeding. I therefore don't feel compelled to contact him. Guys like him are really busy, and I don't want to contact him lightly since I might only get once chance. 

 

However, see this even more recent post to the Fasting thread describing my doubts about whether the benefits of TRF will translate to the kind of 5:2 intermittent fasting that Longo advocates...

 

--Dean

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Hello Dean, no I didnt' read your latest post. I can not keep up with your workload  :)xyz I want to say that I really appreciate what you do, selflessly share the results that come with your study. Others, like for example the founders of CR way, legitimately make a business of their work, but I must say that I prefer,for my character and personal philosophy of life,   an open and communitary model like here.

Edited by Cloud

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I hear you Cloud.

 

Sorry about the workload. You appear not to be alone (also here and here) in feeling a bit overwhelmed sometimes with the amount of content I generate - some of which is even interesting!

 

For you or anyone else who has trouble keeping up with my prolific posting, here are two tips.

 

For my most important (and longest) posts, I try to summarize the results in the title of the thread, or in a Bolded and Underlined Title at the top of the post - that will give you the post's sound bite. Then I try to spend the last couple paragraphs summarizing the results, and their practical implications.

 

If you are pressed for time and/or don't care about the details (and you trust my analysis...) you can read the title and the last couple paragraphs to get the gist of it, and skip the meat in the middle until later, or forever.

 

--Dean

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I did a new search today, don't know how it is that this never came up, I think it could be important (or maybe not).  Possibly a +1 for the doubters in certain respects:

 

Frequent Extreme Cold Exposure and Brown Fat and Cold-Induced Thermogenesis: A Study in a Monozygotic Twin

 

Apparently Wim Hof has a twin brother!  What better situation to study in regards to lifestyle's impact on BAT?

Unfortunately its just one study with N=1 (since its a twin study) so I'm not sure how much stock you should put in it.

 

Conclusion

No significant differences were found between the two subjects, indicating that a lifestyle with frequent exposures to extreme cold does not seem to affect BAT activity and cold induced thermogenesis (CIT). In both subjects, BAT was not higher compared to earlier observations, whereas CIT was very high, suggesting that g-Tummo like breathing during cold exposure may cause additional heat production by vigorous isometric respiratory muscle contraction. The results must be interpreted with caution given the low subject number and the fact that both participants practised the g-Tummo like breathing technique.

 

I haven't looked at the study methods.  But they do specifically mention one genetic marker associated with BAT activity.  This could imply that genetics are more important, and "training" not so much when it comes to BAT in humans.

 

However I should emphasize that even if this is true, it does not negate the potential health benefits of "using what you have" to the extent that you can.

Edited by Gordo

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Thanks Gordo!

 

Interesting study of the Iceman and his twin brother [1]. Their results (namely, no significant difference between the twins in BAT or thermogenesis, despite Wim's frequent cold exposure) fly in the face of many randomized control trials we've discussed showing cold exposure increases BAT/Beige fat volume/activity, as well as thermogenesis in humans. So I wouldn't put much stock in Wim's result. But there definitely is a genetic component to BAT & thermogenesis. Remember the "constitutionally lean" women

 

Reading through the study, both Wim and his brother appear to have a polymorphism associated with reduced UCP1 expression. The authors even say the lack of BAT upregulation by cold may be a result of this mutation. Yet both had glucose uptake in BAT comparable to young men, despite them being 52. Men their age generally have little or no Brown/Beige fat, as we've seen previously in other studies. The authors suggest their increased cold tolerance and thermogenesis upon cold exposure may be a result of their forced breathing technique, based on [2]. I'm reluctant to add that sort of breathing technique to the master list, but maybe I should...

 

You bring up a good point about genetics though. I see a bunch of papers about polymorphisms that impact BAT, UPC1 expression and thermogenesis. Now you're done it. I'm gonna have to do a deep dive into that topic. A post for another day. Stay tuned...

 

--Dean

 

-----------

[1] PLoS One. 2014 Jul 11;9(7):e101653. doi: 10.1371/journal.pone.0101653.
eCollection 2014.
 
Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a
study in a monozygotic twin.
 
Vosselman MJ(1), Vijgen GH(2), Kingma BR(1), Brans B(3), van Marken Lichtenbelt
WD(1).
 
Author information: 
(1)Department of Human Biology, School for Nutrition, Toxicology and Metabolism -
NUTRIM, Maastricht, the Netherlands. (2)Department of Surgery (G.V.), Erasmus
Medical Center, Rotterdam, the Netherlands. (3)Department of Nuclear Medicine,
Maastricht University Medical Center+, Maastricht, the Netherlands.
 
INTRODUCTION: Mild cold acclimation is known to increase brown adipose tissue
(BAT) activity and cold-induced thermogenesis (CIT) in humans. We here tested the
effect of a lifestyle with frequent exposure to extreme cold on BAT and CIT in a 
Dutch man known as 'the Iceman', who has multiple world records in withstanding
extreme cold challenges. Furthermore, his monozygotic twin brother who has a
'normal' sedentary lifestyle without extreme cold exposures was measured.
METHODS: The Iceman (subject A) and his brother (subject B) were studied during
mild cold (13°C) and thermoneutral conditions (31°C). Measurements included BAT
activity and respiratory muscle activity by [18F]FDG-PET/CT imaging and energy
expenditure through indirect calorimetry. In addition, body temperatures,
cardiovascular parameters, skin perfusion, and thermal sensation and comfort were
measured. Finally, we determined polymorphisms for uncoupling protein-1 and
β3-adrenergic receptor.
RESULTS: Subjects had comparable BAT activity (A: 1144 SUVtotal and B: 1325
SUVtotal), within the range previously observed in young adult men. They were
genotyped with the polymorphism for uncoupling protein-1 (G/G). CIT was
relatively high (A: 40.1% and B: 41.9%), but unlike during our previous cold
exposure tests in young adult men, here both subjects practiced a g-Tummo like
breathing technique, which involves vigorous respiratory muscle activity. This
was confirmed by high [18F]FDG-uptake in respiratory muscle.
CONCLUSION: No significant differences were found between the two subjects,
indicating that a lifestyle with frequent exposures to extreme cold does not seem
to affect BAT activity and CIT. In both subjects, BAT was not higher compared to 
earlier observations, whereas CIT was very high, suggesting that g-Tummo like
breathing during cold exposure may cause additional heat production by vigorous
isometric respiratory muscle contraction. The results must be interpreted with
caution given the low subject number and the fact that both participants
practised the g-Tummo like breathing technique.
 
PMCID: PMC4094425
PMID: 25014028
 
----------

[2] PLoS One. 2013;8(3):e58244. doi: 10.1371/journal.pone.0058244. Epub 2013 Mar 29.

 
Neurocognitive and somatic components of temperature increases during g-tummo
meditation: legend and reality.
 
Kozhevnikov M(1), Elliott J, Shephard J, Gramann K.
 
Author information: 
(1)Psychology Department, National University of Singapore, Singapore.
psymaria@nus.edu.sg
 
Stories of g-tummo meditators mysteriously able to dry wet sheets wrapped around 
their naked bodies during a frigid Himalayan ceremony have intrigued scholars and
laypersons alike for a century. Study 1 was conducted in remote monasteries of
eastern Tibet with expert meditators performing g-tummo practices while their
axillary temperature and electroencephalographic (EEG) activity were measured.
Study 2 was conducted with Western participants (a non-meditator control group)
instructed to use the somatic component of the g-tummo practice (vase breathing) 
without utilization of meditative visualization. Reliable increases in axillary
temperature from normal to slight or moderate fever zone (up to 38.3°C) were
observed among meditators only during the Forceful Breath type of g-tummo
meditation accompanied by increases in alpha, beta, and gamma power. The
magnitude of the temperature increases significantly correlated with the
increases in alpha power during Forceful Breath meditation. The findings indicate
that there are two factors affecting temperature increase. The first is the
somatic component which causes thermogenesis, while the second is the
neurocognitive component (meditative visualization) that aids in sustaining
temperature increases for longer periods. Without meditative visualization, both 
meditators and non-meditators were capable of using the Forceful Breath vase
breathing only for a limited time, resulting in limited temperature increases in 
the range of normal body temperature. Overall, the results suggest that specific 
aspects of the g-tummo technique might help non-meditators learn how to regulate 
their body temperature, which has implications for improving health and
regulating cognitive performance.
 
PMCID: PMC3612090
PMID: 23555572

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Fascinating analysis of that TRF paper Dean. Loved the visceral fat photos, cytokine data, even the agility testing. Here's a possibly related anecdote:

 

I typically have eaten more of a 10 - 12 hr TRF window the past several years, but coincidentally in the last 3 weeks have experimented with shrinking the eating window to 4 to 6 hrs targeted on breakfast and lunch (influenced by Gordo and Paul M's great glucose numbers). Also for the last 5 weeks have been experimenting with various forms of CE. So in the midst of this, 9 days ago I had to eat out once. Don't normally like to eat out much any more, but for this dinner I let loose and had a super high fat combo of salmon, some very buttery mashed potatoes, and an incredibly rich 1000 calorie brownie dessert. The interesting bit is that a couple hours later when back home and watching tv on the couch I couldn't help but notice a very unusual amount of warmth radiating off my body, including arms/legs. It was notable enough I wrote it down in my food log notes, and lasted at least an hour or more. Take it with a grain of salt, but it reminds me now of those FT mice UCP spike graphs.

 

I've been starting to see some interesting hints in my glucose numbers, so will stick with CE and tightened TRF to see if there are further developments. Also have been making some further dietary improvements many of which discussed here. Too many competing possible factors being changed at once in my lifestyle to say if any one thing is improving my data, but as long as the data moves in the right direction I'm not complaining...

 

Questions for anyone using the Cool Fat Burner (CFB) or other cooling vests:

 

1. Does using it without a shirt increase the intensity significantly? And is that safe for the skin? So far I've been using a t-shirt, but have noticed in past couple weeks the intensity feels subjectively less and I no longer shiver.

 

2. I find if I use it in the afternoon, a few hours after my last meal of the day, it does drop my glucose readings a bit and also makes me hungry. Does anyone else find CE to be a "hunger accelerant"? And what in general might be the most ideal time to use intense CE each day if you only have 1 set of ice packs? Better to use during the largest meal of day to help blunt glucose spikes? Or during non-meal times to perhaps achieve lower than ordinarily possible glucose readings for a few hours?

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BrianA,

 

I too have had similar experiences. Let me explain.

 

On very rare occasions I eat dinner out, usually with my wife and daughter. When I do I don't usually eat very much, or very crappy stuff. But even eating light and healthy, whenever I eat in the evening I inevitably experience being very warm in bed for several hours after retiring for the night. I normally sleep without covers in a cool room with a tabletop fan blowing lightly on me. On nights that I eat I find myself having to turn the fan up to high in order to avoid being uncomfortably hot. After eating in the evening I also always see the next morning that my overnight resting heart rate was elevated by a 2-3 beats per minute as reported by my FitBit.

 

I take these as pretty good indicators that I've increased my thermogenic capacity via cold exposure and all the other practices I engage in. 

 

Regarding timing of cold vest usage. I generally wear mine for most of the afternoon, with a t-shirt and going through two sets of cold packs. I think it would probably be better to do it in the morning starting immediately after I eat, but I'm generally exercising then, and it isn't convenient. Wearing the vest without a t-shirt would likely increase the intensity marginally, but also risks skin damage. I actually haven't tried it. My t-shirt generally gets damp from the condensation of the ice packs, so I'm not sure it serves as much of an insulator.

 

Speaking of exercise and heat conductance, I've started swimming again, which is a great way to boost BAT, particularly if the water is cool (like my community swimming pool) because water conducts heat so well. I've been swimming 1/2 mile per day about 1.5 hours after I finish eating during the lap swim period that my pool is open prior to public access. I follow up my swim with a cold shower and I blast the A/C in the car on my short drive home.  Feels very refreshing and really gets the blood and the thermogenesis pumping!

 

--Dean

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That's interesting that you can sleep well without covers - I can do it, but need PJ's or long-sleeve shirt to cover the skin not to be "distracted" by the air brownian motion up against the skin even if there is no fan blowing and the temperature is fine. If you do wear a PJ top, given all the research you do optimizing your CE regimen, what do you use?

 

Also, ( sorry if I missed it ) what temperature overnight?

Edited by Mechanism

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Mechanism,

 

Sleeping without covers or bedclothes definitely take some getting used to, but I've adapted over time. Regarding bedroom temperature, it varies somewhat with outdoor temperature, but generally 68-70 degF.

 

--Dean

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I suspect most everyone will have seen it, but in case you missed it, I made a new, rather provocative post over on the Will Serious CR Beat a Healthy, Obesity-Avoiding Diet and Lifestyle thread which analyzes a new study (PMID 27304509) that further calls into question the wisdom of serious CR. 

 

Here is a short summary of my interpretation of the mouse part of that paper (they also did experiments with yeast and worms). They tested 20% and 40% CR in male and females from two commonly employed strains of laboratory mice, by gradually introducing CR when the mice were the human equivalent of about 30 years old. The mouse were housed at a cool-for-mice temperature of 20-22 °C.

 

The result will be pretty surprising for some, and hopefully stir conversation over there. In no combination of sex or strain did the CR40 mice live significantly longer than the CR20 mice. On the contrary, in several instances the CR20 mice lived longer than both ad lib and CR40 mice.

 

In the post I discuss several explanations for that startling (for some) result, the most relevant of which for this thread is the following: From measurements of rectal temperatures of the different CR groups, it appears the groups which had the highest rectal temperature, and therefore likely engaged in the most thermogenesis, lived the longest. The group that lived the longest (20% CR females from the C57BL/6J strain) had the highest rectal temperature. All the CR40 groups had lower rectal temperature than the corresponding CR20 group except for one (DBA/2J males), and that was the one group were it looked like CR40 may have had tiny (non-significant) advantage in max (but not mean) lifespan.

 

Another piece of evidence in favor of an explanation involving thermogenesis for these results was the fact that the longest lived groups also had the highest circulating adiponectin level, which is associated with both cold exposure and longevity, as we've discussed earlier in this thread.

 

In short, one hypothesis that explains the data from that study is the one I've been suggesting here all along - namely that modest (net) CR + cold exposure to induce extra thermogenesis is better for promoting health and longevity than more severe CR without (much) thermogenesis. Unfortunately, the researchers didn't measure BAT volume, BAT activity, UPC1 expression or even metabolic rate, so it's impossible from the data available to validate or disprove that thermogenesis was the determining factor for the longevity differences in the CR mice in this study.

 

As you might imagine, this hypothesis is likely to receive some criticism, which I welcome, especially if constructive. I give several other possible explanations too (as do the authors). It's a really interesting study which I suggest people interested in CE (and CR) read about. And if you do, please post a response over there - you can hear a pin drop on that thread right now!

 

--Dean

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More on the Relationship between FGF21, Cold Exposure, and BAT

 

We've discussed the relationship between Cold Exposure, BAT and Fibroblast Growth Factor 21 (FGF21) before, in most detail here, along with here and here. Among other goodies, those posts document that elevated FGF21 is:

  • is associated with extended mouse lifespan along with an increase food consumption (PMID 23066506).
  • is associated lower insulin & IGF-1, and better glucose control.
  • is not increased by CR, and only increases after 6-10 days of water only fasting in humans.
  • is increased by cold exposure in rodents and humans.
  • is associated with increased core temperature during cold exposure.

This new review paper [1] adds quite a few new and interesting insights to my understanding of FGF21 in general, and it's relation to BAT and cold exposure.

 

First, here are a few interesting facts about FGF21 I learned from [1] which aren't (directly) related to BAT or thermogenesis. See the full text for references:

  • One of its primary roles is in glucose and lipid metabolism.
  • It is synthesised in the liver, WAT, BAT, skeletal muscle, heart and pancreatic β-cells.
  • FGF21 (some of which is synthesized in the liver) signals the hypothalamus in the brain to tell the liver to synthesize glucose from protein and/or fat (gluconeogenesis) via the so-called "liver-brain" axis. How convoluted is that!?
  • Fructose ingestion increases circulating FGF21 levels in humans. Yeah fruit!
  • FGF21 looks like it's upregulated by protein restriction rather than calorie restriction.
  • Methionine restriction in mice showed higher FGF21 expression in liver, lower fat mass and better insulin sensitivity.
  • FGF21 increases the burning of fats/triglycerides (lipolysis) in skeletal muscles and BAT.
  • FGF21 protects against oxidative stress, lipotoxicity and glucotoxicity to reduce cell dysfunction and apoptosis.
  • Exogenous FGF21 protects against insulin resistance induced by a high-fat, high-carb diet in mice and monkeys by increasing glucose and lipid metabolism.
  • Exogenous FGF21 has been shown to elevate that other good guy, adiponectin, in rodents and monkeys, but not visa versa.
  • Intravenous administration of two different FGF21-analogs in two different studies of diabetic humans were shown to improve glucose metabolism, lipid profile and induce weight loss.
Now here are some things about FGF21 interaction with BAT & thermogenesis that I learned from [1] (again, see full text for references):
  • FGF21 (both native & exogenous) protects against weight gain by increasing BAT activity and WAT browning rather than reducing calorie intake or physical activity.
  • BAT and FGF21 appear to be in a reciprocal relationship. Circulating FGF21 increases BAT activity, and BAT in turn synthesizes FGF21, apparently in proportion to UCP1 level in mitochondria.
  • It appears FGF21 also promotes the browning of white fat, particularly subcutaneous white fat.
  • But cold is important for FGF21 to turn WAT to brown fat: "significant browning of WAT by FGF21 is temperature dependent, present only in a cold (21 °C) environment [ref]. Under 30 °C temperature, mice also reduce weight and improve glucose metabolism after FGF21-analog treatment but without increasing BAT and UCP1 expression, suggesting other mechanisms different to UCP1 for energy expenditure induced by FGF21 [ref]".
  • Here is more about the BAT ⇄ FGF21 positive feedback loop I alluded to above: "FGF21 induction of PGC-1-α exerts strong effect on “browning” of WAT [refs]. Then, this “new” BAT becomes the target of FGF21 and also a site of FGF21 synthesis and secretion [refs].
  • Here is an interesting prolongevity pathway the paper mentions: 
    FGF21 → ↑ hypothalamic norepinephrine release → ↑ BAT thermogenesis → ↑ SIRT1 & AMPK expression

Here is a schematic diagram based on insight gathered from [1] depicting the feedback loops between WAT, BAT and Beige Fat triggered as a result of cold exposure:

 

EewXq1t.png

 

As you can see, cold exposure induces BAT activity, which not only generates heat by burning glucose and fats via UCP1 but also releases FGF21. The FGF21 causes WAT to synthesize health-promoting adiponectin, as well as undergo "browning" to become beige fat by synthesizing more mitochondria and UCP1, which in turn generates more heat, and more FGF21 in a positive feedback loop.

 

Note that white fat, especially subcutaneous white fat is required in order for this beneficial cold-induced feedback loop to occur. This may explain why super-skinny CR rodents and (quite possibly) people:

  1. Have trouble staying warm
  2. Can become glucose intolerant - e.g. Fontana human CR study PMID 19904628
  3. Don't benefit as much or as consistently from CR (e.g. PMID 27304509 discussed here yesterday). In particular, it's been observed several times by several research groups that the rodents that benefit the most from CR are the ones that maintain the most fat mass and have the highest metabolic rate, as discussed in that post yesterday. 

In short, when practicing CR, it doesn't pay to get too skinny, or to avoid the cold.

 

--Dean

 

P.S. I went through my occasional routine of backing up this thread to a PDF on Dropbox, and happened to notice this thread has now grown to 550 pages!

 

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

[1] Horm Mol Biol Clin Investig. 2016 Jun 20. pii: doi: 10.1515/hmbci-2016-0023. [Epub ahead of print]

 
Modulation of energy balance by fibroblast growth factor 21.
 
Cuevas-Ramos D, Aguilar-Salinas CA.
 

Full text: http://sci-hub.cc/10.1515/hmbci-2016-0023

 
Fibroblast growth factors (FGFs) are a superfamily of 22 proteins related to cell
proliferation and tissue repair after injury. A subgroup of three proteins,
FGF19, FGF21, and FGF23, are major endocrine mediators. These three FGFs have low
affinity to heparin sulfate during receptor binding; in contrast they have a
strong interaction with the cofactor Klotho/β-Klotho. FGF21 has received
particular attention because of its key role in carbohydrate, lipids, and energy 
balance regulation. FGF21 improves glucose and lipids metabolism as well as
increasing energy expenditure in animal models and humans. Conditions that induce
human physical stress such as exercise, lactation, obesity, insulin resistance,
and type 2 diabetes influence FGF21 circulating levels. FGF21 also has an
anti-oxidant function in human metabolic diseases which contribute to
understanding the FGF21 compensatory increment in obesity, the metabolic
syndrome, and type 2 diabetes. Interestingly, energy expenditure and weight loss 
is induced by FGF21. The mechanism involved is through "browning" of white
adipose tissue, increasing brown adipose tissue activity and heat production.
Therefore, clinical evaluation of therapeutic action of exogenous FGF21
administration is warranted, particularly to treat diabetes and obesity.
 

PMID: 27318658

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Very impressive Dean. Thank you for your ongoing posts. Many of us who do not necessarily comment / contribute to this thread regularly continue to follow the updates with interest. The process, irregardless of the eventual conclusions, is a microcosm of science: unraveling a mystery one data point at a time.

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Hi Dean, aside from the theory, do you have a procedure based on your experience (cold exposure for dummies may I say ?) on how to increase cold exposure gradually without getting sick and how to measure the improvements (glucometer ? thermometer ?). And how to handle the experience with a family that is not willing to take part of your experience (i have read about the cooling vest)

 

I have tried for example for one day to stay at home shirtless during my sleep but I did catch a light cold.
 

Feel free to redirect me to another topic if my question is not relevant. Also If I am asking too much, feel free to tell me to go to hell :D
 

ps: sorry in advance if my writings contain some english mistakes but it is not my mother language

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Dean (or anyone), interested in any thoughts on how to "balance" CR vs CE, in terms of maintaining a "good amount" of subcutaneous fat while at same time increasing CE results in more calories being burned for heat. Just eat as many extra calories as required, while maybe periodically testing IGF-1 and other lab data to try and hold on to CR benefits?

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BrianA,

 

Gordo has put together a great overview and beginner's guide to cold exposure over on the cold exposure thread he started at Longecity.com. It has some great tips on how to get started, as well as a really good summary of the science. Thanks Gordo!

 

Some of those tips include:

  • drinking ice water,
  • taking cold showers,
  • sleeping in a cool room w/o bedclothes/covers,
  • wearing a cooling vest,
  • Employing fans and/or car & home air conditioners.
     

Regarding markers of effective cold exposure practice, here are a few:

  • Increased subjective cold tolerance - not suffering when exposed to cold
  • Increased objective cold tolerance - Absence of shivering in response to cold
  • A localized or body-wide feelings of warmth when exposed to cold or after a meal. This can be body-wide or a localized feeling of warmth/tingling, particularly in upper back, chest and/and legs
  • Improved fasting and post-prandial glucose levels
  • Increased resting heart rate

 

Regarding the right CR vs. CE balance - that's anyone's guess.

 

On one extreme are Sthira and Kenton, trying to hue more to the CR side of the equation (it seems to me). Then there is me who pushes the other way - eating a lot (once a day) and staying thin through CE & lots of exercise. Gordo probably tries the most to take a middle ground between CR and CE. But it's anyone's guess what the best point to be at is.  That's why, as you point out, blood tests are important to see what results you are getting, and to make sure you are maintaining a healthy and hopefully longevity-promoting, metabolic state. 

 

--Dean

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

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]

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

 

 

Regarding Zusanli -acupuncture point: From today I have more free time from work and I restarted to practise moxa on zusanli points.Moxa  is cheap and can be practiced by non-medical people also.

Zusanli point is an important point in Chinese medicine, it is considered a point promoting health and longevity. I practise moxa on zusanli for about half an hour, usually while reading some book. (the only risk is if you are distracted -or fall asleep! :) and burn skin  )

If someone need more details can ask me. I use some moxa stick like this.  A good book is this.

As easier alternative to the use of moxa or acupuncture, you can simply massage zusanli point.(example) Sometime at the end of my taiji classes I propose a brief automassage session finishing beating with fists on zusanli points.

 

Always on the side of Chinese medicine, I have also just found this article: "Berberine activates thermogenesis in white and brown adipose tissue"  PMID 25423280

I haven't find cited berberine in the Dean's listmaybe deserve to be inserted?

Berberine is contained in Berberis vulgaris , I used to put some barberries in my almond's milk at breakfast.

 

 

 

Edited by Cloud

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BioRestorative Therapies, Inc. ("BRT" or "the Company") (BRTX), a life sciences company focused on stem cell-based therapies, today announced that promising data has been developed on the transplantation of human stem cell-derived tissue engineered brown fat into an encapsulation device to be used as a cell delivery system for the Company’s metabolic platform program for the treatment of type 2 diabetes, obesity, hyperlipidemia and hypertension. This advancement may lead to successful transplantation of brown fat in humans.

 

The Company’s study entitled, “In Vitro Evaluation of an Encapsulation System for the Transplantation of a Human Stem Cell-Derived Tissue Engineered Brown Fat” has been accepted for presentation at the upcoming International Society for Cellular Therapy (ISCT) Annual Meeting (Singapore, May 25 – 28, 2016). The study showed how brown adipose-derived stem cells, that were differentiated step-wise to functional 3D brown adipocyte constructs, were loaded into an encapsulation device designed to be used as a cell-based therapeutic for treating metabolic disorders. These cells appear to display high viability and they differentiated into metabolically active brown adipocytes as shown by UCP-1 expression.

 

[MR: Red flag here: while still frustratingly common practice, we've learned very clearly over the years that it's highly unreliable to assume that a given cell type has been differentiated out of stem cells based on a single or even a standard panel of expressed genes or cell-surface markers — let alone that said differentiation is stable, or that the cells behave functionally like native cells, or can integrate into local tissue and regenerate its structure. The former is a very significant caveat; OTOH, it is clearly not the goal to actually have these cells integrate with native brown adipose tissue, since they are doing  cell encapsulation. The idea will be instead to create an implant that can be, er, implanted at some convenient site in the body where they can hook it up with the circulation (either blood or possibly just plasma) let blood sugar and other metabolites diffuse into the construct, where the machinery of the encapsulated brown fat will sense the need to activate, triggering thermogenesis and doing all the wonderful things that native brown fat does to bring down blood glucose and regulate metabolism].

 

... BRT is evaluating the next generation of brown adipose tissue constructs that will first be tested in small animal models. No assurance can be given that this delivery system will be effective in vivo in animals or humans. ...

 

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders: [...]

 

• Metabolic Program (ThermoStem®): We are developing a cell-based therapy to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (“BAT”). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in the body may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

 

http://www.biorestorative.com/content/biorestorative-therapies-announces-promising-data-advance-its-program-treatment-metabolic

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Berberine Increases White and Brown Fat Thermogenesis via Upregulating AMPK (with Some Qualifications)

 

Cloud,

 

Always on the side of Chinese medicine, I have also just found this article: "Berberine activates thermogenesis in white and brown adipose tissue"  PMID 25423280

I haven't find cited berberine in the Dean's listmaybe deserve to be inserted?

Berberine is contained in Berberis vulgaris , I used to put some barberries in my almond's milk at breakfast.

 

Fascinating! You're right - I hadn't seen that paper [1] about berberine (BBN) and thermogenesis.

 

I'd heard of Berberine before of course, and knew it was an herbal treatment for diabetes. Here is a good blog post from Authority Nutrition (who I'm always a bit skeptical about, but he provides copious references) on Berberine and particularly its effects on glucose and weight control. I didn't follow all of the references but it appears berberine in the appropriate dosage can improve glucose regulation in people as well as some common diabetes drugs like metformin.

 

One of the studies he cites [2], confirms what your study [1] found - namely that berberine upregulates expression of AMP-activated Kinase (AMPK). It's well known that AMPK boosts BAT activity and the browning of white fat (see here, here and here), so it makes sense: If berberine can indeed boost AMPK then it should boost thermogenesis in both brown and white adipose tissue, and improve glucose metabolism and insulin sensitivity via the same set of pathways I illustrated a couple days ago, reproduced here:

 

EewXq1t.png

 

 

Here are a few of the graphs from [1] showing just how effective berberine is when it comes to upregulating thermogenesis, at least in obesity-prone Ob/Ob mice.

 

First, a little background on the method of [1]. They employed Ob/Ob mice fed ad lib and treated intravenously with BBN for four weeks while housed at normal (cool-for-mice) lab temperature (22 °C).

 

The BBN-treated Ob/Ob mice ate somewhat less food and so were presumably less subjectively hungry, but had slightly higher levels of Michael's so-called hunger hormone, NPY. So much for the old hunger hypothesis via NPY theory, once again...

 

6XOxCiC.png

 

The BBN-treated mice weighed less (a), and has much lower fat mass (b), serum free fatty acids ©, better glucose response to a glucose challenge (d, e) using less insulin (f), increased insulin sensitivity (g) and a significantly higher body temperature (h) - indicative of thermogenesis:

 

YaAgcu8.png

 

Quite dramatic results - no wonder berberine appears to be a pretty effective treatment for diabetes in humans too.

 

How did BBN work its magic? Via upregulated oxygen consumption (b, d) as a result of increased heat production (f) rather than physical activity, via a ~5x increase in BAT activity (i). As a result, the BBN mice were able to better maintain their body temperature when subjected to a 4°C cold-challenge (g):

 

mQi5piP.png

 

Activity wasn't increased in the BBN mice (data not shown), and their respiratory exchange ratio reflected that the BBN mice were burning more fat. A bunch of thermogenic genes were upregulated in BAT, including a 2x increase in UCP1 expression. BBN also resulted in the browning of white fat. The subcutaneous fat deposit called inguinal white adipose tissue (iWAT) saw a bunch of thermogenic genes upregulated by a factor of 2-3, including UCP1 (3x increase) - graphs not shown. Interestingly, this white fat browning effect of BBN was not observed in visceral epididymal WAT (eWAT). As discussed above, the authors show that this upregulation of BAT and browning of iWAT was orchestrated by an increase in AMPK expression in the various fat tissues that BBN affected, but not in the hypothalamus. 

 

Very interestingly, thermoneutral housing temperatures (30 °C) blocked the increase in BAT activity and UCP1 expression in both BAT and iWAT, thereby dramatically blunting, and in some instances entirely eliminating, the beneficial metabolic effects of BBN.  In particular, thermoneutral housing dramatically blunted the benefits of BBN on weight management (a vs b), average skin temperature over BAT (d vs. e), cold-challenge response (f vs g), 24h oxygen consumption (h vs. i), and UCP-1 expression in BAT (k) and iWAT (l):

 

 

51m45CT.png

 

So it looks like BBN alone, in the absence of cold exposure, won't do you much if any good for promoting BAT or thermogenesis. This is a very important observation, and something we've seen a lot with many of these thermogenesis inducers (e.g. capsaicin). 

 

But before we all go out and buy berberine supplements to boost the effectiveness of our cold exposure practice, there are two things to keep in mind about [1]. First, it was a study in genetically messed up, obesity-prone Ob/Ob mice. Second, the berberine was injected into the mice, rather than taken orally. Both of these facts obviously undermine the relevance of this study to humans (ignoring the whole rodent-to-human translation thing...).

 

Fortunately, study [2] (actually a much older study) addresses both these concerns. First, [2] replicated many of the same findings as [1] with Ob/Ob mice (actually vis versa, given the dates of the two studies...). Like [1], study [2] also tested Ob/Ob mice fed ad lib and treated intravenously with BBN for four weeks while housed at normal (cool-for-mice) lab temperature (21 °C). The Ob/Ob mice in [2] treated with berberine (BBR) ate as much (unlike in [1]), but weighed dramatically less than the control mice, as seen in [1]. For what it's worth as an indicator of hunger (probably very little as we saw yesterday ☺), the BBN mice also had the same level of NPY mRNA as the controls:

 

ofpIal9.png

 

Interestingly though, while study [1] only tested obesity-prone Ob/Ob mice, [2] also tested intravenous BBN on normal (wild-type - WT) mice.  They found that BBN injections only benefited fasting glucose and glucose clearance in the obesity-prone Ob/Ob mice, not normal-weight, wild-type mice:

 

jYrNc35.png

 

 

So that largely seems to hose the idea that we skinny folks who already have good glucose control will benefit from BBN, even if injected ☹.

 

In the second experiment in [2], they tested another model of diabetes - namely rats fed a high-fat diet, this time using oral BBN delivery. They also did the same oral delivery of BBN in rats fed normal rodent chow (CH). What they found was interesting. Oral BBN reduced weight gain © without reducing food intake (D) in either normal chow (CH) or high fat (HF) fed rats. However oral BBN only improved serum triglycerides (E) or insulin sensitivity (F) in the rats fed the high fat, obesity-inducing diet.

 

c6e0nSt.png

 

So it looks like BBN may have metabolic benefits if taken orally too, but perhaps only to a significant degree when eating an obesity-inducing high-fat diet.

 

In conclusion, it looks like berberine:

  • Increases BAT, white fat browning, and thermogenesis if injected into genetically obesity- and diabetes-prone Ob/Ob mice.
  • But may not have the same effect if injected into normal mice.
  • Does have similar positive effects on metabolic health if given orally to rats on an obesogenic, high-fat diet.
  • But may not work so well in rats fed a normal, lower-fat diet.
  • Only has benefits in the above conditions if combined with cold exposure.

 

So I'm going to add berberine to the list of BAT / thermogenesis inducers, but obvious some caveats are in order. It's cool to see how beneficial thermogenesis can be for combating obesity & diabetes, whether induced by cold exposure, or in this case, by berberine + cold exposure. But I personally don't plan to use berberine to boost my thermogenesis.

 

Thanks again for the nice study Cloud!

 

--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, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana
  • Time Restricted Feeding - most calories at breakfast
  • 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] Nat Commun. 2014 Nov 25;5:5493. doi: 10.1038/ncomms6493.

Berberine activates thermogenesis in white and brown adipose tissue.

Zhang Z(1), Zhang H(1), Li B(1), Meng X(2), Wang J(1), Zhang Y(1), Yao S(1), Ma
Q(1), Jin L(1), Yang J(1), Wang W(1), Ning G(1).

Author information:
(1)Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical
Center for Endocrine and Metabolic Diseases, China.

 

Free full text: http://www.nature.com/ncomms/2014/141125/ncomms6493/full/ncomms6493.html

Obesity develops when energy intake exceeds energy expenditure. Promoting brown
adipose tissue formation and function increases energy expenditure and hence may
counteract obesity. Berberine (BBR) is a compound derived from the Chinese
medicinal plant Coptis chinensis. Here we show that BBR increases energy
expenditure, limits weight gain, improves cold tolerance and enhances brown
adipose tissue (BAT) activity in obese db/db mice. BBR markedly induces the
development of brown-like adipocytes in inguinal, but not epididymal adipose
depots. BBR also increases expression of UCP1 and other thermogenic genes in
white and BAT and primary adipocytes via a mechanism involving AMPK and PGC-1α.
BBR treatment also inhibits AMPK activity in the hypothalamus, but genetic
activation of AMPK in the ventromedial nucleus of the hypothalamus does not
prevent BBR-induced weight loss and activation of the thermogenic programme. Our
findings establish a role for BBR in regulating organismal energy balance, which
may have potential therapeutic implications for the treatment of obesity.

PMID: 25423280

 

--------

[2] Diabetes. 2006 Aug;55(8):2256-64.

 
Berberine, a natural plant product, activates AMP-activated protein kinase with
beneficial metabolic effects in diabetic and insulin-resistant states.
 
Lee YS(1), Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT,
Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB.
 
Author information: 
(1)Department of Biological Sciences, Seoul National University, San 56-1,
Sillim-Dong, Kwanak-Gu, Korea.
 
Berberine has been shown to have antidiabetic properties, although its mode of
action is not known. Here, we have investigated the metabolic effects of
berberine in two animal models of insulin resistance and in insulin-responsive
cell lines. Berberine reduced body weight and caused a significant improvement in
glucose tolerance without altering food intake in db/db mice. Similarly,
berberine reduced body weight and plasma triglycerides and improved insulin
action in high-fat-fed Wistar rats. Berberine downregulated the expression of
genes involved in lipogenesis and upregulated those involved in energy
expenditure in adipose tissue and muscle. Berberine treatment resulted in
increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and
L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 
3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1
adipocytes. These findings suggest that berberine displays beneficial effects in 
the treatment of diabetes and obesity at least in part via stimulation of AMPK
activity.
 
PMID: 16873688
 

As discussed above, these effects seem to have been brought about by an increase in AMPK expression in the fat tissues BBN affected, but not in the hypothalamus. 

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Michael,

 

BioRestorative Therapies, Inc. ("BRT" or "the Company") (BRTX), a life sciences company focused on stem cell-based therapies, today announced that promising data has been developed on the transplantation of human stem cell-derived tissue engineered brown fat into an encapsulation device to be used as a cell delivery system for the Company’s metabolic platform program for the treatment of type 2 diabetes, obesity, hyperlipidemia and hypertension. This advancement may lead to successful transplantation of brown fat in humans.
 ...

 

Thanks! Now there's a method for increasing BAT I hadn't thought of - brown fat tissue implants! It seems like a much better way to treat obesity than AspireAssist,  the new external stomach drainage system recently approved by the FDA. That reminds me way too much of bulimia!

 

[MR: ... we've learned very clearly over the years that it's highly unreliable to assume that a given cell type has been differentiated out of stem cells based on a single or even a standard panel of expressed genes or cell-surface markers — let alone that said differentiation is stable, or that the cells behave functionally like native cells, or can integrate into local tissue and regenerate its structure. The former is a very significant caveat; OTOH, it is clearly not the goal to actually have these cells integrate with native brown adipose tissue, since they are doing  cell encapsulation. The idea will be instead to create an implant that can be, er, implanted at some convenient site in the body where they can hook it up with the circulation (either blood or possibly just plasma) let blood sugar and other metabolites diffuse into the construct, where the machinery of the encapsulated brown fat will sense the need to activate, triggering thermogenesis and doing all the wonderful things that native brown fat does to bring down blood glucose and regulate metabolism].

 

Very interesting. Hopefully this sort of encapsulated delivery of the stem-cell-derived BAT would avoid the problems others have seen as a result of stem cell tourism - i..e. traveling to another country to get stem cells injected only to see them later turn cancerous. 

 

When it becomes available and is demonstrated to be reasonably safe and effective, I'll definitely add it to the list of BAT and thermogenesis inducers!

 

--Dean

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