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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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A recent deluge of new hits for "brown adipose" have turned up on google scholar.  The ones of interest to me include:

 

1) An additional drug/herb might be added to Dean's list of BAT activators, called Bofutsushosan.

 

2) These scientists are using a DNA Virus to boost BAT activity in mice.

 

3) Not really new to us, but a new study finds that a metformin-induced increase of lipid and glucose utilization in BAT may participate in the mechanism of improving metabolic syndrome and related disorders.

 

4) Possibly the most interesting of the bunch to me, a new patent application has been filed called Methods and Devices for Activating Brown Adipose Tissue Using Electrical Energy  "Methods and devices are provided for activating brown adipose tissue (BAT) using electrical energy. In general, the methods and devices can facilitate activation of BAT to increase thermogenesis. The BAT can be activated by applying an electrical signal thereto that can be configured to target sympathetic nerves that can directly innervate the BAT. The electrical signal can be configured to target the sympathetic nerves using fiber diameter selectivity. In other words, the electrical signal can be configured to activate nerve fibers having a first diameter without activating nerve fibers having diameters different than the first diameter. Sympathetic nerves include postganglionic unmyelinated, small diameter fibers, while parasympathetic nerves that can directly innervate BAT include preganglionic myelinated, larger diameter fibers. The electrical signal can be configured to target and activate the postganglionic unmyelinated, small diameter fibers without activating the preganglionic myelinated, larger diameter fibers."

 

5) Two hits related to new ways of imaging BAT:  Certain curcumin analogs can be used to non-invasively image BAT in vivo (patent application).   AND  Measuring Supraclavicular Skin Temperature for the Detection of Brown Adipose Tissue in Adult Humans using Infrared Thermography

 

6) New study looks at the role of leptin on BAT:  The physiological effect of leptin to reduce thermal conductance contributes to maintenance of core body temperature under sub-thermoneutral conditions.

 

7) New study looks at diet induced thermogenesis (DIT) in particular, and how it relates to BAT.  No surprise, but DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism.

 

8) I think we've only touched the surface on this topic, and we should discuss it more.  Some of the early CE pioneers talk about hot to cold transittions but thus far I dont' remember seeing much data about this.  A new study seems to provide evidence of increased BAT activity when going from hot to cold vs. room temp to cold.  This could potentially change the way some of us practice CE.  I would love to see more research along these lines.  "Conclusion: Acclimation at 32ºC produces a greater and earlier response to cold in the supraclavicular area than room temperature acclimation. The thermal response after 32ºC acclimation is reproducible and unlikely to be affected by outdoor temperature and subcutaneous fat in the neck. These data suggest that the use of infrared thermography using the 32ºC-cold protocol may be effective for detecting the metabolic activity of brown adipose tissue."  Also note that these guys induced BAT activity using only mild cooling of the torso with cooling blankets.

 
9) I'm including this one only as a joke.  Apparently nitrous oxide should NOT be added to Dean's list of BAT activators.  That's a real shame because further experimentation could have been fun!   :rolleyes:
 
Regards,
Gordo

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Gordo,

 

Thanks for the update on new BAT studies. I've got a few new ones of my own to catch up with posting about, but the largely don't overlap with yours. It's amazing how much interest there is these days in brown / beige fat, most for weight loss and metabolic health benefits. A few brief comments on the links you posted.

 

1) An additional drug/herb might be added to Dean's list of BAT activators, called Bofutsushosan.

 

Actually, it's a cocktail of several drugs. From the abstract:

 

 Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries.

 

Such a potpourri of "crude drugs", many without much research to back them up or check for side effects, would make me very nervous. I don't think it wise to add it to the master list, despite it's apparent efficacy for boosting brown and beige fat in mice fed a high fat diet.

 

3) Not really new to us, but a new study finds that a metformin-induced increase of lipid and glucose utilization in BAT may participate in the mechanism of improving metabolic syndrome and related disorders.

 
This appears to be the abstract for an oral presentation (probably not peer reviewed) at the European Atherosclerosis Society (EAS) annual meeting. It is a study of rats fed a high fat diet for 4 weeks either alone or supplemented with metformin. There doesn't appear to be a paper written up for it, but here are the slides from the presentation. It basically found that metformin upregulates fatty acid and glucose metabolism in BAT and possibly WAT as well. It also reduced serum triglycerides, fasting insulin, and C-reactive protein, while boosting adiponectin. As you indicate, this backs up other research (discussed here) that metformin upregulates BAT and thermogenesis. So metformin remains on the list of BAT activators.
 

4) Possibly the most interesting of the bunch to me, a new patent application has been filed called Methods and Devices for Activating Brown Adipose Tissue Using Electrical Energy...

 

That one does look interesting. Unfortunately I couldn't find any published papers by the inventors or (almost) anyone else to show BAT can be simulated with electrical stimulation of the skin. Plenty of papers showing electrical stimulation of the hypothalamus will increase BAT activity, but brain surgery is not really an option for most of us ☺. I did find one paper (PMID 23995053) which found electrical stimulation to the skin of rats above interscapular BAT increased the skin temperature of the area, but only when the BAT was enervated by nerve fibers from the brain - suggesting that electrical stimulation of the skin might augment β-adrenergic signalling from the hypothalamus to BAT. That paper was published in 2013, shortly before this patent application was filed (by other folks - not the authors of PMID 23995053). I don't see anything more recent, and I'm skeptical that localized electrical stimulation would be more effective (or more tolerable!) than localized cold stimulation of the skin surface above BAT using our cooling vests. Intriguing idea though.

 

7) New study looks at diet induced thermogenesis (DIT) in particular, and how it relates to BAT.  No surprise, but DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism.

 

I discussed that one here last week (while you were away). Interesting paper, backing up much of what we've seen about BAT being involved in energy metabolism and metabolic health.

 

8) I think we've only touched the surface on this topic, and we should discuss it more.  Some of the early CE pioneers talk about hot to cold transittions but thus far I dont' remember seeing much data about this.  A new study seems to provide evidence of increased BAT activity when going from hot to cold vs. room temp to cold.  This could potentially change the way some of us practice CE.  I would love to see more research along these lines.  "Conclusion: Acclimation at 32ºC produces a greater and earlier response to cold in the supraclavicular area than room temperature acclimation. The thermal response after 32ºC acclimation is reproducible and unlikely to be affected by outdoor temperature and subcutaneous fat in the neck. These data suggest that the use of infrared thermography using the 32ºC-cold protocol may be effective for detecting the metabolic activity of brown adipose tissue."  Also note that these guys induced BAT activity using only mild cooling of the torso with cooling blankets.

 

That does sound interesting and I too think cold contrast (e.g. sauna or hot shower → cold water immersion) is worth further exploration. But this study (which appears to have been a students master's thesis) seems a bit weak. I was unable to get the full text, so I can't check out the details, but what it appears to show is that the delta in temperature of  the skin above BAT was greater going from 32 °C (90 °F) to 12 °C (54 °F) than when going from room temperature (~22 °C) to 12 °C. But the difference was pretty small  (0.22 ±0.19 vs 0.13±0.17ºC, p=0.053). Notice both the small magnitude and large ranges on those temperature deltas. And the fact that the ambient temperature difference was twice as large between the 32 → 12 °C condition and the 22 → 12 °C condition makes a doubling of the skin temperature differential not all that surprising. I wonder what the temperature differential of skin that wasn't over BAT would be in the two conditions. I wouldn't be at all surprised if it saw something similar above non-BAT areas, since the 90 °F will obviously heat up all skin surfaces, making a drop to 54 °F more substantial.

 

--Dean

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Mild CR (20%) + Cold Exposure Boosts BAT_Activity

 

We've seen previously that some (e.g. Speakman et al 2005, discussed here), but not all previous research has found that BAT is preferentially spared during calorie restriction. Based on results in humans and rodents, it looks like the sweet spot is a body weight that is thin but not too thin, equating to a BMI in the low 20's for humans. In contrast, severe CR leaves no fat mass available to become BAT or beige fat. We've also seen in several studies (e.g. discussed here) that CR without CE doesn't seem to work to extend lifespan of rodents. 

 

With that background, I stumbled across a really interesting new study [1] looking at the effects of long-term, mild CR on BAT activity and WAT browning, presented at the same European Atherosclerosis Society (EAS) annual meeting as the study on metformin and BAT that Gordo pointed to. 

 

In [1], researchers studied mice starting at 3 month of age (young adults - human equiv of ~25 years old). They fed one group of mice ad lib and another group 20% less than ad lib (very mild CR) for 8 months until they were the human equivalent of about 42 years old, at which point they were sacrificed to look at the BAT and other blood markers. They don't mention housing temperature in the slides, so I think it safe to assume they housed the mice at cool-for-mice room temperature (~22 °C). So the mice in both the AL and CR groups were almost certainly also cold-exposed.

 

Here was the weight of the ad lib and 20% CR mice, illustrating the CR was quite mild indeed:

 

XsjsHqT.png

 

Notice the weight of the CR group was stable at about 25g vs ~30g for the ad lib mice. This is a much higher weight for the CR mice than is typically seen in serious CR experiments (like those that combined CR & cold exposure discussed here), where mice subjected to 40% CR weighed in the range of 18-20g.

 

In short, this looks like a study of mild CR + cold exposure. What did they find? All the good things you'd expect, including:

  • Lower fasting glucose and insulin in the mice subjected to mild CR + CE.
  • Improved insulin sensitivity and glucose metabolism during an OGTT in mild CR + CE mice.
  • Higher adiponectin in the mild CR + CE mice.
  • Increased expression of markers for healthy lipid metabolism in both visceral and subcutaneous fat of the mild CR + CE mice.
  • Reduced markers of inflammation (TNF-α and Mcp-1) in subcutaneous fat of the mild CR + CE mice.
  • Increased expression of UCP1, mitochondria-promoting PGC-1α and other markers of thermogenesis in BAT and subcutaneous WAT of the mild CR + CE mice.

Here was the authors' conclusions:

 

Long-term CR prevents the morphological and initial aged-related metabolic changes in
WAT and BAT. The browning effect observed in scWAT and the activation of BAT could be explained
by improved thyroid hormones status and function of CNS.

 

In short, it appears that cold exposure plus long-term mild CR (20% reduction relative to ad lib, enough to avoid obesity) boosts BAT activity and the browning of subcutaneous white adipose tissue. As I've pointed out in many places recently (especially in the Will Serious CR Beat a Healthy Obesity Avoiding Diet and Lifestyle? thread) obesity-avoiding 20% restriction is also the longevity "sweet spot" when it comes to adult onset CR, so this is yet another shining example of the BAT Rule1.

 

I've added "Mild CR + cold exposure" to the master list of BAT promoters below.

 

--Dean

 

----

1BAT Rule - Virtually every dietary or lifestyle intervention that is known to be healthy and/or longevity-promoting is also associated with an increase in BAT activity, browning of white fat and/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
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • 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)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • 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, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana, melatonin
  • 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
  • Time Restricted Feeding - most calories at breakfast
  • Mild CR + cold exposure - 20% CR relative to ad lib.
  • Exercise & elevated lactate / lactic acid
  • 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]
  • [being of genotype TT for rs1800592 and AA for rs4994 as reported by 23andMe]

---------

[1] Annual meeting of the European Atherosclerosis Society (2015)

 

Impact of caloric restriction on initial age-associated metabolic alterations and browning effect in

mice
 
P. Corrales-Cordon1, Y. Vivas1, D. Horrillo1, A. Izquierdo1, P. Seoane2, C. Martinez-Garcia1
, M.Lopez2, M. Ros1, M. Obregon3, G. Medina-Gomez1
 
1Universidad Rey Juan Carlos, Madrid, 2Universidade Santiago de Compostela, 3
Instituto deInvestigaciones Biomédicas Alberto Sols/CSIC-UAM, Madrid, Spain.
 
 
Background and aims: Changes in the distribution and function of different deposits of white adipose
tissue (WAT) and brown adipose tissue (BAT) occur during ageing. These changes are usually associated
to metabolic alterations like Insulin Resistance (IR) and Metabolic Syndrome. It is also known that
caloric restriction (CR) reduces the metabolic changes associated with age. Nevertheless, it is difficult to
establish when age-associated alterations start. Similarly, the severity and the time-extent to CR are
variables under debate. The aim of this work is to investigate the impact of the CR iniciated sind 3
months of age and maintained until 12 months of age, in the development of IR and other metabolic
disorders.
Materials and methods: 3 and 12-month-old male mice fed ad libitum and 12-month-old mice under CR
(20%) from 3 months of age were used (n=10-12 animals/group). For in vivo studies, we performed
glucose (1 g/kg body weight) and insulin (0.75 U/kg body weight) tolerance test in mice. Serum
concentration values of glucose, insulin and different cytokines were quantified by Bio-plex ProTM
Diabetes Assays. Gen expression involved in lipid metabolism was measured in BAT and epididimal
(eWAT) and subcutaneous (scWAT) WAT. Immunohistochemistry and mRNA expression of UCP-1 was
also detected. Total triiodothyronine (T3) and thyroxine (T4) concentrations were determined by
radioimmunoassay (RIA) in serum and BAT. Protein levels of lipogenic enzymes in the Central Nervous
System (CNS) were also measured.
Results: Our data showed age-associated IR significantly (p<0.05; t-Student) appeared at maturity and is
prevented with CR (AUC mean+-SE: 1536.64+-115.94 in 12-month old mice compared to 1587+-151.23
in animals fed with CR). These findings were in agreement with serum concentration values quantified.
Cytokines serum levels were measured. Adiponectin level significantly (p<0.05) decreased with ageing
(5.57+-0.47 ug/ml) and increased with CR (13.62+-2.53 ug/ml), while the leptin serum levels
significantly (p<0.05) increased with ageing (10.5+-3.095 ng/ml) but decreased with CR (2.61+-0.74
ng/ml). Furthermore, CR restored initial age-associated alterations in lipid metabolism and markers of
macrophage infiltration, such as MCP-1 (2.00+-0.38 with ageing; 1.32+-0.16 with CR), only in scWAT.
Remarkably, brown like adipocytes or browning effect was detected in scWAT in old animals subject to
CR. The lower browning process associated to ageing was accompanied by a significant (p<0.05)
decrease in the expression of some brown fat-selective genes (such as UCP-1, PRDM16, FGF21), but
restored with CR. T3 and T4 levels in BAT were significantly (p<0.05) decreased with ageing but
restored by CR. In addition, serum T3 levels were significantly (p<0.05) decreased with ageing. Finally,
we also found significantly (p<0.05) changes in lipogenic enzymes such as ACC and AMPK in the
hypothalamic AMPK pathway during the first stages of agein.
Conclusion: Long-term CR prevents the morphological and initial aged-related metabolic changes in
WAT and BAT. The browning effect observed in scWAT and the activation of BAT could be explained
by improved thyroid hormones status and function of CNS.

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All,

 

A while back, in response to the new Fontana study (PMID 27346343) on the positive metabolic effects of protein/BCAA/Leucine restriction discussed here, Tom asked the following:

 

I don't think he [Michael] will like it if you make any claims about restricting BCAAs or leucine. How was such restriction achieved in humans according to PMID:27346343? According to the supplemental material:

 

"Human PR Diet - Each participant randomized to the PR diet was fed costumized isocaloric PR diets prepared by the Metabolic kitchen of the Washington University CARS.

 

Not super helpful.

 

Shortly after Tom asked about the diet, I emailed the nutritionist who works with Luigi and who helped with the human CR study some of us were involved in. She pointed out the obvious (even in the link you provided), namely that the diet of the men in the study was reduced in protein but not specifically BCAA or leucine. Here is what she said:

 

The average male in the study at baseline consumed 17.4% of calories from protein; those randomized to the reduced protein meals consumed 8.3% of their calories from protein.  This is a significant decrease in total protein consumed for 4 to 6 weeks.

 

I followed up with a question about the type of proteins included, and she said:

 

Because the study participants had to obtain adequate calories but limit protein intake, they received plant-based proteins, fish and cheese on the reduced protein diet.  At baseline all participants were omnivorous.

 

So there you go. As a reminder, here is the graphical abstract from Luigi's study:

 

fx1.jpg

 

showing the men on the reduced protein diet had reduced weight and fat, improved glucose metabolism and increased FGF21. As mentioned here, in personal communications with Luigi he confirmed that he and his co-authors now suspect that the metabolic improvements observed in the mice fed a low BCAA diet resulted from increased mitochondrial uncoupling (via UPC1). In the men, the observed metabolic improvements could have similarly resulted from lower BCAAs in the reduced protein diet, or perhaps from the reduced methionine, which has also been shown to boost thermogenesis (as discussed here), not to mention longevity.

 

--Dean

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The following mostly has nothing to do with CE, but there is one brief mention that could throw a light on when it is exactly that humans used calories to warm themselves to any great degree. Perhaps that shows that burning calories for heat was a physiological strategy with a definite pedigree and age at the dawn of humanity:

 

Our Weird Lack of Hair May be Key to Our Success

 

"They argue that, in order to survive without fur at night, hominins needed to burn many more calories. That means our ancestors needed to fuel their bodies with calorie-rich food during the day."

 

I guess that the need to keep warm at night in a sense caused greater intake of calories. This is the reversal of the usual thought process when looking at experiments like the "rats with cold feet" - it is not that the cold therapy allows us to consume more calories, rather that the cold demands us to consume more calories. The cold came first, as it were, then came the greater consumption of calories. In the same way that we don't exercise so that we can eat more, rather we eat more so that we can exercise more (chase down our prey).

 

The cold came first, demanding more calories to burn. And so, we are not penalized for eating more... as long as we are cold.

Edited by TomBAvoider

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TomB,

 

Interesting, although seemingly quite speculative argument about how:

  1. We may have lost our hair (and increased our sweating capacity) so we could hunt (and especially run to chase game) in the middle of the hot day on the African savannah.
  2. Without hair, we needed to get more calories to stay warm, especially at night.
  3. So we developed cooking to extract more calories from food with less physical and digestive effort, as well as improved our hunting skills, our ability to collaborate, which lead to socialization, sharing, culture, etc.

I'm not sure I buy it, but it is an interesting hypothesis.

 

This is the reversal of the usual thought process when looking at experiments like the "rats with cold feet" - it is not that the cold therapy allows us to consume more calories, rather that the cold demands us to consume more calories.

 

I agree that it isn't that cold allows us to consume more calories - that is a very modern, anthropocentric way to look at it.

 

Instead, I think the better way to explain how and why the CE response came about is the one described in the CR + CE synergy post. Namely, that our distant pre-hominid ancestors developed metabolic responses to cope with the simultaneous lack of calories and lack of heat that would frequently occur during long cold spells and the near the end of winter. Ancestors that developed an effective, unified hormetic response to these two stressors survived the cold & famine, and passed on their ability to cope with them to their offspring. In modern society, where both calories and warmth are superabundant, we almost never encounter such metabolic challenges, and so almost never trigger the health-promoting metabolic responses to cope with them. So we don't live as long or as healthy lives as we might if challenged. This is similar to Ray Cronise's Metabolic Winter hypothesis

 

--Dean

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For the past 3 days I've been testing the waters of cold and heat exposure through bathing.  A cold bath after my morning workout and a hot bath after my evening walk before going to bed.  With the hot bath I've been increasingly pushing myself deeper into heat shock to stimulate heat shock proteins, in particular hsp70 which has been shown to be very therapeutic for my neuromuscular disease.  The results have been excellent.  I nearly overdid it with the heat shock last night, as with most anything too much can be bad.  I need to fine tune my approach as I think this is going to be a key part of my long term regimen.

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Mild CR + Exercise But Without Cold Exposure Appears to WHITEN Adipose Tissue in Humans

 

Well, hot off the heals of my somewhat optimistic posts above showing mild (20%) CR + CE boosted BAT activity in mice, comes this rather discouraging study [1] about the ability of mild CR to boost beige fat in humans.

 

The researchers put 80 overweight/obese women (avg BMI 31.6) on a program of diet (200kcal/d deficit ≈ 10% CR) + exercise 7d/week for 16 weeks. By the end of the study, the women had lost about 10lbs on average (BMI 31.6 → 29.7). So between the diet and exercise they were running a pretty consistent calorie deficit enabling them to lose about ½ lb per week, but they weren't slim at the the end of the study, by any means.

 

What they found was (my emphasis):

 

... UCP1 expression [in subcutaneous WAT] was negatively correlated with weight loss in humans in response to exercise training combined with modest energy restriction [P = 0.006]. Our data appear to rule out the hypothesis that exercise promotes weight loss through brite formation (10) at least in women and when a negative energy balance is induced via a combination of strategies.

 

So a combination of mild calorie restriction, modest weight loss and exercise without cold exposure resulted in a decrease in beige fat (i.e. fat whitening), and the greater the weight loss, the whiter their adipose tissue became.

 

Of course these were obese/overweight women, so it might not work exactly the same in thin men like most of us. But the interesting thing is that being overweight / obese is normally associated with less beige fat, so you'd think moving towards the beige fat "sweet spot" (i.e. thin, but not too thin, BMI ~21-25) by losing weight and exercising, would result in an increase the amount of beige fat these women had. But apparently not.

 

Instead, it looks like CR & weight loss without cold exposure trumps the effects of moving towards the best BMI for beige fat synthesis, resulting in a decrease in thermogenic beige fat. Reducing beige fat may have been a way the women's bodies tried to defend their original weight.

 

--Dean

 

-----------
[1] Am J Clin Nutr. 2016 Aug 3. pii: ajcn132563. [Epub ahead of print]
 
Biomarkers of browning of white adipose tissue and their regulation during
exercise- and diet-induced weight loss.
 
Nakhuda A(1), Josse AR(2), Gburcik V(3), Crossland H(4), Raymond F(5), Metairon
S(5), Good L(3), Atherton PJ(1), Phillips SM(6), Timmons JA(7).
 
Author information: 
(1)School of Medicine, Derby Royal Hospital, University of Nottingham,
Nottingham, United Kingdom; (2)Department of Kinesiology, Brock University, St.
Catharines, Canada; (3)Royal Veterinary College, London, United Kingdom;
(4)Division of Genetics and Molecular Medicine, King's College London, London,
United Kingdom; (5)Functional Genomics, Nestle Institute of Health Sciences,
Lausanne, Switzerland; and. (6)Exercise Metabolism Research Group, McMaster
University, Hamilton, Canada. (7)Division of Genetics and Molecular Medicine,
King's College London, London, United Kingdom; jamie.timmons@gmail.com.
 
BACKGROUND: A hypothesis exists whereby an exercise- or dietary-induced negative 
energy balance reduces human subcutaneous white adipose tissue (scWAT) mass
through the formation of brown-like adipocyte (brite) cells. However, the
validity of biomarkers of brite formation has not been robustly evaluated in
humans, and clinical data that link brite formation and weight loss are sparse.
OBJECTIVES: We used rosiglitazone and primary adipocytes to stringently evaluate 
a set of biomarkers for brite formation and determined whether the expression of 
biomarker genes in scWAT could explain the change in body composition in response
to exercise training combined with calorie restriction in obese and overweight
women (n = 79).
DESIGN: Gene expression was derived from exon DNA microarrays and preadipocytes
from obesity-resistant and -sensitive mice treated with rosiglitazone to generate
candidate brite biomarkers from a microarray. These biomarkers were evaluated
against data derived from scWAT RNA from obese and overweight women before and
after supervised exercise 5 d/wk for 16 wk combined with modest calorie
restriction (∼0.84 MJ/d).
RESULTS: Forty percent of commonly used brite gene biomarkers exhibited an exon
or strain-specific regulation. No biomarkers were positively related to weight
loss in human scWAT. Greater weight loss was significantly associated with less
uncoupling protein 1 expression (P = 0.006, R(2) = 0.09). In a follow-up global
analysis, there were 161 genes that covaried with weight loss that were linked to
greater CCAAT/enhancer binding protein α activity (z = 2.0, P = 6.6 × 10(-7)),
liver X receptor α/β agonism (z = 2.1, P = 2.8 × 10(-7)), and inhibition of
leptin-like signaling (z = -2.6, P = 3.9 × 10(-5)).
CONCLUSION: We identify a subset of robust RNA biomarkers for brite formation and
show that calorie-restriction-mediated weight loss in women dynamically remodels 
scWAT to take on a more-white rather than a more-brown adipocyte phenotype.
 
DOI: 10.3945/ajcn.116.132563 

 

PMID: 27488235

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More on cold microbiota:

 

Brown fat induction in treatment of metabolic disorders

"Our recent findings show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota (Chevalier et al., 2015). 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 atPL 7 26 Maced. pharm. bull., 62 (suppl) 25 - 26 (2016) Mirko Trajkovski tenuated, 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 remodelling and suppression of apoptosis - effect diminished by co-transplanting the most cold-downregulatedbacterial strain Akkermansiamuciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand ((Chevalier et al., 2015). We recently also showed that the development of functional beige fat is promoted by microbiota depletion either by means of antibiotic treatment or in germ-free mice within the white adipose tissues (SuárezZamorano et al., 2015). This leads to improved glucose tolerance, insulin sensitivity and decreased white fat and adipocyte size in lean mice and obese mice."

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From the renowned Dr. John Speakman:  

Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature

 

Nothing really earth shattering, but more people are starting to understand that cold exposure helps prevent diabetes even if it makes you hungry ;)

 

"Previous work has demonstrated that this BAT activity is responsive to changes in ambient temperature11,12,13,14,15,16 and that levels of BAT activity vary seasonally17,18, being higher in the winter when it is colder. This indirect evidence suggests that humans do indeed expend energy on thermoregulation, and more so when it is colder. This effect occurs despite spending long periods of time indoors buffered from such ambient extremes by the spread of central heating and air-conditioning19,20."

 

srep30409-f3.jpg

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Gordo,

 

 

Great find! It is nice to see Dr. Speakman continuing to study the effects of cold exposure and BAT, and expanding from the rodents studies he's done and we've discussed earlier. It's really hard to control for all the differences between people living in different areas (e.g. northern vs. southern US). But these results showing reduced risk of diabetes in northern (cooler) latitudes jibes well with the study (discussed here) of 97 species each of whose habitat spans a wide range of latitudes, which found that individuals within a species living in cooler, more northerly (or southerly, if in the southern hemisphere) latitudes live longer than those living at warmer latitudes.

 

I found Speakman's summary pretty interesting (my emphasis):

 

Low temperature may have an impact on the prevalence of type 2 diabetes in the absence of an effect on obesity because colder ambient temperatures stimulate brown adipose tissue [refs] which is capable of disposing large quantities of glucose and lipids [refs]... Interestingly, a small clinical trial recently showed that mild cold exposure (15 °C) for 6 hours per day had marked benefits with respect to glucose homeostasis, and this happened despite only a modest increase in brown adipose tissue activation [ref]. Although unfeasible as a clinical treatment option, this points to the possibility that cold may activate other, brown adipose tissue independent, pathways that influence glucose homeostasis, explaining the patterns we observed. If this is true, understanding the impact of cold on glucose homeostasis in humans should become a key future goal.

 

The fact that living in a cool climate correlated with reduced diabetes but not reduced obesity rates is quite interesting, since it suggests it's not that being overweight or obese per se that gets one into metabolic trouble. Instead, it suggests one can be heavy and remain healthy, if one avoids having large amounts of diabetes- and inflammation-promoting white visceral fat, via exposure to colder temperatures to promote healthy, glucose gobbling brown / beige fat.

 

His mention of alternative thermogenic pathways is also interesting. As we've seen (and perhaps Speakman has not), there are quite a few alternative pathways implicated in thermoregulation in humans in response to cold exposure, including the beiging of subcutaneous WAT, sarcolipin-induced futile calcium-ion cycling in muscles (discussed herehere, here  and most recently, here), and futile creatine cycling.

 

It is interesting he didn't mention this research during the CR Conference, even when I broached the subject of cold exposure with him, since this paper was obviously in the works at that time, and clearly (albeit indirectly) supports the thesis that cold is good for you.

 

Finally, I'm not sure why he says "Although unfeasible as a clinical treatment option, this points to the possibility that cold may activate other, brown adipose tissue independent..." I wonder why he considers cold therapy in unfeasible treatment option? It seems to me that many people (esp. heavy, diabetes-prone people) might very much prefer a little cold exposure to exercise, and certainly to injecting themselves with insulin for the rest of their lives!

 

--Dean

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Yes Dean, the "unfeasible" comment perplexes me, is it because there is no drug to sell? I bet many people would love to have an option to avoid diabetes that simply involves wearing a cooling vest (while they sit and watch TV or otherwise)

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More Evidence EPA & Fish Oil Boost Brown Fat and Thermogenesis

 

Recall from this this post in April, researchers have found that a diet supplemented with long-chain PUFAs EPA/DHA and fish oil boosts brown/beige fat and thermogenesis in rodents and human fat cells. This new study [1] provides further support for the BAT-boosting effects of EPA and fish oil, and elucidates some of the genes/proteins involved in the process. 

 

Much of the paper focuses on teasing out the specific microRNAs in the pathway from EPA to brown fat adipogenesis via in vitro experiments with fat progenitor cells, but that is a story I'll skip over for the moment, and focus on the in vivo part of their study.

 

Starting at 8-weeks of age, they fed C57BL/6 male mice four different diets, either low fat  (LF; 10% calories from fat) diet or an isocaloric high fat (HF; 50% calories from fat) diet which was enriched with different FA for 12 weeks. The AIN-93G rodent formulation was modified for fat composition containing 15% of fat (w/w) from either palm oil (HF+PO), olive oil (HF+OO), or fish oil (HF+FO). All diets contained the same amount of soy bean oil (5% w/w) as a source for essential FA.

 

A diet composed of 15% fish oil by weight is a honkin' amount of fish oil, which I consider to be a weakness of this study relatively to the one discussed in the above-linked post, which supplemented with a much less insane amount of FO. Housing temperature wasn't mentioned, so presumably the mice were housed at standard (cool-for-mice) laboratory temperature (21-23 °C).

 

What they found after 16 weeks on the different diets was really interesting. The fish oil group (HF+FO) ate the same amount as the mice fed either palm oil (HF+PO) or olive oil (HF+OO), but had much more lean mass and much less fat mass than the other high fat groups. In fact, their levels of lean mass and fat mass were comparable to the low-fat diet group (LF). They also had much lower fasting glucose than either of the other high-fat groups, and even much lower fasting glucose than the LF group. Here are the graphs for food intake (A), n-6/n-3 ratio in fat tissue (B), lean and fat masses ©, and fasting glucose (D):

 

cLIqmrq.png

 

What accounts for this remarkable improvement in metabolic health in the mice fed the fish oil? As you might expect, it was the increased expression of UCP1 and other thermogenesis promoting genes in BAT, which you can see from these graphs was elevated across the board in the HF+FO group:

 

2nIwF6g.png

 

Not surprisingly, these elevated thermogenic genes in brown adipose tissue turned the FO-fed mice into little furnaces. When the exposed the mice to cold (8 °C) for 45 min, the HF+FO group was much better able to maintain their body temperature than any of the other groups, as you can see from this graph of rectal temperatures and color thermographs showing the radiating body heat coming off representative mice from the four diet groups:

 

hhlzY78.png

 

In the in vitro part of their study that I alluded to earlier, the researchers determined that the mechanism by which fish oil boosts BAT is via an increase in expression and activity of a protein called Free Fatty Acid Receptor 4 (FFAR4), a receptor for omega-3 fatty acids, was responsible for the synthesis of brown fat via a pathway involving cyclic AMP (cAMP) and several microRNAs messengers.

 

Previously, the authors have found that cold exposure (5-8 °C for 2 weeks!) also boosts FFAR4 expression in mice. So they tried it again, and found that not only does cold exposure boost FFAR4 & UCP1, adding fish oil on top of cold exposure boosts both proteins even further, as illustrated in the four graphs below. The top two graph represent UCP1 (left) and FFAR4 (right) expression in response to cold alone (vs. housing at normal temperature). The bottom two graphs represent UCP1 (right) and FFAR4 (left) when mice were housed in cold temperature for two weeks and either fed fish oil (FO+) or a control diet (FO-):

 

oD1a28f.png

 

As you can see, cold alone boosts UPC1 and FFAR4, but cold + fish oil boosts both a lot further. The authors provide a nice figure showing the entire pathway from EPA (fish oil) to increased UPC1 and other thermogenic genes:

 

qisfeBF.png

 

Basically, EPA circulating in the bloodstream binds to Free Fatty Acid Receptor 4 (FFAR4) on the outer membranes of fat cells. Activation of FFAR4 triggers the second messenger cAMP to signal the nucleus of the fat cells to produce more of all the usual thermogenic genes like UCP1, PCG1α, CIDEA, more FFAR4 etc.

 

The fact that both cold exposure, omega-3s and especially the combination of the two boost FFAR4 is really interesting, since FFAR4 has been previously determined to be responsible for both the anti-inflammatory properties of Omega-3 fatty acids, as well as in improved glucose metabolism [2]. And you can chalk one up for vegan sources of omega-3 as well, since [2] says:

 

It is known that the ω3-FAs, such as α-linolenic acid (α-LA), docosahexaenoic acid (DHA), and eicosapentaeonic acid (EPA) are endogenous ligands for the free fatty acid receptor 4 (FFAR4).

 

and [3] found quite directly that alpha linolenic acid in flaxseed oil binds to and boosts expression of FFAR4.

 

For most of us, the exact pathway involved isn't all that important. The key is that long-chain omega-3 fatty acids, especially EPA, boosts BAT and thermogenesis, and improves glucose metabolism.

 

Unfortunately and somewhat paradoxically, fish consumption does not appear to provide the same benefit, at least in a US populations. In fact, it appears to do the opposite, i.e. eating fish appears to increase the risk of impaired glucose metabolism and diabetes by 5-17% in the US population [4]:

 

 For each serving per week increment in fish consumption, the RRs (95% CIs) of type 2 diabetes were 1.05 (1.02-1.09), 1.03 (0.96-1.11), and 0.98 (0.97-1.00) combining U.S., European, and Asian/Australian studies, respectively. For each 0.30 g per day increment in long-chain n-3 fatty acids, the corresponding summary estimates were 1.17 (1.09-1.26), 0.98 (0.70-1.37), and 0.90 (0.82-0.98).

 

I suspect the problem is that fatty fish (esp salmon) in the US is largely farm-raised, and comes loaded with several diabetes-promoting toxins, including heavy metals (mercury, lead), arsenic, and PCBs which likely trump the beneficial effects of their Omega-3s. Fish oil supplements aren't usually quite so contaminated, and algae-derived EPA/DHA supplements are better still.

 

So study [1] provides additional support for including EPA and fish oil in the list of BAT and thermogenesis promoters updated below. I've added "alpha linolenic acid / flaxseeds / flax oil" to the list of healthy fats that boost BAT, based on the fact that the ALA in flax activates FFAR4, which [1] shows boosts BAT and glucose metabolism.

 

Give that most of us consider long-chain omega-3s to be healthy, and pesco-vegetarian Adventists live slightly longer than even the vegans, this appears to be yet another example of the BAT Rule1.

 

--Dean

 

----

1BAT Rule - Virtually every dietary or lifestyle intervention that is known to be healthy and/or longevity-promoting is also associated with an increase in BAT activity, browning of white fat and/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
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • 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)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Healthy Fats - DHA / EPA / fish-oil; ALA / Flaxseeds / Flax oil; MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • 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, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng, cannabidiol / hemp oil / medicinal marijuana, melatonin
  • 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
  • Time Restricted Feeding - most calories at breakfast
  • Mild CR + cold exposure - 20% CR relative to ad lib.
  • Exercise & elevated lactate / lactic acid
  • 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]
  • [being of genotype TT for rs1800592 and AA for rs4994 as reported by 23andMe]

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

[1] J Biol Chem. 2016 Aug 3. pii: jbc.M116.721480. [Epub ahead of print]

 
EPA potentiates brown thermogenesis through FFAR4-dependent upregulation of
miR-30b and miR-378.
 
Kim J(1), Okla M(1), Erickson A(1), Carr T(1), Natarajan SK(1), Chung S(2).
 
Author information: 
(1)University of Nebraska, United States. (2)University of Nebraska, United
States schung4@unl.edu.
 
Emerging evidence suggests that n-3 poly unsaturated fatty acids (PUFA) promote
BAT thermogenesis. However, underlying mechanisms remain elusive. Here, we
hypothesize that n-3 PUFA promote brown adipogenesis by modulating miRNAs. To
test this hypothesis, murine brown preadipocytes were induced to differentiate
with fatty acids of palmitic (PA), oleate (OA), or eicosapentaenoic acid (EPA).
The increase of brown-specific signature genes and oxygen consumption rate (OCR) 
by EPA were concurrent with upregulation of miR-30b and 378, but not by OA or PA.
Next, we hypothesize that free fatty acid receptor 4 (FFAR4), a functional
receptor for n-3 PUFA, modulates miR-30b and 378. Treatment of FFAR4 agonist
(GW9805) recapitulated the thermogenic activation of EPA by increasing OCR,
brown-specific marker genes, and miR-30b and 378, which were abrogated in
FFAR4-silenced cells. Intriguingly, addition of miR-30b mimic was unable to
restore EPA-induced Ucp1 expression in FFAR4-depleted cells, implicating that
FFAR4 signaling activity is required for upregulating brown-adipogenic program.
Moreover, blockage of miR-30b or 378 by LNA inhibitors significantly attenuated
FFAR4 as well as brown-specific signature gene expression, suggesting the
signaling interplay between FFAR4 and miR-30b/378. The association between
miR-30b/378 and brown thermogenesis was also confirmed in fish oil-fed C57/BL6
mice. Interestingly, the FFAR4 agonism-mediated signaling axis of
FFAR4-miR-30b/378-UCP1 was linked with an elevation of cAMP in brown adipocytes, 
similar to cold-exposed or fish oil-fed brown fat. Taken together, our work
identifies a novel function of FFAR4 in modulating brown adipogenesis partly
through a mechanism involving cAMP activation and upregulation of miR-30b and
miR-378.
 
Copyright © 2016, The American Society for Biochemistry and Molecular Biology.
 
DOI: 10.1074/jbc.M116.721480 
PMID: 27489163
 
 
-----
[2] Front Endocrinol (Lausanne). 2014; 5: 115. doi:  10.3389/fendo.2014.00115
 
Omega-3 Fatty Acids and FFAR4
 
Da Young Oh, and Evelyn Walenta
 
Abstract
The beneficial roles of omega-3 fatty acids (ω3-FAs) on obesity, type 2 diabetes, and other metabolic diseases are well known. Most of these effects can be explained by their anti-inflammatory effects triggered through their receptor, free fatty acid receptor 4 (FFAR4) activation. Although the whole mechanism of action is not fully described yet, it has been shown that stimulation of ω3-FA to FFAR4 is followed by receptor phosphorylation. This makes FFAR4 to be capable of interacting with β-arrestin-2, which in turn, results in association of β-arrestin-2 with TAB1. This stealing of an important partaker of the inflammatory cascade leads to interruption of the pathway, resulting in reduced inflammation. Besides this regulation of the anti-inflammatory response, FFAR4 signaling also has been shown to regulate glucose homeostasis, adiposity, gastrointestinal peptide secretion, and taste preference. In this review, we summarize the current knowledge about the interaction of ω3-FAs with FFAR4 and the consequent opportunities for the application of ω3-FAs and possible FFAR4 targets.
 
Keywords: omega-3 fatty acids, FFAR4, anti-inflammation, insulin resistance, obesity
 
----------
[3] Inflamm Res. 2015 Oct;64(10):809-15. doi: 10.1007/s00011-015-0864-3. Epub 2015
Aug 15.
 
Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the
rat colon.
 
Cheshmehkani A(1), Senatorov IS(1), Kandi P(1), Singh M(1), Britt A(1), Hayslett 
R(1), Moniri NH(2).
 
Author information: 
(1)Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University,
3001 Mercer University Drive, Atlanta, GA, 30341, USA. (2)Department of
Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer
University Drive, Atlanta, GA, 30341, USA. moniri_nh@mercer.edu.
 
BACKGROUND AND OBJECTIVE: Omega-3 fatty acids, such as α-linolenic acid (ALA),
eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are polyunsaturated 
fatty acids (PUFA) that have long been associated with anti-inflammatory activity
and general benefit toward human health. Over the last decade, the identification
of a family of cell-surface G protein-coupled receptors that bind and are
activated by free-fatty acids, including omega-3 fatty acids, suggest that many
effects of PUFA are receptor-mediated. One such receptor, free-fatty acid
receptor-4 (FFAR4), previously described as GPR120, has been shown to modulate
anti-inflammatory and insulin-sensitizing effects in response to PUFA such as ALA
and DHA. Additionally, FFAR4 stimulates secretion of the insulin secretagogue
glucagon-like peptide-1 (GLP-1) from the GI tract and acts as a dietary sensor to
regulate energy availability. The aim of the current study was to assess the
effects of dietary omega-3 fatty acid supplementation on FFAR4 expression in the 
rat colon.
METHODS: Sprague-Dawley rats were fed control soybean oil diets or alternatively,
diets supplemented with either fish oil, which is enriched in DHA and EPA, or
flaxseed oil, which is enriched in ALA, for 7 weeks. GLP-1 and blood glucose
levels were monitored weekly and at the end of the study period, expression of
FFAR4 and the inflammatory marker TNF-α was assessed.
RESULTS: Our findings indicate that GLP-1 and blood glucose levels were
unaffected by omega-3 fatty acid supplementation, however, animals that were fed 
fish or flaxseed oil-supplemented diets had significantly heightened colonic
FFAR4 and actin expression, and reduced expression of the pro-inflammatory
cytokine TNF-α compared to animals fed control diets.
CONCLUSIONS: These results suggest that similar to ingestion of other fats,
dietary-intake of omega-3 fatty acids can alter FFAR4 expression within the
colon.
 
DOI: 10.1007/s00011-015-0864-3 
PMCID: PMC4565737 [Available on 2016-10-01]
PMID: 26275932
 
---------
[4] Diabetes Care. 2012 Apr;35(4):918-29. doi: 10.2337/dc11-1631.
 
Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2
diabetes: systematic review and meta-analysis of prospective studies.
 
Wallin A(1), Di Giuseppe D, Orsini N, Patel PS, Forouhi NG, Wolk A.
 
Author information: 
(1)Division of Nutritional Epidemiology, Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden.
 
Comment in
    Diabetes Care. 2012 Apr;35(4):666-8.
 
OBJECTIVE: The evidence on the association between fish consumption, dietary
long-chain n-3 fatty acids, and risk of type 2 diabetes is inconsistent. We
therefore performed a systematic review and meta-analysis of the available
prospective evidence.
RESEARCH DESIGN AND METHODS: Studies were identified by searching the PubMed and 
EMBASE databases through 15 December 2011 and by reviewing the reference lists of
retrieved articles. Prospective studies were included if they reported relative
risk (RR) estimates with 95% CIs for the association between fish consumption
and/or dietary long-chain n-3 fatty acids and incidence of type 2 diabetes. A
dose-response random-effects model was used to combine study-specific RRs.
Potential sources of heterogeneity were explored by prespecified stratifications.
RESULTS: Sixteen studies involving 527,441 participants and 24,082 diabetes cases
were included. Considerable statistical heterogeneity in the overall summary
estimates was partly explained by geographical differences. For each serving per 
week increment in fish consumption, the RRs (95% CIs) of type 2 diabetes were
1.05 (1.02-1.09), 1.03 (0.96-1.11), and 0.98 (0.97-1.00) combining U.S.,
European, and Asian/Australian studies, respectively. For each 0.30 g per day
increment in long-chain n-3 fatty acids, the corresponding summary estimates were
1.17 (1.09-1.26), 0.98 (0.70-1.37), and 0.90 (0.82-0.98).
CONCLUSIONS: Results from this meta-analysis indicate differences between
geographical regions in observed associations of fish consumption and dietary
intake of long-chain n-3 fatty acids with risk of type 2 diabetes. In
consideration of the heterogeneous results, the relationship warrants further
investigation. Meanwhile, current public health recommendations on fish
consumption should be upheld unchanged.
 
DOI: 10.2337/dc11-1631 
PMCID: PMC3308304
PMID: 22442397

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All,

 

I just posted about a new review paper that looks at the major causes of aging. Despite not mentioning cold exposure directly, the paper is relevant to the cold exposure thread because loss of PGC1α signalling (and the resulting mitochondrial dysfunction) is implicated in 4 of the 9 hallmarks of aging they identify. As we've seen many times on this thread and as discussed in [1], cold exposure is one of the best ways to boost PGC1α, which in turn promotes mitochondria biogenesis.

 

--Dean

 

------------
[1] Adv Physiol Educ. 2006 Dec;30(4):145-51.

PGC-1alpha: a key regulator of energy metabolism.

Liang H(1), Ward WF.

Author information:
(1)Department of Cellular and Structural Biology, Audie Murphy Veterans
Administration Medical Center and University of Texas Health Science Center, San
Antonio, Texas 78229-3900, USA.

Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is a
member of a family of transcription coactivators that plays a central role in the
regulation of cellular energy metabolism. It is strongly induced by cold
exposure, linking this environmental stimulus to adaptive thermogenesis.
PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of
muscle tissue to a fiber-type composition that is metabolically more oxidative
and less glycolytic in nature, and it participates in the regulation of both
carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is
intimately involved in disorders such as obesity, diabetes, and cardiomyopathy.
In particular, its regulatory function in lipid metabolism makes it an inviting
target for pharmacological intervention in the treatment of obesity and Type 2
diabetes.

DOI: 10.1152/advan.00052.2006
PMID: 17108241

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Another Genetic Marker for Thermogenesis

 

Mutations in the FTO gene have been repeatedly found to be associated with obesity. In fact, almost exactly a year ago, long before my obsession with cold exposure ☺, I penned this post on the relationship between variants of the FTO gene and obesity.

 

Today I rediscovered a paper [1] that I featured in that post, which focused on one specific single-nucleotide polymorphism (SNP) of the FTO gene - rs1421085.  Here is how I described [1] in that post from last year:

 

The newest study [1], focused on [...] SNP rs1421085, and did something really cool and cutting edge. They took fat cells from mice and humans and used the recently-developed CRISPR gene editing technique to change this particular SNP from the 'lean' variant ('T') to the 'obese' variant ('C'), and then observed what happened to the cells. What they found was that the fat cells converted from being thermogenically active, 'beige' fat cells (i.e. like brown fat cells) to 'white' fat cells that are much more efficient at storing fat, rather than burning it. This can be spun as a nice mechanistic story to explain why at least this SNP is associated with obesity. People who have 'C' for rs1421085 produce more white fat cells, making them more efficient at storing fat - i.e. they have a more 'thrifty' genotype and will therefore (presumably) store more fat for a given calorie intake.

 

In short, if you have a the risk allele 'C' for SNP rs1421085 (i.e. if you are CC or CT as reported here by 23andMe), your preadipocytes more readily differentiate into white fat cells rather than thermogenic beige fat cells, leading to great fat accumulation and higher risk of obesity. Conversely, if you are TT for rs1421085, you produce more beige fat cells, and burn more calories via thermogenesis. The effect is quite dramatic, at least in vitro. Researchers observed an 7x increase in fat cell thermogenesis when they used CRISPR to flip rs1421085 from C to T :

 

... CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.

 

An interesting thing is that the 'C' risk allele for rs1421085 is quite common. In fact, only about 33% of caucasians have the TT allele, while 58% have CT and 8% are unlucky enough to have CC (see here for frequency data).

 

I'm fortunate enough to be among the 33% with TT for rs1421085. Not so my always-chilly, sweater-in-summer-wearing wife, who, perhaps not surprisingly, turns out to be CT for rs1421085. 

 

So I'm 3-for-3 when it comes to the genetic variants most associated with elevated thermogenesis: TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe. So I've got that goin' for me, which is nice. Anyone else care to report their genotype for rs1421085?

 

I've updated the list below of factors associated with more brown/beige fat and thermogenesis to include SNP rs1421085.

 

--Dean

 

-------------------------------
[1] N Engl J Med. 2015 Aug 19. [Epub ahead of print]
FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.
 
Claussnitzer M(1), Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V,
Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH,
Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M.
 
 
Background Genomewide association studies can be used to identify
disease-relevant genomic regions, but interpretation of the data is challenging. 
The FTO region harbors the strongest genetic association with obesity, yet the
mechanistic basis of this association remains elusive. Methods We examined
epigenomic data, allelic activity, motif conservation, regulator expression, and 
gene coexpression patterns, with the aim of dissecting the regulatory circuitry
and mechanistic basis of the association between the FTO region and obesity. We
validated our predictions with the use of directed perturbations in samples from 
patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples 
from patients. Results Our data indicate that the FTO allele associated with
obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a
tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts
a conserved motif for the ARID5B repressor, which leads to derepression of a
potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during
early adipocyte differentiation. This results in a cell-autonomous developmental 
shift from energy-dissipating beige (brite) adipocytes to energy-storing white
adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as 
well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in
mice reduced body weight and increased energy dissipation without a change in
physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes
from participants with the risk allele restored thermogenesis, increasing it by a
factor of 7, and overexpression of these genes had the opposite effect in
adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by
CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the
risk allele restored IRX3 and IRX5 repression, activated browning expression
programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions
Our results point to a pathway for adipocyte thermogenesis regulation involving
ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced
pro-obesity and anti-obesity effects. (Funded by the German Research Center for
Environmental Health and others.).
 
PMID: 26287746
 

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

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
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • 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)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • 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, melatonin
  • Time Restricted Feeding - most calories at breakfast
  • Exercise & elevated lactate / lactic acid
  • 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]
  • [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

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Ahh, darn I'm CT on rs1421085. No wonder I up until recently I was the one who always wanted the thermostat set warmer. After forcing myself to do CE for a while now, I'm pretty much over that though. Looking forward to winter!

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Hi Brian - I have always loved the cold but THAT was in the context of being warmly dressed (or wet-suited, or blanketed in bed).  Being cold is less than heaven on earth (comparatively speaking, being hungry seems a cake walk :~).  I think Khurram (K^2) may agree on 'having less than an overpowering preference for being cold' at a low BMI.  Your rs2421085 CT status likely would not make it much easier if your BMI is still low.  Also, your CT status makes you "at risk for accumulating fat and obesity"--highly doubtful.

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Kenton et al.

 

I think Khurram (K^2) may agree on 'having less than an overpowering preference for being cold' at a low BMI. 

 

Yes, and Sthira too. I would add that if you're really thin, cold exposure may not only be uncomfortable, but also a waste of time, since you won't have the brown/beige fat or the muscle mass to support non-shivering thermogenesis.

 

--Dean

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I've gained about 7lbs so it's not so bad and life is still good.  However, I thought CE even w/o significant fat was still benefit.  Kindly succinctly recap on how it's a waste.  BTW, as you  may have gathered, I'm a mild CE practicer 24x7 pretty much like lab counterparts (i.e., I'm not an ICE VEST TOTER!)  cheers.

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Kenton,

 

However, I thought CE even w/o significant fat was still benefit.  Kindly succinctly recap on how it's a waste.

 

I'm not definitively saying it's a waste, just that it very well might be. Speakman found that CR did not result in reducing in BAT in mice (as discussed here), but others have failed to replicate that result, and instead have found old CRed rats had about 60% less total brown adipose tissue and about 30% less BAT as a percentage of body weight relative to old AL-fed rats (PMID 3826341). And remember rodents generally are much better than humans at maintaining BAT and thermogenesis, since it is so critical for their survival. So the CR-induced disproportionate loss of BAT with CR in rodents suggest it will happen at least as dramatically in humans.

 

To wit, from PMID 23393181 (discussed here), only constitutionally lean women (i.e. those who are thin without CR) with high metabolic rate expressed BAT. Thinness resulting from intentional excessive weight loss resulted in zero BAT, even after weight was regained.

 

So while it's not definitive, the evidence appears to suggest being either too heavy or too skinny puts the kibosh on BAT and BAT thermogenesis.

 

--Dean

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If you're saying it's likely unproductive wrt BAT, fine, but my Q was not wrt BAT but rather in general, i.e., wrt health and longevity.  Is there a difference?  (Evidence may be compelling re brown adipose tissue benefits (BATBs), but does that make BATBs the only plausible objective for wanting to practice CE.)  Is CE only about BATBs for you?

Edited by Kenton

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Kenton,

 

If you're saying it's likely unproductive wrt BAT, fine, but my Q was not wrt BAT but rather in general, i.e., wrt health and longevity.  Is there a difference?  (Evidence may be compelling re brown adipose tissue benefits (BATBs), but does that make BATBs the only plausible objective for wanting to practice CE.)  Is CE only about BATBs for you?

 

There may be benefits from simply reducing core body temperature. That appeared to have been Michael's hypothesis for CE benefits, at least early on back in this post from March (which prompted my "CE Albatross" response). I'm not sure if he thinks differently now, but I sure do. Cold changes a lot of things, but it's actions are largely mediated by increased expression of brown & beige adipose tissue. More brown and beige adipose tissue improves metabolic health (e.g. glucose and fatty acid metabolism - glucose metabolism being particularly important concern for IGT-prone CR folks), reduces pro-inflammatory cytokine / adipokines, and boosts expression of beneficial compounds like SIRT1, FOXO, AMPK, adiponectin and FGF-21. Cold may also have beneficial effects via its effects on skeletal muscles, i.e. via sarcolipin-mediated futile cycling of Ca++ ions, or futile cycling of creatine.

 

But the loci of these benefits (adipose tissue and skeletal muscle) require you to have some meat on your bones for the benefits to be realized. 

 

--Dean

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