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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Cold Exposure Exercise Fasting UCPs UCP1 UCP3 FGF21

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#41 AlPater

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Posted 07 February 2016 - 01:32 PM

Sorry, Dean, I am cryptic.  The message I was trying to say was that the control mice with the same treatments except cold exposure did not get plaque.  Mice with wild type genes and good diet would never get plaque.


A person who overdoes exercise ignores the advice given to check with your doc first.  If one has the rare heart conditions predisposing sudden death when exercise moderately or excessively, don't exercise that way.  If cold exposure might induce plaque, ...

#42 Dean Pomerleau

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Posted 07 February 2016 - 01:36 PM

Al wrote:

 If cold exposure might induce plaque, ...


I did a little more research on the issue Al raised - the potential for increased LDL cholesterol and cardiovascular disease risk associated with cold-exposure. Good news! The Pubmed gods were smiling on me today. Study [1] addresses exactly the point I was making, and vindicates the perspective I expressed above on the subject. You gotta love it when that happens. :-)


This study used mice as well, but mice that weren't messed up in their APoE or LDL-receptor genes, as the mice were in the study Al reference above (PMID 23823482). As the authors say in [1]:


[This strain of mice is] a well-established model for human-like lipoprotein metabolism that unlike

hyperlipidemic Apoe(-/-) and Ldlr(-/-) mice [i.e. the one's used in Al's study] expresses functional apoE and LDLR [LDL cholesterol receptor].


The authors have a good explanation for the process by which cold exposure leads to increased burning of fat via brown adipose tissue (BAT) activation:


[C]old exposure activates BAT via stimulation of noradrenalin release by sympathetic neurons, which
subsequently binds to b3-adrenergic receptor (b3-AR) on the brown adipocyte membrane (11)...
Activation of the b3-AR on brown adipocytes rapidly induces intracellular lipolysis of triglycerides (TGs)
from lipid droplets, resulting in release of fatty acids (FAs) into the cytoplasm. FAs are directed towards
mitochondria where they either activate the uncoupling protein-1 (UCP1) in the inner membranes of
mitochondria (13) or undergo oxidation. The intracellular TG stores of brown adipocytes are rapidly replenished
mainly by uptake of FA derived from lipolysis of TG-rich lipoproteins (TRLs) in the plasma (14).
In other words, cold exposure activates BAT, which burns free fatty acids, which come from triglycerides. The triglycerides in the BAT cells are replenished by sucking triglycerides out of the bloodstream, which the author's note is a good thing for lowering plasma triglycerides and combatting obesity. But, citing Al's study (Dong et al), the author's acknowledge that the breaking down of triglycerides can result in elevated cholesterol-rich 'remnants' in the blood (e.g. LDL and VLDL cholesterol) that can contribute to atherosclerotic plaques:
However, increased lipolytic processing of plasma TRL naturally accelerates
formation of pro-atherogenic cholesterol-rich remnants as well, which are usually cleared by the liver. Thus, Dong et al.(20)
described that BAT activation by cold exposure aggravates hypercholesterolaemia and atherosclerosis development in
Apoe/ and Ldlr/ mice, which are the most widely used atherosclerosis mouse models.
But, in short, they say what I did above, namely that the genetically messed up mice in Al's study aren't very representative of most humans. To illustrate, study [2] observes that "The [APoE knockout] mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months." A 3 month-old mouse with serious atherosclerosis is about the equivalent of a 18-year-old human with serious heart disease - not exactly representative of the general population...
The authors then go on to say they've got a better mouse model of CVD:
It is likely to be that the enhanced clearance of plasma TGs on BAT activation may require efficient clearance of
cholesterol-enriched lipoprotein remnants by the liver, a pathway that is considered to be crucially dependent on a
functional apoE-LDLR axis (21)....
The APOE*3-Leiden.CETP (E3L.CETP) [mouse] model is a well established model for hyperlipidaemia and atherosclerosis, which,
unlike Apoe/ and Ldlr/ mice, responds well to the lipid lowering and anti-atherogenic effects of statins, fibrates
and niacin. E3L.CETP mice express a naturally occurring mutant form of human apoE3 that slows down remnant
clearance, but does not completely abrogate the interaction with the LDLR. This results in attenuated hepatic remnant clearance
that is sufficient to induce hyperlipidaemia and atherosclerosis when feeding a Western-type diet (WTD), but, importantly, the
hepatic remnant clearance route is still functional and can be modulated. In addition, E3L.CETP mice are transgenic for human
cholesteryl ester transfer protein (CETP), which transfers cholesteryl esters from HDL to (V)LDL particles and for which
rodents are naturally deficient. Hence, E3L.CETP mice are considered to display a more human-like lipoprotein metabolism.
So they are going to activate BAT in their strain of mice and observe the same markers of lipid metabolism and plaque formation that Al's study measured. But rather than torturing the mice with cold (although they do that too - see below), they are going to short circuit the process of activating BAT by using a pharmacological treatment, namely a b3-adrenergic receptor (B3-AR) agonist, rather than cold exposure:
[T]he cold-stimulated activation of brown adipocytes inducing thermogenesis can be pharmacologically
mimicked by selective b3-AR agonists such as CL316243, one the most selective b3-AR agonists available (11,12).

Specifically what they did was feed their strain of mice an "atherogenic Western Type Diet (WTD)" for 10 weeks, both with a B3-AR agonist to stimulate brown fat (BAT) activity (the treatment group) and without the B3-AR agonist (the control group).


What did they find?


First, mice in the treatment group (labelled 'CL316243' - the name of the B3-AR agonist) with activated BAT gained dramatically less fat mass (b), without reduced lean mass (c) or food intake (d), relative to control mice (labelled 'Vehicle') when both were fed a crappy Western diet:



They observe the treatment group avoided getting fat because of their increase in BAT-mediated thermogenesis, rather than increased physical activity:


The b3-AR-mediated prevention of body fat gain was probably
the consequence of increased adaptive thermogenesis, as total EE
was markedly increased on the day of treatment (+17%; Fig. 2a)
without differences in activity levels (Fig. 2b). The increase in EE
was confined to increased FA oxidation (+67%; Fig. 2c) rather
than carbohydrate oxidation


Here is the graph of fatty acid oxidation - as you can see it was markedly elevated in the mice treated with B3-AR to simulate cold exposure, but only on the treatment days:




So the mice were burning more fat, and avoiding getting fat as a result of simulated cold exposure. But what about their cholesterol? Did it shoot up like it did in the Al's study mice?


Nope - it went down - dramatically.


In particular, triglycerides when down by an average of -54% (a), total cholesterol went down by -23% (c), LDL and VLDL cholesterol went down by -27% (d,e), without negatively impacting the level of "good" HDL cholesterol - if anything it slightly raised it relative to controls (e):





So did this improvement in cholesterol translate into better cardiovascular health - i.e. fewer plaques?  As you might guess by now - yes, by nearly 50% as illustrated in this graph:




Alright you might say - that looks all well and good. But is their treatment with this mysterious "CL316243" b3-adrenergic receptor agonist really equivalent to exposing the mice to cold in terms of its impact on cholesterol and heart disease?


Apparently yes. They did a further experiment, exposing a bunch of mice from their strain to cold (39degF for 7 days - ouch!) and found: 


This lipid-lowering effect of CL316243-mediated brown fat activation
did not differ from cold-induced effects, as cold exposure
reduced hyperlipidaemia in E3L.CETP mice as well (Fig. 5a,b),
despite a marked increase in dietary cholesterol intake in the cold (Fig. 5c).


Basically, the cold-exposed mice ate almost 100% more food (c) and hence consumed almost 100% more dietary cholesterol (from the crappy western diet they were fed) than controls, but nonetheless had dramatically lower levels of triglycerides (a) and total cholesterol (b) in their blood than controls (note: the y-axis in Figure b is mislabelled 'Plasma TG' rather than 'Plasma TC'):




They go on to show through a series of additional histological tests that all these positive effects of cold exposure and its pharmacologically-induced equivalent are indeed mediated by activation of brown adipose tissue (BAT), and that an intact liver for processing the cholesterol remnants released from this fat oxidation is important (and why Al's study mice didn't benefit).


In short, these researchers showed that cold exposure (and its pharmacologically-induced equivalent) dramatically reduces cholesterol levels and arterial plaque formation in their more accurate mouse model of human cholesterol processing and cardiovascular diseases. They conclude:


[A]ctivation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis.


So it looks like unless you've got some sort of freakish, familial hypercholesterolemia due to unfortunate genetics which prevents your liver from processing cholesterol, cold exposure is likely to be beneficial when it comes to cardiovascular disease risk.





[1] Nat Commun. 2015 Mar 10;6:6356. doi: 10.1038/ncomms7356.

Brown fat activation reduces hypercholesterolaemia and protects from
atherosclerosis development.

Berbée JF(1), Boon MR(1), Khedoe PP(2), Bartelt A(3), Schlein C(4), Worthmann
A(4), Kooijman S(1), Hoeke G(1), Mol IM(1), John C(4), Jung C(5), Vazirpanah
N(1), Brouwers LP(1), Gordts PL(6), Esko JD(6), Hiemstra PS(7), Havekes LM(8),
Scheja L(4), Heeren J(4), Rensen PC(1).


Full text: http://www.nature.co...ncomms7356.html

Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering
plasma triglyceride levels and reducing obesity. However, the precise role of BAT
in plasma cholesterol metabolism and atherosclerosis development remains unclear.
Here we show that BAT activation by β3-adrenergic receptor stimulation protects
from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a
well-established model for human-like lipoprotein metabolism that unlike
hyperlipidemic Apoe(-/-) and Ldlr(-/-) mice expresses functional apoE and LDLR.
BAT activation increases energy expenditure and decreases plasma triglyceride and
cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances
the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT,
subsequently accelerating the hepatic clearance of the cholesterol-enriched
remnants. These effects depend on a functional hepatic apoE-LDLR clearance
pathway as BAT activation in Apoe(-/-) and Ldlr(-/-) mice does not attenuate
hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is
a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from

PMCID: PMC4366535
PMID: 25754609



[2] Science  16 Oct 1992: Vol. 258, Issue 5081, pp. 468-471

DOI: 10.1126/science.1411543


Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E

SH Zhang, RL Reddick, JA Piedrahita, N Maeda
Apolipoprotein E (apoE) is a ligand for receptors that clear remnants of chylomicrons and very low density lipoproteins. Lack of apoE is, therefore, expected to cause accumulation in plasma of cholesterol-rich remnants whose prolonged circulation should be atherogenic. ApoE-deficient mice generated by gene targeting were used to test this hypothesis and to make a mouse model for spontaneous atherosclerosis. The mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months. These spontaneous lesions progressed and caused severe occlusion of the coronary artery ostium by 8 months. The severe yet viable phenotype of the mutants should make them valuable for investigating genetic and environmental factors that modify the atherogenic process.

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#43 AlPater

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Posted 08 February 2016 - 02:13 PM

A few items came to my mind, Dean.


Your paper [1] does not need access via Sci-Hub, which makes things like searching for "plaque", which it did not have, can be readily be search in the freely available full-texts:





The Dong et al paper I introduced can also be seen via its pdf:




[1] fed mice cholesterol, not too good, I thought.  It actually looked at cold exposure effects too, but only treated to cold 7 days, not 8 weeks and in the Dong et al paper.  It looked at total cholesterol after cold exposure, not LDL as Dong et al did, despite [1] making much of the Dong et al paper, and mislabeled total cholesterol as triglyeride in Figure 5b.


The experiments were very different, I grant you that, but the bottom line, I am uncertain about. 


The Dong et al paper also looked at the effects of cold exposure in human subjects, and their LDL levels went up significantly.

#44 Dean Pomerleau

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Posted 08 February 2016 - 03:53 PM



[Dean's paper - PMID 25754609) fed mice cholesterol, not too good, I thought.  


Yes they did feed the mice cholesterol. Here is the diet statement from the Methods section:


Mice were fed a WTD [Western Type Diet] (HopeFarms, Woerden, The Netherlands) supplemented with 0.1% cholesterol...
What's wrong with that? It seems reasonable to simulate a diet containing cholesterol, since that is what most people eat. It would seem to stack the deck towards seeing elevated serum cholesterol - wouldn't you think? Also remember, this strain of mice in my study has cholesterol processing genes similar to humans, unlike the mice from your study. 

 It [Dean's paper] actually looked at cold exposure effects too, but only treated to cold 7 days, not 8 weeks and in the Dong et al paper [Al's paper].


Seems like a minor distinction to me. I'd like to see you try living for 7 days at a constant temperature of 39 degF :-).

It [Dean's paper] looked at total cholesterol after cold exposure, not LDL as Dong et al [Al's paper] did


My paper looked at LDL and VLDL in the main part of the study (where they pharmacologically-induced BAT activity to simulate cold exposure) and both were dramatically reduced in the treated mice relative to controls. They did the cold exposure experiment with their strain of mice simply to validate their model, and show similar results were elicited from actual cold exposure as with pharmacologically-induced simulated cold exposure. Results were similar between the two treatments. 

The Dong et al paper [Al's paper] also looked at the effects of cold exposure in human subjects, and their LDL levels went up significantly.


Did you see that that was an experiment with five human subjects with already high LDL cholesterol conducted over two days with only 2 hours of cold exposure per day at 60degF? The authors don't even appear to have controlled for diet over those two days in the human subjects, at least their diet isn't mentioned. For all we know the cold-exposed men may have gone out for a Double Big Mac meal (or a McDonald's kale salad :-) ) to compensate for the extra calories they burned via thermogenesis. I'd say it's pretty hard to draw conclusions from such a small, biased, short and poorly-controlled pilot study, and your study's authors apparently concur:
We admit the fact that only a small number of human subjects were recruited at this time,
and this pilot study may lack a sufficient statistical power to justify a definite conclusion.
But I'll once again acknowledge (as I have several times in this thread), if you have pathologically high (or even just unusually high) cholesterol despite a good diet and lifestyle, suggesting that your body just doesn't process cholesterol very well (likely due to genetics), than it may be prudent to check your cholesterol level when you start to practice cold exposure - since cold exposure preferentially burns fat, which naturally releases cholesterol remnants which your body will have to clear.
Fortunately there are very few people practicing CR, or eating a plant-based diet and getting sufficient exercise, who have to worry about high cholesterol. You and I certainly don't!

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#45 Dean Pomerleau

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Posted 08 February 2016 - 04:24 PM



One other thing I forgot to mention from my paper (PMID 25754609). They tested the same pharmacologically-induced simulated cold exposure in mice that had their APOE gene or their LDL-receptor gene knocked out, just like in your study (PMID 23823482). Unlike their own strain of mice (with an intact, human-like cholesterol processing system), and like the Dong et al (Al's study) mice, these knockout mice did not benefit from BAT activation (i.e. simulated cold exposure) as reflected by either their cholesterol level or plaque formation. The authors of my study explain these results quite clearly in the context of Dong et al:


Our study indicates that the ability of the liver to clear apoE-enriched lipoprotein remnants via the LDLR is a prerequisite for

the anti-atherogenic potential of BAT activation. According to this view, it is not surprising that Dong et al.20 recently observed
that BAT activation by cold exposure in Apoe[-knockout] and Ldlr[-knockout] mice actually increased plasma (V)LDL-C levels and
In fact, they mention something I didn't notice when I read you study Al (my emphasis):
In fact, Dong et al.20 did show that activation of BAT by cold in normolipidemic wild-type C57Bl/6 mice actually decreased
plasma TC and (V)LDL-C levels, which is in full accordance  with a functional hepatic apoE–LDLR clearance route of lipoprotein
remnants in wild-type mice.


In short - the evidence appears pretty strong that cold exposure will improve serum cholesterol level and CVD risk in mice (and probably people), as long as they have intact genes which allow their liver to clear cholesterol remnants.



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#46 Dean Pomerleau

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Posted 09 February 2016 - 06:55 PM



In this post earlier in this thread, I cited a study (PMID 9032756) which showed that housing B57BL/6 mice at what for them is a cool temperature was necessary for CR to have lifespan benefits. CR did not extend median lifespan of mice relative to ad lib-fed controls when they both were housed at what for mice is a thermally-neutral temperature. But neither that study, nor the infamous "rats with cold feet" study (PMID 3781978), measured the physiological effects (particularly the activity of brown adipose tissue (BAT)) of cool housing temperature on the mice.


This new study [1] fills in that gap. Researchers at Williams College1 subjected the same strain of mice (C57BL/6) as in PMID 9032756 to either thermally-neutral temperature (30°C = 86°F) or typical laboratory temperature (20°C = 68°F), either alone or in group cages, either with or without bedding. When housed alone, either with or without bedding, mice kept at the cool (but typical) temperature showed many overt signs of thermal stress (including elevated heart rate, blood pressure, shivering, lower core body temperature) relative to the mice housed at thermal neutrality. Most interestingly, the cool-housed mice showed a 22-fold increase in activity of the gene which measures brown adipose tissue (BAT) activity relative to warm-housed mice.


They found that living in a group cage blunted this effect, presumably because the mice are able to huddle together in a group cage to stay warm. Adding bedding to the cages of singly-housed mice did not blunt the effects.


In most well-conducted CR rodent experiments, including PMID 9032756 which showed C57BL/6 mice need to be kept cold to benefit from CR, the animals are housed individually and at temperatures well below thermal neutrality, which means they are cold-stressed and have highly activated brown fat, based on the results of [1].


So it's looking more and more like cold exposure (and BAT activation) may be required for anyone hoping to mimic the conditions of CR experiments with rodents, the one group of mammals where CR has been shown to pretty robustly extend lifespan.





1Williams College is my undergraduate alma mater. Weird how the two studies I've posted today come from the two schools (Williams and CMU) that I attended after graduating from high school!



[1] Am J Physiol Regul Integr Comp Physiol. 2015 Jun 15;308(12):R1070-9. doi:

10.1152/ajpregu.00407.2014. Epub 2015 Apr 15.

Group housing and nest building only slightly ameliorate the cold stress of
typical housing in female C57BL/6J mice.

Maher RL(1), Barbash SM(1), Lynch DV(1), Swoap SJ(2).

Author information:
(1)Department of Biology, Williams College, Williamstown, Massachusetts.
(2)Department of Biology, Williams College, Williamstown, Massachusetts

Huddling and nest building are two methods of behavioral thermoregulation used by
mice under cold stress. In the laboratory, mice are typically housed at an
ambient temperature (Ta) of 20°C, well below the lower end of their thermoneutral
zone. We tested the hypothesis that the thermoregulatory benefits of huddling and
nest building at a Ta of 20°C would ameliorate this cold stress compared with
being singly housed at 20°C as assessed by heart rate (HR), blood pressure (BP),
triiodothyronine (T3), brown adipose (BAT) expression of Elovl3 mRNA, and BAT
lipid content. A series of experiments using C57BL/6J female mice exposed to 20°C
in the presence or absence of nesting material and/or cage mates was used to test
this hypothesis. Mice showed large differences in HR, BP, shivering, and core
body temperature (Tb) when comparing singly housed mice at 20°C and 30°C, but
only a modest reduction in HR with the inclusion of cage mates or bedding.
However, group housing and/or nesting at 20°C decreased T3 levels compared with
singly housed mice at 20°C. Singly housed mice at 20°C had a 22-fold higher level
of BAT Elovl3 mRNA expression and a significantly lower triacylglycerol (TAG)
content of BAT compared with singly housed mice at 30°C. Group housing at 20°C
led to blunted changes in both Elovl3 mRNA and TAG levels. These findings suggest
that huddling and nest building have a limited effect to ameliorate the cold
stress associated with housing at 20°C.

Copyright © 2015 the American Physiological Society.

PMID: 25876655

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#47 AlPater

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Posted 10 February 2016 - 12:56 PM

Translating animal model research: does it matter that our rodents are cold?
Physiology (Bethesda). 2014 Nov;29(6):413-20. doi: 10.1152/physiol.00029.2014.
Maloney SK, Fuller A2, Mitchell D, Gordon C, Overton JM.
PMID: 25362635
Free full text
Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? We compile evidence showing that such rodents are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever-resistant, aging-resistant, and tumor-prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality.
"Rodent Longevity
The rodent models that have attracted public attention, perhaps more than any others, are those demonstrating artificially enhanced longevity. Engineering a mouse's hypothalamus to overproduce uncoupling protein 2 results in the local production of heat in the hypothalamus. Because the hypothalamus is the most thermosensitive region in the mammalian body and provides the majority of the input signal for thermoregulation (26), the local heating results in a lower than normal Tb everywhere else in the body. Those engineered mice also live longer than normal (14), providing evidence of an association between Tb, energetics, and longevity (3).
There are other mouse genotypes that live longer than average. These genotypes produce dwarf strains, and their LCTs are higher than those of the average mouse. They tend to have lower Tb than normal mice, even at Ta of 26°C (7). The hypopituitary Ames and Snell strains live for ∼1,150 days compared with 720 days for a normal mouse (8). In dwarf mice, the longevity appears to be related to increased metabolic rate (3). The long-lived growth hormone-resistant (GHR-KO) strain has a metabolic rate higher than that of wild-type mice when housed at 23°C but not when housed at 30°C (3), implying that enhanced longevity would not be evident in the TNZ. That implication is manifested in the C57Black-6 (B6) strain of mouse that lives for ∼785 days (35) when its lifespan is extended by calorie restriction (CR). Placing B6 mice onto a CR diet, where they receive 60% of their normal daily energy requirement, extends their life to ∼1,148 days at 21°C (35). If the B6 mice are fed a CR diet at thermoneutrality, they live for ∼810 days, not significantly different from the 785 days of the control-fed mice (35). So CR does not extend lifespan in B6 mice in their TNZ. Koizumi (35) thought that the explanation lay in the restricted use of torpor at the higher Ta, but Bartke (3) reports that the long-lived genotypes do not use torpor and thus maintain a high metabolism when they are exposed to 21°C. There is clearly much we do not understand about the interactions between Ta, Tb, metabolism, and longevity."
Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans.
Speakman JR, Keijer J.
Mol Metab. 2012 Nov 8;2(1):5-9. doi: 10.1016/j.molmet.2012.10.002. Review.
PMID: 24024125 Free PMC Article
It has been argued that mice should be housed at 30 °C to best mimic the thermal conditions experienced by humans, and that the current practice of housing mice at 20-22 °C impairs the suitability of mice as a model for human physiology and disease. In the current paper we challenge this notion. First, we show that humans routinely occupy environments about 3 °C below their lower critical temperature (T lc), which when lightly clothed is about 23 °C. Second, we review the data for the T lc of mice. Mouse T lc is dependent on body weight and about 26-28 °C for adult mice weighing >25 g. The equivalent temperature to that normally experienced by humans for most single housed adult mice is therefore 23-25 °C. Group housing or providing the mice with bedding and nesting material might lower this to about 20-22 °C, close to current standard practice.
Ambient temperature; Human; Lower critical temperature; Mouse; Thermoneutral; Thermoregulation
Letter-to-the-editor on "Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans".
Gaskill BN, Garner JP.
Mol Metab. 2013 May 21;3(4):335-6. doi: 10.1016/j.molmet.2013.05.003. eCollection 2014 Jul. No abstract available.
PMID: 24944886 Free PMC Article
Not so nuanced: Reply to the comments of Gaskill and Garner on 'Not so hot: Optimal housing temperatures for mice to mimic the environment of humans'.
Speakman JR, Keijer J.
Mol Metab. 2013 Jun 3;3(4):337. doi: 10.1016/j.molmet.2013.05.007. eCollection 2014 Jul. No abstract available.
PMID: 24944887 Free PMC Article

#48 Dean Pomerleau

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Posted 10 February 2016 - 01:43 PM



Its very hard to tell since this is another one of your all-too-frequent posts without any helpful commentary or context :-(, but I assume you remember you posted the first, helpful paper (PMID 25362635) very early on in this thread, in fact as the second post, and I discussed it, including the passage you quote, in this subsequent post. The short summary is that the normal (68-72 °F) housing temperature for mice results in thermal stress, which is likely to make them live longer and be less prone to obesity and other maladies.


To summarize the back-and-forth debate over the Speakman & Keijer (PMID 24024125) paper (which is new and interesting - thanks!) - they argue that to mimic the kind of mild cold stress that humans are sometimes exposed to (e.g. a 68 °F home or office environment with light clothing), singly-housed mice should be kept in the range of 74-77 °F, which is somewhat below their thermoneutral temperature.  Gaskill & Garner think it should be somewhat higher in order to mimic more typical human lifestyle & preferences (e.g. since people normally turn up the thermostat or wear heavier clothes in a 68°F environment).


But both sets of researchers agree that mice housed in the mid-70F range are (at least mildly) cold stressed, and at the normal housing temperature for mice (68-72 °F) they are quite thermally stressed, particularly when housed singly, as is standard in rodent CR experiments. Not only are such low housing temperatures a bit cruel from an animal welfare perspective, they aren't a good parallel with the way we humans typically live, resulting in errors when researchers try to generalize from the results of rodent experiments to humans. 


This is exactly what I've been arguing throughout this thread - in order to mimic CRed mice in hopes of gaining longevity, we can't just copy their diet - we likely need to expose ourselves to colder temperatures than we typically do.



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#49 Dean Pomerleau

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Posted 10 February 2016 - 05:42 PM

Alternatives to Cold Exposure for Activating Brown Adipose Tissue (BAT)


So in this thread I've been touting the likely health benefits of cold exposure, primarily through its activating of brown adipose tissue (BAT). But for those delicate souls who resist the cold, are there alternative ways to activate BAT which might have similar benefits as cold exposure, without the physical hardship?


Tantalizingly, the answer is "yes, perhaps". I say tantalizingly, because two compounds that seem to increase BAT activity are well-known to us - metformin and capsaicin. 





In particular, [1] found that metformin appears to reduce plasma cholesterol & triglycerides largely by upregulating BAT activity so as to burns more fatty acids. And significantly, metformin was found to increase expression of AMP-kinase in BAT. They say:


 Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.


What makes this metformin-BAT connection all the more interesting is the theory that metformin may be a CR mimetic (a claim not without controversy), and has been shown to extending lifespan in rodents via increased AMP-kinase activity [2] and perhaps even diabetic humans, although both these results are pretty highly disputed, perhaps even debunked, as Michael points out in this post.


So while I personally wouldn't run out and take metformin, as I recall some pretty well-respected scientists (Spindler, IIRC?) take metformin, and someone from Big Pharma has convince enough people in Washington that metformin has enough anti-aging potential to test it in the first government-sponsored human longevity trial (popular press coverage) . In my book this makes the link between metformin and BAT quite interesting, if for no other reason than to lend additional indirect support to the theory that increased BAT activity through cold exposure is likely to be beneficial for health and longevity, perhaps through some of the same pathways as CR (e.g. AMPK).


I wonder if the benefits of metformin are confined to (or larger in) individuals with appreciable amounts of BAT. I suspect they would be...




In study [3], researchers exposed 18 healthy young men to cold and did a PET scan to figure out which of them had detectable levels of BAT. It turned out that 10 of them did (the BAT+ group), and 8 didn't (the BAT- group). Then in a randomized, cross-over design, they fed both groups capsaicin (in pill form) or placebo and measured their resting energy expenditure. They found that only the BAT+ group exhibited increased resting energy expenditure from ingesting capsaicin (relative to placebo). Here are the graphs from the full text:




In their discussion, the researchers conclude:


These results indicate that BAT is involved in the capsinoid-induced increase in EE, as proposed in small rodents (19, 20)....
Recently, Kawabata et al (19) showed in mice that capsaicin and capsinoids activated BAT thermogenesis and increased EE..
It is thus likely in humans, as in small rodents, that orally ingested capsinoids activate BAT ... and increase EE.

Our results indicate that the stimulatory effect of capsinoids on EE is largely attributable to the activation of BAT, which suggests that BAT is the site responsible for the antiobesity effect of capsinoids. This implies that capsinoids are effective in people with BAT, but not in those without detectable BAT. However, note that BAT can be recruited after chronic activation of the sympathetic nervous system. For example, prolonged cold exposure or treatment with b3-adrenoceptor agonists produces hyperplasia of BAT and ectopic induction of brown-like adipocytes in white fat pads in small rodents and dogs (17, 30–33).


In short, the effects of capsaicin appears to have been mediated by BAT. But it was a relatively small effect - only about 120kcal/day if you took a capsaicin pill once every hour for the whole day. This is less than a third of the increase in energy expenditure (406kcal/day) observed by these same researchers in BAT+ (but not BAT-) healthy young men in response to cold exposure, consisting of "2-h at 66 °F with light-clothing and intermittently putting their legs on an ice block" [4].


I found this capsaicin result interesting in light of Michael's admission that hot chili peppers (the best source of capsaicin) are one of the few "functional foods" he considers worth eating, based on results from [5] which found that in nearly 500,000 people, those who ate spicy foods nearly every day had a 14% reduced rate of all-cause mortality relative to those to eschewed spicy foods (like 102 year-old Olive Watson...). It would be interesting (although extremely difficult logistically) to determine if the mortality benefits of spicy foods are confined to (or larger in) the ~50% of the population who have detectable levels of BAT. I suspect they would be.


In summary, taking metformin and/or eating capsaicin/chili-peppers may potentiate BAT activity, but only if you've got brown adipose tissue to begin with, and to insure that you'll likely have to expose yourself to cold...





[1] Diabetes. 2014 Mar;63(3):880-91. doi: 10.2337/db13-0194. Epub 2013 Nov 22.

Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by
brown adipose tissue in mice.

Geerling JJ(1), Boon MR, van der Zon GC, van den Berg SA, van den Hoek AM, Lombès
M, Princen HM, Havekes LM, Rensen PC, Guigas B.


Free Full text: http://diabetes.diab...t/63/3/880.long

Metformin is the first-line drug for the treatment of type 2 diabetes. Besides
its well-characterized antihyperglycemic properties, metformin also lowers plasma
VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms
in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein
metabolism. We found that metformin markedly lowered plasma total cholesterol and
TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was
slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG
production, VLDL particle composition, and hepatic lipid composition but
selectively enhanced clearance of glycerol tri[(3)H]oleate-labeled VLDL-like
emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet
content were reduced in metformin-treated mice, pointing to increased BAT
activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression
and activity and HSL and mitochondrial content were increased in BAT.
Furthermore, therapeutic concentrations of metformin increased AMPK and HSL
activities and promoted lipolysis in T37i differentiated brown adipocytes.
Collectively, our results identify BAT as an important player in the TG-lowering
effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and
subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be
considered as a future therapeutic strategy for the treatment of dyslipidemia.

PMID: 24270984



[2] Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192.

Metformin improves healthspan and lifespan in mice.

Martin-Montalvo A(1), Mercken EM, Mitchell SJ, Palacios HH, Mote PL,
Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M,
Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR,
Bernier M, de Cabo R.

Free full text: http://www.ncbi.nlm....les/PMC3736576/

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes.
Here we show that long-term treatment with metformin (0.1% w/w in diet) starting
at middle age extends healthspan and lifespan in male mice, while a higher dose
(1% w/w) was toxic. Treatment with metformin mimics some of the benefits of
calorie restriction, such as improved physical performance, increased insulin
sensitivity, and reduced low-density lipoprotein and cholesterol levels without a
decrease in caloric intake. At a molecular level, metformin increases
AMP-activated protein kinase activity and increases antioxidant protection,
resulting in reductions in both oxidative damage accumulation and chronic
inflammation. Our results indicate that these actions may contribute to the
beneficial effects of metformin on healthspan and lifespan. These findings are in
agreement with current epidemiological data and raise the possibility of
metformin-based interventions to promote healthy aging.

PMCID: PMC3736576
PMID: 23900241



[3] Am J Clin Nutr. 2012 Apr;95(4):845-50. doi: 10.3945/ajcn.111.018606. Epub 2012

Feb 29.

Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the
activation of brown adipose tissue in humans.

Yoneshiro T(1), Aita S, Kawai Y, Iwanaga T, Saito M.

Author information:
(1)Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido
University Graduate School of Medicine, Sapporo, Japan.


Free full text: http://ajcn.nutritio...6.full.pdf html

BACKGROUND: Capsinoids-nonpungent capsaicin analogs-are known to activate brown
adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in
small rodents. BAT activity can be assessed by [¹⁸F]fluorodeoxyglucose-positron
emission tomography (FDG-PET) in humans.

OBJECTIVES: The aims of the current study were to examine the acute effects of
capsinoid ingestion on EE and to analyze its relation to BAT activity in humans.
DESIGN: Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold
exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature,
after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm
conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover

RESULTS: When exposed to cold, 10 subjects showed marked FDG uptake into adipose
tissue of the supraclavicular and paraspinal regions (BAT-positive group),
whereas the remaining 8 subjects (BAT-negative group) showed no detectable
uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226
kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group
(NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7
± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P <
0.01). Placebo ingestion produced no significant change in either group. Neither
capsinoids nor placebo changed the skin temperature in various regions, including
regions close to BAT deposits.

CONCLUSION: Capsinoid ingestion increases EE through the activation of BAT in
humans. This trial was registered at http://www.umin.ac.jp/ctr/as UMIN

PMID: 22378725



[4] Obesity (Silver Spring). 2011 Jan;19(1):13-6. doi: 10.1038/oby.2010.105. Epub

2010 May 6.

Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy
adult men.

Yoneshiro T(1), Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M.

Author information:
(1)Department of Nutrition, School of Nursing and Nutrition, Tenshi College,
Sapporo, Japan.

Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose
(FDG)-positron emission tomography (PET) in adult humans. Thirteen healthy male
volunteers aged 20-28 years underwent FDG-PET after 2-h cold exposure at 19 °C
with light-clothing and intermittently putting their legs on an ice block. When
exposed to cold, 6 out of the 13 subjects showed marked FDG uptake into adipose
tissue of the supraclavicular and paraspinal regions (BAT-positive group),
whereas the remaining seven showed no detectable uptake (BAT-negative group). The
BMI and body fat content were similar in the two groups. Under warm conditions at
27 °C, the energy expenditure of the BAT-positive group estimated by indirect
calorimetry was 1,446 ± 97 kcal/day, being comparable with that of the
BAT-negative group (1,434 ± 246 kcal/day). After cold exposure, the energy
expenditure increased markedly by 410 ± 293 (P < 0.05) and slightly by 42 ±
114 kcal/day (P = 0.37) in the BAT-positive and -negative groups, respectively. A
positive correlation (P < 0.05) was found between the cold-induced rise in energy
expenditure and the BAT activity quantified from FDG uptake. After cold exposure,
the skin temperature in the supraclavicular region close to BAT deposits dropped
by 0.14 °C in the BAT-positive group, whereas it dropped more markedly (P < 0.01)
by 0.60 °C in the BAT-negative group. The skin temperature drop in other regions
apart from BAT deposits was similar in the two groups. These results suggest that
BAT is involved in cold-induced increases in whole-body energy expenditure, and,
thereby, the control of body temperature and adiposity in adult humans.

PMID: 20448535



[5] Lv J, Qi L, Yu C, Yang L, Guo Y, Chen Y, Bian Z, Sun D, Du J, Ge P, Tang Z, Hou W, Li Y, Chen J, Chen Z, Li L; China Kadoorie Biobank Collaborative Group. Consumption of spicy foods and total and cause specific mortality: population based cohort study. BMJ. 2015 Aug 4;351:h3942. doi: 10.1136/bmj.h3942. PubMed PMID: 26242395; PubMed Central PMCID: PMC4525189. (See also the Rapid Response by Prof. Nicholas D Moore).

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#50 Dean Pomerleau

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Posted 11 February 2016 - 04:19 PM



In my continuing obsession with cold exposure, I did some more research into compounds that can activate brown adipose tissue (BAT), in addition to metformin and capsaicin discussed in the previous post.


It turns out that caffeine [1][2] and especially caffeinated green tea [3][4][5], also activates BAT!  Of course all these studies except for [4] were performed in rodents, which naturally possess significant amounts of BAT, particularly when housed at chilly (for them) typical lab temperatures. Study [4] was in humans, and showed that caffeinated green tea promoted more thermogenesis than its caffeine content would predict. Study [4] is from 1999, a decade before it was discovered that (some) humans have BAT, so they weren't even in a position to speculate that the increased thermogenesis was likely a result of activating BAT. But we know now that is probably the mechanism.


Of course, like with metformin and capsaicin, you need to have brown adipose tissue before green tea can activate it - which again probably requires cold exposure. 


I find it really intriguing (and encouraging) that three compounds known to promote health and possibly lifespan, metformin, capsaicin, and green tea, all seem to have their effect, at least in part, via activating brown adipose tissue.





[1] J Nutr Sci Vitaminol (Tokyo). 1990 Apr;36(2):173-8.

Caffeine activates brown adipose tissue thermogenesis and metabolic rate in mice.
Yoshioka K(1), Yoshida T, Kamanaru K, Hiraoka N, Kondo M.
Author information: 
(1)First Department of Internal Medicine, Kyoto Prefectural University of
Medicine, Japan.
To clarify the effect of caffeine on brown adipose tissue (BAT) thermogenesis, we
measured guanosine-5'-diphosphate (GDP) binding, a thermogenic indicator of BAT, 
and oxygen consumption in BAT mitochondria as well as BAT temperature and resting
metabolic rate (RMR) in mice. Intraperitoneal injection of caffeine (60 mg/kg)
significantly elevated BAT temperature with less effect on core temperature, and 
increased significantly GDP binding and oxygen consumption in BAT mitochondria,
and RMR. These results suggest that caffeine activates BAT thermogenesis, which
may contribute to the increase of RMR.
PMID: 2388099
[2] Int J Obes. 1991 May;15(5):317-26.
Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown
adipose tissue.
Dulloo AG(1), Seydoux J, Girardier L.
Author information: 
(1)Centre Medical Universitaire, Department of Physiology, University of Geneva, 
The peripheral mechanisms by which ephedrine and caffeine influence thermogenesis
were investigated in innervated rat interscapular brown adipose tissue (IBAT) by 
assessing its rate of oxygen consumption (MO2) in vitro. Dose-response
measurements with tissues from intact or sympathectomized (6-OHDA) animals
indicate that the thermogenic effects of low concentrations of ephedrine and also
of caffeine are entirely dependent upon the presence of intact sympathetic nerve 
endings, and thus depend on presynaptic mechanisms. Direct postsynaptic
stimulation of thermogenesis is only apparent at much higher concentrations,
namely greater than 1 microM for ephedrine and greater than 2mM for caffeine. At 
subminimal concentrations that neither ephedrine nor caffeine influenced basal
tissue respiration, they induced a 4-5-fold increase in basal MO2 when
administered in combination, a synergistic response prevented by pre-treatment of
the rat with 6-OHDA. Synergistic increases in IBAT respiration were also obtained
when subminimal concentration of ephedrine was added to 3-propylxanthine (a
specific inhibitor of phosphodiesterase), to 8-phenyltheophylline (a potent
adenosine receptor antagonist) or to adenosine deaminase (for enzymatic
inactivation of endogenous adenosine). Conversely, the marked synergism in
thermogenic response with ephedrine + caffeine was reduced in the presence of
2-chloroadenosine (an adenosine analogue). In tissues from fasted rats, the
ephedrine + caffeine synergism in thermogenic response, although attenuated, was 
nevertheless present. These studies therefore demonstrate that ephedrine, at
doses comparable with therapeutic use, stimulates thermogenesis in BAT via
sympathetically released NA. In addition, a synergistic interaction between
caffeine and ephedrine on BAT thermogenesis is explained by ephedrine's
enhancement of sympathetic neuronal release of NA, together with caffeine's dual 
ability to antagonize adenosine and to inhibit cellular phosphodiesterase
PMID: 1885257


[3] Int J Obes Relat Metab Disord. 2000 Feb;24(2):252-8.

Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine 
and sympathetic activity.
Dulloo AG(1), Seydoux J, Girardier L, Chantre P, Vandermander J.
Author information: 
(1)Institute of Physiology, University of Fribourg, Fribourg, Switzerland.
The thermogenic effect of tea is generally attributed to its caffeine content. We
report here that a green tea extract stimulates brown adipose tissue
thermogenesis to an extent which is much greater than can be attributed to its
caffeine content per se, and that its thermogenic properties could reside
primarily in an interaction between its high content in catechin-polyphenols and 
caffeine with sympathetically released noradrenaline (NA). Since
catechin-polyphenols are known to be capable of inhibiting
catechol-O-methyl-transferase (the enzyme that degrades NA), and caffeine to
inhibit trancellular phosphodiesterases (enzymes that break down NA-induced
cAMP), it is proposed that the green tea extract, via its catechin-polyphenols
and caffeine, is effective in stimulating thermogenesis by relieving inhibition
at different control points along the NA-cAMP axis. Such a synergistic
interaction between catechin-polyphenols and caffeine to augment and prolong
sympathetic stimulation of thermogenesis could be of value in assisting the
management of obesity. International Journal of Obesity (2000) 24, 252-258
PMID: 10702779




[4] Am J Clin Nutr. 1999 Dec;70(6):1040-5.

Efficacy of a green tea extract rich in catechin polyphenols and caffeine in
increasing 24-h energy expenditure and fat oxidation in humans.
Dulloo AG(1), Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P,
Vandermander J.
Author information: 
(1)Department of Physiology, Faculty of Medicine, University of Geneva.
BACKGROUND: Current interest in the role of functional foods in weight control
has focused on plant ingredients capable of interfering with the sympathoadrenal 
OBJECTIVE: We investigated whether a green tea extract, by virtue of its high
content of caffeine and catechin polyphenols, could increase 24-h energy
expenditure (EE) and fat oxidation in humans.
DESIGN: Twenty-four-hour EE, the respiratory quotient (RQ), and the urinary
excretion of nitrogen and catecholamines were measured in a respiratory chamber
in 10 healthy men. On 3 separate occasions, subjects were randomly assigned among
3 treatments: green tea extract (50 mg caffeine and 90 mg epigallocatechin
gallate), caffeine (50 mg), and placebo, which they ingested at breakfast, lunch,
and dinner.
RESULTS: Relative to placebo, treatment with the green tea extract resulted in a 
significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h
RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen.
Twenty-four-hour urinary norepinephrine excretion was higher during treatment
with the green tea extract than with the placebo (40%, P < 0.05). Treatment with 
caffeine in amounts equivalent to those found in the green tea extract had no
effect on EE and RQ nor on urinary nitrogen or catecholamines.
CONCLUSIONS: Green tea has thermogenic properties and promotes fat oxidation
beyond that explained by its caffeine content per se. The green tea extract may
play a role in the control of body composition via sympathetic activation of
thermogenesis, fat oxidation, or both.
PMID: 10584049
[5] J Nutr Biochem. 2003 Nov;14(11):671-6.

Green tea reduces body fat accretion caused by high-fat diet in rats through
beta-adrenoceptor activation of thermogenesis in brown adipose tissue.

Choo JJ(1).

Author information:
(1)Department of Foods and Nutrition, Kunsan National University, Kunsan,
Cheollabuk-do 573-701, South Korea. jjchoo@kunsan.ac.kr

The aim of the present study was to investigate body fat-suppressive effects of
green tea in rats fed on a high-fat diet and to determine whether the effect is
associated with beta-adrenoceptor activation of thermogenesis in brown adipose
tissue. Feeding a high-fat diet containing water extract of green tea at the
concentration of 20g/kg diet prevented the increase in body fat gain caused by
high-fat diet without affecting energy intake. Energy expenditure was increased
by green tea extract which was associated with an increase in protein content of
interscapular brown adipose tissue.
The simultaneous administration of the
beta-adrenoceptor antagonist propranolol(500 mg/kg diet) inhibited the body
fat-suppressive effect of green tea extract. Propranolol also prevented the
increase in protein content of interscapular brown adipose tissue caused by green
tea extract. Digestibility was slightly reduced by green tea extract and this
effect was not affected by propranolol. Therefore it appeared that green tea
exerts potent body fat-suppressive effects in rats fed on a high-fat diet and the
effect was resulted in part from reduction in digestibility and to much greater
extent from increase in brown adipose tissue thermogenesis through
beta-adrenoceptor activation.

PMID: 14629899

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#51 Dean Pomerleau

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Posted 12 February 2016 - 01:51 AM

Thanks to Al Pater for sending me a pointer to this study [1] characterizing BAT in humans. From the full text, it appears that cold exposure can greatly increase the amount of BAT a person has, and it has a significant effect on one's metabolic rate:


In healthy lean male and female adults (mean 6 SD age 40 6 9 years), mean weight of cold-activated human BAT calculated by PET-CT was 34 g (range 9–90) (8). ... That estimate compares with the mean 151 g (range 29–296) in cold-exposed young men (9)... Based on the calculation of 63 g cervical BAT reported in a different study by Virtanen et al. (7), it was estimated that activated BAT thermogenesis contributed 4.5% to whole body energy expenditure, which was considered to be significant (23) and commensurate with the goal of exploiting BAT to burn excess calories stored in WAT for weight loss in obesity and type 2 diabetes (3). The 5% figure cited above could be an underestimate by a factor of two to three in some subjects because of their greater BAT mass.


What's pretty amazing to me is that so little active brown adipose tissue (e.g. 150g or 1/3 of a pound) can contribute as much as 10-12% of whole body energy expenditure. Those are some active fat cells!


The paper goes on to discuss in excruciating detail the distribution of BAT around the body and its evolutionary purpose (to generate heat in order to keep key organs warm). Regarding distribution of BAT, the bottom line appears to be that most of it is located in the upper chest, upper back, and along the spine. Here is a pretty cool image of someone with a lot of activated BAT:




It talks about how obese and diabetic people have less BAT, and less BAT activity, than lean people (yeah for us!):


Obesity is associated with a reduction in BAT activity
(6,44) but the extent to which obesity is cause or effect or
involved in a vicious cycle or energy intake exceeding
expenditure remains to be established.


It discusses various ways of increasing/activating BAT in obese/diabetic people, including cold exposure "if tolerated by people". The authors speculate about the alternative possibility of injecting harvested and cultured BAT cells either into the neck region or abdominal region of obese people to trigger thermogenesis and energy expenditure. Seems pretty extreme, when cold exposure seems to be able to accomplish BAT activation, without the surgery.





[1] Diabetes. 2013 Jun;62(6):1783-90. doi: 10.2337/db12-1430.

Anatomical locations of human brown adipose tissue: functional relevance and
implications in obesity and type 2 diabetes.

Sacks H(1), Symonds ME.

Author information:
(1)Endocrinology and Diabetes Division, VA Greater Los Angeles Healthcare System,
Los Angeles, California, USA. hsacks@hotmail.com


Free full text: http://diabetes.diab...3.full.pdf html

We will review information about and present hypotheses as to the anatomy of
brown adipose tissue (BAT). Why is it located where it is in humans? Its
anatomical distribution is likely to confer survival value by protecting critical
organs from hypothermia by adaptive thermogenesis. Ultimately, the location and
function will be important when considering therapeutic strategies for preventing
and treating obesity and type 2 diabetes, in which case successful interventions
will need to have a significant effect on BAT function in subjects living in a
thermoneutral environment. In view of the diverse locations and potential
differences in responsiveness between BAT depots, it is likely that BAT will be
shown to have much more subtle and thus previously overlooked functions and
regulatory control mechanisms.

PMCID: PMC3661606
PMID: 23704519

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#52 Dean Pomerleau

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Posted 12 February 2016 - 06:15 PM



Before anyone (else) considering experimenting with cold exposure goes out and buys the TechKewl cooling vest I pointed to earlier, which sounds like it may not be a great fit for small folks like many of us, you might want to consider this other product I discovered, the Cool Fat Burner (CFB). It comes in two styles and a variety of sizes. The "original" style costs $86 including tax and shipping.


It comes in two styles:


                     Original ($86 incl S&H)     "Gut Buster" Vest ($106 incl S&H)            






Here is what the "original" looks like on someone:




Given that most BAT is located in the clavicle region and is responsive to local cooling, this original form factor makes sense. If you're only going to buy one of them, it seems to me therefore the original version is the way to go. But if you buy both together you get a 25% discount...


They've got some pretty cool scientific tests and case studies of brown fat activation as a result of using the CFB. Consistent use definitely appears to promote the generation and activation of BAT. 


I haven't bought any vest yet - it's still a "balmly" 14F outside in Pittsburgh, and 58F in my basement "man cave" so extra cooling isn't yet required. But I'll probably give this one a try.  It comes with a 60-day, 110% guarantee if not completely satisfied.



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#53 Dean Pomerleau

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Posted 13 February 2016 - 04:42 PM



In my continuing quest to find ways to maximize brown adipose tissue (BAT) activity, this study [1] found that a low protein diet was conducive to high BAT activity, independent of whether the protein was replaced by carbohydrates or fats. This is interesting because protein restriction is yet another intervention that is thought to be healthy and potentially extend lifespan, in fact some people think protein restriction may be the way calorie restriction actually has its benefits. 


So protein restriction can be added to the growing list of interventions that activate BAT and also are thought to be health / lifespan promoting. The list now includes:

  • Cold exposure - by far the best BAT activator
  • Metformin
  • Green Tea
  • Caffeine
  • Capsaicin
  • A low protein diet

The fact that so many compounds and interventions thought to be healthy are BAT activators suggests to me that BAT may be an important contributor to health and longevity.






[1] J Nutr. 1987 Oct;117(10):1721-6.

Influence of carbohydrate and fat intake on diet-induced thermogenesis and brown
fat activity in rats fed low protein diets.

Rothwell NJ(1), Stock MJ.

Author information:
(1)Department of Physiology, St. George's Hospital Medical School, Tooting,
London, United Kingdom.

Voluntary intake of protein, fat and carbohydrate (CHO) was modified by feeding
young rats either a control purified diet [% metabolizable energy (ME): protein
21, fat 7, CHO 72], a control diet plus sucrose solution (20%) to drink (final
intakes 17, 6 and 77% ME as protein, fat and CHO, respectively) or a low protein
diet substituted with either CHO (8, 7 and 85% ME as protein, fat and CHO,
respectively) or fat (8, 20 and 72% ME as protein, fat and CHO, respectively).
Total ME intakes corrected for body size were similar for all rats, but body
weight, energy gain and net energetic efficiency were lower in both low
protein-fed groups than in the control group. The acute thermogenic response (%
rise in oxygen consumption) to a standard balanced-nutrient meal was higher (12%)
in sucrose-supplemented and in low protein groups (15-16%) than in control rats
(8%). Brown adipose tissue protein content and thermogenic capacity (assessed
from purine nucleotide binding to isolated mitochondria) were greater than
control values in sucrose-fed and protein-deficient animals, and the greatest
levels of activity were seen in low protein-fed rats with a high fat intake. The
results demonstrate that the changes in energy balance, thermogenesis and brown
adipose tissue activity that result from protein deficiency cannot be ascribed to
changes in the level of energy intake or to a specific increase in the amount or
proportion of either CHO or fat. They suggest that the protein-to-energy ratio
must be the primary influence on thermogenesis and brown fat activity in these

PMID: 3668686 

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#54 Dean Pomerleau

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Posted 14 February 2016 - 05:17 PM

Here is an interesting new study [1] (press release) thanks to Al Pater. It found that mice exposed to cold lost weight, at least for the first few weeks, as a result of increased BAT-mediated thermogenesis - no surprise.


But what was surprising was the mechanism they discovered by which cold exposure appeared to influence BAT - namely via the mice's gut bacteria. At the bottom is the helpful graphical abstract from the full text helps to illustrate what the researchers did, and what they found. FIrst they exposed two groups of mice to either cold or normal (warm) conditions for 10 days. The gut microbiome of the cold-exposed mice (the "cold microbiome") was dramatically different from the microbiome of the warm mice (the "warm microbiome"). They then transferred the cold and warm microbiomes to two different groups of germ-free mice. Surprisingly, receiving the cold microbiome resulted in the conversion of white adipose tissue (WAT) to brown (or beige) adipose tissue (BAT), with an accompanying increase in insulin sensitivity and thermogenesis - all without ever being exposed to cold!


The mice that received the cold microbiome initially lost weight as a result of increased thermogenesis. But remarkably, after several weeks the weight loss stopped despite no change in food intake. What they discovered was that the cold microbiome caused the mice's intestine to grow in size and triggered an increase in the surface area of intestinal cells that absorb nutrients. The lead researcher said:


"These findings demonstrate that gut microbes enable mammals to harvest more energy from food as a way to adapt to the increased energy demand associated with long periods of cold exposure, thereby helping to protect against hypothermia," Trajkovski says. "We were surprised to see that gut microbes had such dramatic effects on the structure and function of the intestine."


This is yet another dramatic illustration of how important and influential the gut microbiome is for health. It suggests, at least theoretically, one more intervention for increasing BAT expression - get a poop transplant from someone who have undergone consistent exposure to cold :-).








[1] Cell. 2015 Dec 3;163(6):1360-74. doi: 10.1016/j.cell.2015.11.004.


Gut Microbiota Orchestrates Energy Homeostasis during Cold.


Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S, Montet X, Seimbille Y, Zamboni N, Hapfelmeier S, Trajkovski M.


Full text: http://linkinghub.el...8674(15)01484-1


Cold exposure leads to marked changes in the gut microbiota composition

Cold microbiota transplantation increases insulin sensitivity and WAT browning

Cold exposure or cold transplantation increase the gut size and absorptive capacity

Reconstitution of cold-suppressed A. muciniphila reverts the increased caloric uptake


Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.


PMID: 26638070

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#55 Gordo

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Posted 14 February 2016 - 11:08 PM

It is interesting to note that women generally have more BAT than men, and they generally live longer, I do wonder if there is a connection there.


Is there evidence that cooling specific body parts such as the clavicle area where BAT is more common actually results in increased BAT formation vs. other types of cooling?  Some of the studies Dean posted links to showed increases in BAT when subjects were only getting direct cooling to their legs (where little to no BAT exists).


Regarding the Techkewl vest, I've done a bit more experimentation with it.  With a complete charge (still not sure how long that takes, I had mine in a deep freezer for many days) the vest will cool for up to 5 hours.  The vest has 4 cooling panels, each consisting of 4 sealed packs (16 packs in all).  After 4 hours, 2 out of the 16 PCM packs were 100% liquid, but overall I would estimate about 80% phase change had occurred. After 5 hours the vest was still cooling, and 7 out of 16 packs were 100% liquid but 95% phase change had occurred overall.  I had done a light HIIT exercise routine during this period, stair runs and pull ups, while wearing the vest, house temps were between 70-75 the whole time.


Also I found that just putting a belt around the vest between its velcro straps results in an excellent fit with all 16 PCM packs making solid contact to my body.  



Note that simply by pulling the two front cooling panels upward, although probably not designed for this, the vest works very well for directly cooling both the neck and clavicle areas where BAT is most prevalent and seems to stay in place surprisingly well even when walking around.  The total PCM material looks to be possibly double (or more?) in the techkewl vs. the cool fat burner (although that is hard to tell just from pictures).  If you were only interested in cooling the neck/clavicle area, you could just use two of the four techkewl PCM panels and always have one set in the freezer for continuous cooling by swapping out the panels every 4-5 hours.


Example with front panels pulled up, covering the clavicles:



I doubt it would be necessary but you could also put something into the bottom of the vest PCM panel pockets like a sponge or a sock that would make it impossible for the panel to move back down from the raised position shown.

#56 Gordo

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Posted 14 February 2016 - 11:50 PM

This seems like a decent video from the cool fat burner people, that shows where BAT tends to build up (10 minutes in starts the PET scan):


Ribs (all of them) and spine seem to be quite significant.

#57 Dean Pomerleau

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Posted 15 February 2016 - 11:39 AM


Thanks for all the helpful information about the TechKewl vest. It sounds much better than the impression I got from your initial review. The belt looks like a very good idea, and your observation that a charge lasts 4-5 hours sounds great!


Yes, I'd watched that Cool Fat Burner video and found it pretty helpful. For a product you'd expect to be a total weight loss scam, the inventor (I presume) does some pretty interesting and well-documented self-experiments. He's a man after my own heart! He does have quite a bit of BAT all over his torso, as the PET scan in the video shows. But even for him (with a lot of cold exposure under his belt) it appears concentrated towards the upper chest and shoulders. This Huffington Post article (comparing BAT in caucasians vs. asians - caucasians have more, and lower diabetes risk, suggesting a link there) has a better picture of six men (3 caucasian and 3 asian) with their distribution of BAT:




It looks to me like while some of the men have pockets of BAT all around the chest cavity, the largest, most consistent and most active concentration of BAT is in the shoulders, clavicle area and around the trapezius muscle in the upper middle of the back. Here is where BAT is located as described in this NY Times article:


There was not much brown fat, just a few ounces in the upper back, on the side of the neck, in the dip between the collarbone and the shoulder, and along the spine.


While I'm not certain focusing the cooling on those spots will be more effective than cooling elsewhere on the body - it seems reasonable to suppose based on the fact that BAT activation is temperature dependent and that placing the cooling source near it will likely affect its temperature more than cooling more distant parts of the body, particularly in spots where the BAT deposits are near the surface, like at the neck, shoulders and trapezius area.


I can't really tell where on the TechKewl vest the cooling packs themselves are located based on your pictures. Do they extend up to and above the horizontal seam in the photo just above the logo on the chest? Similarly, how high do the packs go in the back? If the packs don't extend that high it would seem that they aren't really hitting the shoulder/clavicle/trapezius area very well, even when hiked up.


Regarding women having more BAT than men - I wasn't aware of that. But it appears you are correct! Here is an article from back in 2009 when it was discovery that adult humans have significant brown fat, contrary to previous thinking. Here is a quote from the article:


They also discovered that brown fat is most abundant in young women and least frequent in older, overweight men. In fact, women were more than twice as likely as men to have substantial amounts of brown fat.


"One theory for this is that women may have less muscle mass overall, so they need more brown fat to generate heat and keep warm," Cypess said.


 Stay tuned for my next post in this thread where I'll discuss the topic of women, leanness and BAT prevalence...

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#58 Dean Pomerleau

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Posted 15 February 2016 - 04:33 PM

As promised in my previous post, more on the topic of leanness and brown adipose tissue (BAT) prevalence...
I came across this 2013 study [1] which is quite interesting, and potentially important for lean CR folks hoping to generate and activate BAT.
They tested BAT activity via a PET scan at relatively mild ambient temperatures (low 70s F) in 38 women divided into four different groups:
  1. Constitutionally Lean (CL) women (avg. BMI 16.2) - "Constitutional leanness is a peculiar physiological condition whereby the body is resistant to fat storage, even in overfeeding conditions." That is, women who were naturally skinny without CR.
  2. Anorexic women (AN) women (avg BMI 15.5)
  3. Recovered anorexic (R-AN) women (avg BMI 18.8)
  4. Normal weight control (NW) women (avg BMI 22.2)
Note they were all a pretty thin bunch of women by American standards, even the normal weight controls.
Here is the most important thing they found:
 All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed [measureable BAT activity].
So it was really only the naturally thin women who had active BAT, neither the anorexics nor the normal weight women had much if any. Furthermore, even in the 3 (of 24) normal weight women who appeared to have some BAT, they had only half as much BAT activity as the constitutionally lean women.
Interestingly, they found:
In [the constitutionally lean women], the [measure of BAT activity] was ... inversely correlated
with respiratory quotient.
From the full text of [1], here is the graph illustrating this relationship, with respiratory quotient (RQ) along the X-axis and a measure of BAT activity on the Y-axis. As you can see, a pretty strong inverse linear relationship (r = 0.74).
For those who don't know, respiratory quotient (RQ) is basically a measure of how much fat vs. carbohydrates an organism is burning. A high RQ (towards the right side of the graph) means you are burning a lot of carbs. A low RQ (towards the left side of the graph) means you are burning a lot of fat. Protein is in the middle. What this statement and the corresponding graph are saying/showing is that the naturally thin women with the most BAT activity were the ones who were burning the most fat relative to carbohydrates.
This makes sense, since BAT preferentially burns fat rather than carbohydrates. But it suggests that for those of us without much (white) adipose tissue (i.e. with a low percentage body fat) for the BAT to burn, it will be best to consume sufficient fat in our diet to enable BAT to form and be active. I guess it's good (for BAT activity anyway) that I'm eating quite a bit of fat mostly from nuts, seeds and avocados (in fact both Michael and Sirtuin say I'm eating a "stupid high" amount of such fat :-) ) - rather than a high carb diet I was previously following.
Finally, they found:
In [the constitutionally lean women], the [measure of BAT activity] was directly correlated to resting metabolic rate...
Here is the graph backing up this finding, with metabolic rate along the X-axis and a measure of BAT activity along the Y-axis. It is a pretty clear and dramatic linear relationship (r = 0.81) - a higher metabolic rate equates with more BAT activity:
This suggests that these women were naturally thin because of their higher resting metabolic rate, which resulted from their elevated level of BAT activity.
This is interesting in light of the fact that many of us "naturally thin" CR practitioners have been bemoaning (e.g. in this extended thread) the fact that we may not benefit from CR as much as naturally "thrifty" people who tend retain a lot of weight because we can't cut calories as much as they can without losing too much weight.
The results of this study can be interpreted to suggest quite the opposite. Namely, it seem to suggest that being "naturally thin" may be a result of having more (active) brown fat. And if the hypothesis that I've been promulgating throughout this thread is correct, namely that burning calories "cleanly" via BAT-mediated thermogenesis may be beneficial and perhaps even critical for CR lifespan benefits, than we naturally thin folks may actually have an advantage over our chubbier counterparts, because we have more (active) brown fat.
But the other thing to think about for everyone practicing CR is the results seen in the anorexics in this study. They are obviously quite thin (BMI 15.5!), almost certainly had a relatively low core body temperature and obviously a low percentage of regular (white) adipose tissue, just like most serious CR practitioners. But none of them, not even the one's who had recovered and had a BMI of nearly 19, had any measureable BAT activity. 
This suggests that unless one is naturally quite thin and has a high metabolic rate, simply practicing CR and hoping you'll develop BAT simply because you feel cold much of the time, isn't likely to cut it.
In other words, you won't have much BAT unless you actively expose yourself to cold. And further, you need to literally be cold rather than simply feel cold in otherwise warm conditions, to generate BAT.
[1] J Clin Endocrinol Metab. 2013 Mar;98(3):1214-8. doi: 10.1210/jc.2012-2981. Epub
2013 Feb 7.
Evidence of brown fat activity in constitutional leanness.
Pasanisi F(1), Pace L, Fonti R, Marra M, Sgambati D, De Caprio C, De Filippo E,
Vaccaro A, Salvatore M, Contaldo F.
Author information:
(1)Federico II University of Naples, Department of Clinical Medicine and Surgery,
Via Pansini 5, Naples, Italy. pasanisi@unina.it
BACKGROUND: Brown adipose tissue (BAT) was considered essentially nonexistent in
adults until recent evidence obtained using 18-fluorodeoxyglucose (18-FDG)
positron emission tomography/computed tomography. It seems to play a role in
whole body metabolism, but it has not been evaluated in underweight conditions,
such as in young females with constitutional leanness (CL) or anorexia nervosa
SUBJECTS AND METHODS: Thirty-eight subjects were evaluated from October 2011 to
March 2012 : 7 CL (21.7 ± 3.6 y, body mass index [BMI] 16.2 ± 1.0 kg/m(2)), 7 AN
(23.4 ± 4.5 y, BMI 15.5 ± 0.8), 3 of the 7 AN after stable refeeding (R-AN, 21.3
± 1.5 y, BMI 18.8 ± 1.1), and 24 normal weight (NW) women (25.6 ± 3.9 y, BMI 22.2
± 1.5). Fasting resting metabolic rate and respiratory quotient were measured by
indirect calorimetry, body composition by bioimpedentiometry (only in CL, AN, and
refed AN), and BAT activity by 18-FDG positron emission tomography/computed
tomography scan, all in standardized conditions.
RESULTS: All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW
(12%) subjects showed FDG uptake. Average FDG maximum standardized uptake value
was 11.4 + 6.7 g/mL in CL and 5.5 ± 1.2 g/mL (min 3.7, max 8.3) in the 3 NW
subjects. In CL, the maximum standardized uptake value was directly correlated to
resting metabolic rate, corrected for fat-free mass, and inversely correlated
with respiratory quotient.
CONCLUSION: BAT activity has been shown in CL in resting thermoneutral conditions
and may exert a role against adipose tissue deposition.
PMID: 23393181

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#59 mikeccolella

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Posted 16 February 2016 - 11:37 AM

66 sounds like normal to my thinking and body, although I tend to overdress. So what are we talking about in practical terms here? I drive to work and back with little to no heat. I am shivering at times and that amounts to about an hour a day. For some reason, probably conditioning, I kind of like it during my drives- it's like caffeine lol. Really!

So is an hour of cold/ mild shivering daily going to have any positive impact?

Edited by mikeccolella, 16 February 2016 - 11:40 AM.

#60 Dean Pomerleau

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Posted 16 February 2016 - 11:41 AM

Hi Mike,


Many of the human brown fat experiments are done at temperatures in the low- to mid-60s F.


For example, this study [1], put healthy young men in a cooling suit set to 64F for 3 hours, and observed an 80% increase in total energy expenditure (about an extra 250kcal burned) averaged across subjects, due largely to activation of BAT.


Here are an interesting passage from the full text of this paper:


The wide interindividual differences in detectable BAT volume of activity (from to 31 to 329 ml) observed in young healthy men in the present study suggests that unknown factors may modulate BAT volume and thermogenic capacity in addition to age, sex, body mass index, and diabetes (24). 


So the amount of BAT varied by a factor of 10 among these young male subjects! Pretty dramatic. Part of the variation is probably genetic, and part of it may be differences in prior cold exposure.


Furthermore, we found a significant inverse relationship between BAT volume of activity and shivering.


So while it's hard to measure BAT directly (since it requires a PET scan or autopsy...), is appears that the temperature at which you start shivering might serve as a rough gauge of how much BAT you have.


How low can you go? :-)





[1] J Clin Invest. 2012 Feb;122(2):545-52. doi: 10.1172/JCI60433. Epub 2012 Jan 24.

Brown adipose tissue oxidative metabolism contributes to energy expenditure
during acute cold exposure in humans.

Ouellet V(1), Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE,
Richard D, Carpentier AC.

Author information:
(1)Centre de recherche de l’Institut universitaire de cardiologie et de
pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.


Free full text: http://www.jci.org/a...4aee3d55b74adc8

Comment in
J Clin Invest. 2012 Feb;122(2):486-9.

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure
in rodents, but until recently its presence in adult humans and its contribution
to human metabolism were thought to be minimal or insignificant. Recent studies
using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in
adult humans. However, whether BAT contributes to cold-induced nonshivering
thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG,
and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have
quantified BAT oxidative metabolism and glucose and nonesterified fatty acid
(NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All
subjects displayed substantial NEFA and glucose uptake upon cold exposure.
Furthermore, we demonstrated cold-induced activation of oxidative metabolism in
BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This
activation was associated with an increase in total energy expenditure. We found
an inverse relationship between BAT activity and shivering. We also observed an
increase in BAT radio density upon cold exposure, indicating reduced BAT
triglyceride content. In sum, our study provides evidence that BAT acts as a
nonshivering thermogenesis effector in humans.

PMCID: PMC3266793
PMID: 22269323

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