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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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6 hours ago, Sibiriak said:

 

Moscow resorts to fake snow in warmest December since 1886

But  in Krasnoyarsk--Прогноз погоды  28  декабря суббота  ночь – утро   -33° ощущается как -38°  день – вечер -29° ощущается как -29°

 

It's good to know that Siberia is still holding up!

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Going off topic (perhaps this should be in the "purpose of life" thread):   the Russian national figure skating championship was just held in Krasnoyarsk,  and  this 15 year old girl,  Anna Shcherbakova was just amazing.  The beauty! The perfection!   "Shcherbakova flawlessly nailed a quadruple lutz-quadruple toe-loop combination before adding a single quad lutz and a quad flip triggering standing ovation from the crowd."    Check out what she does with her dress at 2:23.  Very cool!

 

 

Edited by Sibiriak

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That's amazing, Sibirak. Every time I see one of those Boston Dynamics robot "dogs" or other running/jumping robots, I think they still have a ways to go. Let me see a robot that can do what this girl can do, and I'll be impressed. Human beings are pretty amazing machines. For that matter, all organic machines are amazing. I still marvel at the size of a hummingbird - the volume/weight of the brain (control system), and the unbelievably athletic flying capabilities. Heck, even insects like flies - smaller yet - are shockingly adept machines that can avoid attempts at swatting, and fly in almost physics defying ways. I say, robots still have a very, very, very, very, very long way to go to match or surpass these capabilities in such tiny sizes. By comparison, the Boston Dynamics machines seem insanely primitive. Ooops, here I go on yet another of my "HYPE!!!" rants, this time regarding robot capabilities. I see Boston Dynamics creations and I'm supremely unimpressed - I say HYPE!!!

But then again, I don't say "HYPE" when I see what this skater can do - here I am full of unadultarated admiration.

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👏👏

I don't follow figure skating but that performance had me utterly amazed. Looking more of an ethereal figure than a  flesh-and-bones human being.

Her body seems to be optimized for the sport,  very light upper body frame, larger lower body but not too much, optimizing weight and power.

The genetics for a neural-motor coordination must also be unique.  To say nothing of the choice of background music and coreography.

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We will have to add chronic high-sucrose diet to the list 😉

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

Abstract

Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and β-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain.

 

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Lifespan of long-lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning.
Fang Y, McFadden S, Darcy J, Hascup ER, Hascup KN, Bartke A.
Aging Cell. 2020 Feb 28:e13123. doi: 10.1111/acel.13123. [Epub ahead of print]
PMID: 32110850
Abstract
Growth hormone receptor knockout (GHRKO) mice are remarkably long-lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO2 ). Short-term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short-term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C.
KEYWORDS:
GHRKO; growth hormone receptor; lifespan; metabolism; temperature; thermogenesis

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Al,

The paper you just posted [1] comparing growth growth hormone receptor knockout (GHRKO) mice housed at a chilly (for mice) 23degC and thermoneutrality (30degC) is a goldmine. Thanks for finding it!

In summary, the study found that male GHRKO mice lived as long spending their entire adult life at 30degC as 23degC, and female GHRKO mice actually lived longer (both mean and max lifespan) at 30degC compared with 23degC.

It first glance, this result would seem to contradict two of the core tenets of the cold exposure hypothesis that I've been promulgating for years on this thread, namely:

  1. Eating extra calories and burning them through thermogenesis isn't harmful for longevity, and
  2. Brown Adipose Tissue (BAT) is beneficial for health and longevity.

In fact, tenet #1 is supported strongly by this study, at least in the male GHKO mice. Figure 1a shows that the male mice ate about 50% more food per gram of body weight throughout their life when housed at the chilly 23degC compared with 30degC (~0.14mg/gBW vs. ~0.08mg/gBW). And yet the chilly male mice lived just as long as the male mice housed at the warmer temperature. Here are the survival curves for the male (top) and female (bottom) mice housed at 23 (black) and 30 (red):

Screenshot_20200229-143333_Foxit PDF.jpg

If the "calories, calories, calories" mantra was correct, the cold-housed male mice who pigged out relative to those housed at thermoneutrality but burned those calories to stay warm should have lived a lot shorter lives, but they didn't.

But what about tenet #2, and what about the fact that female GHRKO mice lived longer at 30degC than 23degC?

Here is where things get really interesting. Unlike most other, non-mutant rodents, GHRKO mice don't gain weight when housed at thermoneutral 30degC vs. 23degC. Here are the weights of male (while bars) and female (black bars) mice at the two different temperatures:

Screenshot_20200229-144504_Foxit PDF.jpg

In fact, the long-lived females percentage of lean mass actually went down at the higher housing temperature. In a very surprising (to me at least) result, what went up in both male and female warm-housed GHRKO mice was brown adipose tissue! Here is the graph showing an increase in BAT as a percent of body weight, which is equivalent to absolute BAT mass increase, since body weight didn't change between the two housing temperatures:

Screenshot_20200229-150221_Foxit PDF.jpg

This is surprising since in non-mutant rodents, total BAT mass and BAT as a percentage of body weight usually go down at warmer housing temperatures, as a result of less need for thermogenesis to keep warm. This unusual finding speaks to tenet #2, the goodness of having more BAT. In other words, the longevity advantage GHRKO mice enjoy may in part be due to their unusual ability to maintain a lot of BAT, regardless of the housing temperature. As we saw yesterday (here), BAT does much more than simply generate heat, e.g. it produces anti-inflammatory compounds and boost anti-inflammatory cell types (e.g. anti-inflammatory M2 macrophages) that may benefit health and longevity.

But interestingly, one thing the extra BAT in these warm-housed GHRKO mice wasn't doing was generating heat via UCP-1 mitochondrial uncoupling. In fact, expression of the UCP-1 gene in BAT dropped to nearly zero when the mice were housed at the warmer temperature.

That sounds bad for the cold exposure hypothesis.

But in a fascinating twist, oxygen consumption and heat production didn't go down as one would expect when the mice were housed at thermoneutrality compared with 23degC, and as a result the body temperature of both male and female GHRKO mice went up at the warmer housing temperature.

So the mice were continuing to burn calories to generate the same amount of heat at the higher housing temperature, but not via BAT thermogenesis. So how'd they do it? The authors aren't certain, but they suggest the following:

These findings also indicate that UCP1-mediated nonshivering thermogenesis in iBAT of GHRKO mice housed at 30°C might not be a major contributor of their elevated body temperature (Figure 3a). It is plausible that existence of other UCP1-independent thermogenesis, in both adipocytes and muscle, such as creatine and calcium cycling (Betz & Enerback, 2018), might be responsible for the elevation of body temperature of GHRKO mice housed at 30°C. This leads to the speculation that UCP1-independent energy metabolism is negatively regulated by somatotropic signaling, which is deficient in GHRKO mice. This warrants future investigation.

In other words, the authors suggest that at lower housing temperature, GHRKO mice enjoy extended longevity at least in part as a result of improved glucose metabolism and insulin sensitivity mediated by increased UCP1-dependent thermogenesis in BAT. But at the higher housing temperature, the GHRKO mice continue to act like little furnaces, but via different thermogenic pathways, such a futile creatine cycling and/or calcium cycling (via sarcolipin in skeletal muscles), both of which I've discussed before (e.g. here, here and here).

Whatever the mechanism by which GHRKO mice maintain a high level of thermogenesis even at thermoneutrality, the authors suggest that it is this higher thermogenesis relative to normal mice at whatever the housing temperature that enable GHRKO mice to maintain great glucose control and insulin sensitivity and therefore live longer than normal mice:

The data from the current study demonstrate that the UCP1- dependent thermogenesis in iBAT of GHRKO mice might be the major contributor to compensate for extra heat loss by driving high energy metabolism at standard room temperature (23°C), which was eliminated or minimized at 30°C. However, GHRKO mice exposed to 30°C since weaning still maintained their high metabolism even though UCP1-dependent thermogenesis (energy metabolism) in iBAT was severely attenuated. The remaining forms of thermogenesis (energy metabolism) in GHRKO mice at 30°C are the most likely crucial driving forces to maintain glucose homeostasis in these mice. This could explain why the lifespan of GHRKO mice was not normalized (shortened) by the increased eT (30°C).
 

Bottom line, despite its surface appearance, this study appears to support the core tenets of the cold exposure hypothesis that elevated BAT mass and thermogenesis (via BAT or other mechanisms) are good for glucose metabolism and thereby longevity. The lucky little GHRKO mice seem to naturally enjoy higher BAT mass and thermogenesis independent of housing temperature. The rest of us have to work to achieve them, i.e. via cold exposure.

--Dean

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

[1] Lifespan of long-lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning.
Fang Y, McFadden S, Darcy J, Hascup ER, Hascup KN, Bartke A.
Aging Cell. 2020 Feb 28:e13123. doi: 10.1111/acel.13123. [Epub ahead of print]
PMID: 32110850
Abstract
Growth hormone receptor knockout (GHRKO) mice are remarkably long-lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO2 ). Short-term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short-term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C.
KEYWORDS:
GHRKO; growth hormone receptor; lifespan; metabolism; temperature; thermogenesis

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I am not sure if this limited human study has been posted before, but thought it's interesting:

Postprandial Oxidative Metabolism of Human Brown Fat Indicates Thermogenesis

Highlights

A carbohydrate-dominant meal triggers human brown fat thermogenesis

After a meal, the genes involved in fatty acid metabolism are highly expressed in BAT
BAT uptake of circulatory fatty acids after meal consumption is minimal
Postprandial thermogenesis in BAT is linked to circulatory fatty acid uptake

 

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Lack of UCP1 stimulates fatty liver but mediates UCP1-independent action of beige fat to improve hyperlipidemia in Apoe knockout mice.
Kataoka N, Takeuchi T, Kusudo T, Li Y, Endo Y, Yamashita H.
Biochim Biophys Acta Mol Basis Dis. 2020 Mar 13:165762. doi: 10.1016/j.bbadis.2020.165762. [Epub ahead of print]
PMID: 32179129
Abstract
Brown adipose tissue (BAT) plays a critical role in lipid metabolism and may protect from hyperlipidemia; however, its beneficial effect appears to depend on the ambient temperature of the environment. In this study, we investigated the effects of uncoupling protein 1 (UCP1) deficiency on lipid metabolism, including the pathophysiology of hyperlipidemia, in apolipoprotein E knockout (APOE-KO) mice at a normal (23 °C) and thermoneutral (30 °C) temperature. Unexpectedly, UCP1 deficiency caused improvements in hyperlipidemia, atherosclerosis, and glucose metabolism, regardless of an increase in hepatic lipid deposition, in Ucp1/Apoe double-knockout (DKO) mice fed a high-fat diet at 23 °C, with BAT hyperplasia and robust browning of inguinal white adipose tissue (IWAT) observed. Proteomics and gene expression analyses revealed significant increases in many proteins involved in energy metabolism and strong upregulation of brown/beige adipocyte-related genes and fatty acid metabolism-related genes in browned IWAT, suggesting an induction of beige fat formation and stimulation of lipid metabolism in DKO mice at 23 °C. Conversely, mRNA levels of fatty acid oxidation-related genes decreased in the liver of DKO mice. The favorable phenotypic changes were lost at 30 °C, with BAT whitening and disappearance of IWAT browning, while fatty liver further deteriorated in DKO mice compared with that in APOE-KO mice. Finally, longevity analysis revealed a significant lifespan extension of DKO mice compared with that of APOE-KO mice at 23 °C. Irrespective of the fundamental role of UCP1 thermogenesis, our results highlight the importance of beige fat for the improvement of hyperlipidemia and longevity under the atherogenic status at normal room temperature.
KEYWORDS:
Apoe knockout mice; Beige fat; Gene expression; Hyperlipidemia; Longevity; Uncoupling protein 1

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The association of outdoor temperature with blood pressure, and its influence on future cardio-cerebrovascular disease risk in cold areas.
Yu B, Jin S, Wang C, Yan S, Zhou X, Cui X, Tang Z, Luan Q, Guo Y, Bian Z, Li L, Chen Z, Na L.
J Hypertens. 2020 Mar 13. doi: 10.1097/HJH.0000000000002387. [Epub ahead of print]
PMID: 32195817
Abstract
OBJECTIVES:
To explore whether lower outdoor temperature increases cardio-cerebrovascular disease risk through regulating blood pressure and whether indoor heating in winter is beneficial to prevent cardio-cerebrovascular disease in cold areas.
METHODS:
We analyzed the data of 38 589 participants in Harbin from the China Kadoorie Biobank (CKB) during 2004-2008, with an average of 7.14-year follow-up. Linear regression analysis was performed to estimate the relationship between outdoor temperature and blood pressure. Cox regression analysis and logistic regression analysis were used to analyze the association of blood pressure with cardio-cerebrovascular event risk. Mediation analysis was performed to explore the role of blood pressure in the association between outdoor temperature and cardio-cerebrovascular events risk.
RESULTS:
There was an increase of 6.7 mmHg in SBP and 2.1 mmHg in DBP for each 10 °C decrease in outdoor temperature when outdoor temperature was higher than 5 °C. There was an inverse association between outdoor temperature and cardio-cerebrovascular event morbidity. The increases in blood pressure and cardio-cerebrovascular event morbidity were attenuated in months when central heating was fully provided. Participants with hypertension have higher risks of cardio-cerebrovascular disease (hazard ratio 1.347; 95% CI 1.281--1.415), CVD (hazard ratio 1.347; 95% CI 1.282--1.416), MACE (hazard ratio 1.670; 95% CI 1.560--1.788) and stroke (hazard ratio 1.683; 95% CI 1.571--1.803). Mediation analysis demonstrated that the association between outdoor temperature and cardio-cerebrovascular events risk was potentially mediated by blood pressure.
CONCLUSION:
Temperature-driven blood pressure potentially mediates the association between outdoor temperature and cardio-cerebrovascular events risk. Indoor heating in winter is probably beneficial to cardio-cerebrovascular disease prevention by inhibition of blood pressure increase.

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Differential responses of white adipose tissue and brown adipose tissue to calorie restriction during aging.
Sheng Y, Xia F, Chen L, Lv Y, Lv S, Yu J, Liu J, Ding G.
J Gerontol A Biol Sci Med Sci. 2020 Mar 28. pii: glaa070. doi: 10.1093/gerona/glaa070. [Epub ahead of print]
PMID: 32222773
Abstract
Age-related adipose tissue dysfunction is potentially important in the development of insulin resistance and metabolic disorder. Caloric restriction (CR) is a robust intervention to reduce adiposity, improve metabolic health, and extend healthy lifespan. Both white adipose tissue (WAT) and brown adipose tissue (BAT) are involved in energy homeostasis. CR triggers the beiging of WAT in young mice, however, the effects of CR on beiging of WAT and function of BAT during aging are unclear. This study aimed to investigate how age and CR impact the beiging of WAT, the function of BAT, and metabolic health in mice. C57BL/6 mice were fed CR diet (40% less than the ad libitum diet) for 3 months initiated in young (3 months), middle-aged (12 months), and old (19 months) stage. We found age-related changes in different types of adipose tissue including adipocyte enlargement, declined beiging of WAT, and declined thermogenic and β-oxidational function of BAT. Moreover, CR attenuated age-associated adipocyte enlargement and prevented the age-related decline in beiging potential of WAT. These protective effects on the beiging potential were significant in iWAT at all three ages, which were significant in eWAT at young and old age. In contrast, thermogenic and β-oxidational function of BAT further declined after CR in the young age group. In conclusion, our findings reveal the contribution of WAT beiging decline to age-related metabolic disorder, and suggest nutritional intervention, specifically targeting WAT beiging, as an effective approach to metabolic healthy during aging.
KEYWORDS:
BAT; beiging; calorie restriction; eWAT; iWAT

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Medcram Coronavirus series #46 has been an excellent one. The SARS-COV-2 virus has given to us the opportunity to update on basic immunology, and Medcram examines the relationship between the immune system, cold, and heat. Apparently, cold improves the response of the innate immune system, which is the one that tends to be inhibited by SARSCOV2. The innate system, which includes the natural killer-cells,  is very strong in the young (hence the very low Covid19 incidence) and is apparently strengthened by cold temperatures and also heat (inner heat in fevers and artificially caused heat in saunas). Finnish Sauna seems to be particularly apt, with its alternate cold and hot impulses. Dr Seheult cites some scientific articles, which deny all the popular stuff about cold being bad for health and favouring sickness and so on and so forth. Stuff which all of us who practise CE empirically know well is just the opposite of what happens in reality. 

 

Edited by mccoy

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This is the article on CE discussed: Brenner et al., 1999 (I am just wondering if it has already been posted by Dean or others, I'll link it anyway).

 

 

Quote

 

Conclusions

This study suggests that, despite popular beliefs that cold exposure can precipitate a viral infection, the innate component of the immune system is not adversely affected by a brief period of cold exposure. Indeed, the opposite seems the case. The fall in core body temperature resulting from cold exposure led to a consistent and statistically significant mobilization of circulating cells, an increase in NK cell activity, and elevations in circulating IL-6 concentrations. Moreover, in agreement with one of our hypotheses, prior exercise with a thermal clamp significantly augmented the leukocyte, granulocyte, and monocyte response to cold exposure. Prior passive heating and exercise without a thermal clamp also tended to augment the effect of cold exposure alone, but, because of the small sample size and intersubject variability, these changes were not statistically significant.

 

 

 

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Associations of maternal ambient temperature exposures during pregnancy with the placental weight, volume and PFR: A birth cohort study in Guangzhou, China.
Wang J, Liu X, Dong M, Sun X, Xiao J, Zeng W, Hu J, Li X, Guo L, Rong Z, He G, Sun J, Ning D, Chen D, Zhang Y, Zhang B, Ma W, Liu T.
Environ Int. 2020 Apr 1;139:105682. doi: 10.1016/j.envint.2020.105682. [Epub ahead of print]
PMID: 32248024
Abstract
BACKGROUND:
The placenta performs crucial functions to ensure normal fetal development. Experimental studies have indicated associations between exposure to elevated temperatures during pregnancy and reduction in placental weight and volume. However, epidemiological studies in humans are lacking.
OBJECTIVE:
To estimate the associations between prenatal exposure to ambient temperature with placental weight, volume, and the placental weight to birth weight ratio (PFR).
METHODS:
We conducted a prospective birth cohort study using the Prenatal Environment and Offspring Health Cohort (PEOH Cohort) beginning in 2016 in Guangzhou, China. Women in early pregnancy were recruited and followed up during their hospitalization for childbirth. An inverse distance-weighted method was employed to estimate the average temperature exposure of every 4 weeks as well as the trimester-specific average temperature exposure at the individual's residential address. A generalized linear model was applied to estimate the effects of temperature exposure during pregnancy on the placental weight, volume, and PFR.
RESULTS:
A total of 4051 pregnant women were enrolled. Compared with the reference temperature of 20 °C, maternal exposure to 29 °C (95th centile) during late pregnancy was associated with an average of -6.03 g (95% confidence interval [CI]: -11.28 g, -0.78 g) in placental weight, -16.15 cm3 (95% CI: -26.24 cm3, -6.07 cm3) in placental volume, and 0.26 (95% CI: 0.07, 0.45) in PFR. The peak effects of high temperatures on placental weight, volume, and PFR were found from 29 to 32 weeks (β = -3.79 g, 95% CI: -8.39 g, 0.82 g), 37 to 40 weeks (β = -19.34 cm3, 95% CI: -30.99 cm3, -7.69 cm3), and 25 to 28 weeks (β = 0.35, 95% CI: 0.04, 0.66), respectively.
CONCLUSIONS:
Maternal exposure to elevated temperatures was associated with a decrease in placental weight and volume and an increase in PFR. The associations were stronger when exposures occurred during late pregnancy.
KEYWORDS:
Birth cohort study; Heat stress; Placental volume; Placental weight; Placental weight to birthweight ratio; Temperature

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Al posted this interesting mouse study [1], which found CR induces adipose tissue to turn beige via mitochondria biogenesis and returning the mice to an ad lib diet causes the fat cells to change back to white.

At first glance it seems paradoxical that restricting calories triggers fat to become more metabolically active. Naively you would think that when calories are scarce the body would shift to become more thrifty rather than less.

A possible explanation for this paradox is one I've suggested before - namely that during the evolutionary past of mammals food was scarce during the winter when it was also cold. So food scarcity became a signal to trigger the production of heat-generating beige fat cells to help the calorie-starved and poorly-insulated animal stay warm, despite the metabolic cost. 

--Dean

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

[1] Sustained mitochondrial biogenesis is essential to maintain caloric restriction-induced beige adipocytes.
Mooli RGR, Mukhi D, Watt M, Edmunds L, Xie B, Capooci J, Reslink M, Eze C, Mills A, Stolz DB, Jurczak M, Ramakrishnan SK.
Metabolism. 2020 Apr 7:154225. doi: 10.1016/j.metabol.2020.154225. [Epub ahead of print]
PMID: 32275973
Abstract
BACKGROUND:
Caloric restriction (CR) delays the onset of metabolic and age-related disorders. Recent studies have demonstrated that formation of beige adipocytes induced by CR is strongly associated with extracellular remodeling in adipose tissue, decrease in adipose tissue inflammation, and improved systemic metabolic homeostasis. However, beige adipocytes rapidly transition to white upon CR withdrawal through unclear mechanisms.
MATERIALS AND METHODS:
Six-week old C57BL6 mice were fed with 40% CR chow diet for 6 weeks. Subsequently, one group of mice was switched back to ad libitum chow diet, which was continued for additional 2 weeks. Adipose tissues were assessed histologically and biochemically for beige adipocytes.
RESULTS:
Beige adipocytes induced by CR rapidly transition to white adipocytes when CR is withdrawn independent of parkin-mediated mitophagy. We demonstrate that the involution of mitochondria during CR withdrawal is strongly linked with a decrease in mitochondrial biogenesis. We further demonstrate that beige-to-white fat transition upon β3-AR agonist-withdrawal could be attenuated by CR, partly via maintenance of mitochondrial biogenesis.
CONCLUSION:
In the model of CR, our study highlights the dominant role of mitochondrial biogenesis in the maintenance of beige adipocytes. We propose that loss of beige adipocytes upon β3-AR agonist withdrawal could be attenuated by CR.
KEYWORDS:
Beige adipocytes; Caloric restriction; Fission; Fusion; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

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Proc Nutr Soc. 2020 Apr 15:1-19. doi: 10.1017/S0029665120006928. [Epub ahead of print]

Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight.

Abstract

Excessive adipose accumulation, which is the main driver for the development of secondary metabolic complications, has reached epidemic proportions and combined pharmaceutical, educational and nutritional approaches are required to reverse the current rise in global obesity prevalence rates. Brown adipose tissue (BAT) is a unique organ able to dissipate energy and thus a promising target to enhance BMR to counteract a positive energy balance. In addition, active BAT might support body weight maintenance after weight loss to prevent/reduce relapse. Natural products deliver valuable bioactive compounds that have historically helped to alleviate disease symptoms. Interest in recent years has focused on identifying nutritional constituents that are able to induce BAT activity and thereby enhance energy expenditure. This review provides a summary of selected dietary phytochemicals, including isoflavones, catechins, stilbenes, the flavonoids quercetin, luteolin and resveratrol as well as the alkaloids berberine and capsaicin. Most of the discussed phytochemicals act through distinct molecular pathways e.g. sympathetic nerve activation, AMP-kinase signalling, SIRT1 activity or stimulation of oestrogen receptors. Thus, it might be possible to utilise this multitude of pathways to co-activate BAT using a fine-tuned combination of foods or combined nutritional supplements.

KEYWORDS:

Brown adipose tissue; Browning; Energy expenditure; Phytochemicals; Weight management

PMID: 32290888
DOI: 10.1017/S0029665120006928
 
Edited by Iporuru

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Hello folks - I haven't been keeping up (KU) with this list but have been KU with CE!  Here's a brief article that may have tangential topicality or if not that at least entertainment value!  https://tinyurl.com/yyjoffy5

How to Activate Brown Fat

1. Cold Exposure

As mentioned above, exposure to cold temperatures or water can increase brown adipose tissue or promote the transformation from white to brown fat. This is due to brown fat’s thermogenic effects — cold temperatures activate the adipose tissue to burn energy.

Cold exposure can be performed by turning down the thermostat or taking cold showers; the temperature range most often studied is 64-66 degrees Fahrenheit. Although the most benefit is seen with two hours of cold exposure per day, even shorter amounts can be beneficial.

2. Polyphenolic Plant Compounds

The compounds resveratrol, berberine, curcumin, cinnamon, epigallocatechin gallate (EGCG) from green tea, and capsaicin (found in chili peppers) have all been shown to activate or increase brown fat. In addition, omega-3 fatty acids have also been linked to brown fat activation.

3. Moderate Exercise

Physical activity stimulates the production of irisin, a hormone that improves metabolism and is secreted from the muscles in response to exercise. After exercise, irisin then stimulates thermogenesis and the switching of white fat to beige or brown fat. However, you can have too much of a good thing. Over-exercising may have detrimental effects on brown fat activity, especially in females. Therefore, moderate exercise is the key to turning on brown fat. 

4. NMN

Another factor that may play a role in brown fat activity is NMN (nicotinamide mononucleotide), a precursor to the coenzyme NAD+. Research has found that adequate levels of NAD+ in adipose tissue are necessary for thermogenesis. For example, administering NMN to mice with low levels of NAD+ led to restored thermogenesis and brown fat activity. Quality NMN products are available in powder, lozenges, sustained-release, and capsule forms.

Key Takeaways • Brown adipose tissue is a healthier type of body fat that burns energy, increases energy expenditure, and improves glucose metabolism. • Brown fat activity is also linked to increased satiety after meals and reduced inflammation. • Increase brown fat activation through cold exposure, various plant compounds, moderate exercise, and supplemental NMN.

 

Edited by Kenton
typo

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This paper (1) is downright fascinating, linking two topics of interest here through a mitochondrial BCAA transporter:

1) BCAA ( which connects with nutrient-sensing pathways, metabolism, sarcopenia among other themes)

and

2) brown fat metabolism and health

The authors (1) identified a mechanistic link between BCAA's favorable role in energy metabolisms in some contexts, yet contribution to metabolic syndrome and related conditions in others, and it appears that brown fat activity appears to mediate the relationship in a context-dependent manner. 

In a nushell, BCAA catabolism in BAT promotes BCAA utilization and clearance via thermogenesis, and paraphrasing them from below, this mechanism has the potential to mitigate diet-induced obesity and glucose intolerance. 

Remarkably in the follow-up work from their rodent models they found that valine and leucine "was significantly reduced, preferentially in high BAT subjects following cold exposure, whereas no statistical change was seen in low BAT subjects." 

The cold exposure was not extreme, and was set at deliberately below the shivering thermogenesis temperature threshold, with cold exposure (19°C) for 2 hours - that's just over 66 Farenheit(!).    We still need to study and measure the clinical impact of these reductions in BCAA, but taking it from lab to the subjects and then measuring and confirming a significant drop in BCAA ( a surrogate for metabolic health among sequela) is very much to their credit, and a boon to the potential implications of this work.

The abstract pretty much sums it up:

"Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health."

The discussion was short, but to the point:

Our study suggests the following model (Fig.4j besides glucose and fatty acids, cold stimuli potently increase mitochondrial BCAA uptake and oxidation in BAT, leading to enhanced BCAA clearance in the circulation. This process requires SLC25A44, a previously uncharacterized mitochondrial BCAA transporter in brown adipocytes. In turn, defective BCAA catabolism in BAT leads to impaired BCAA clearance and thermogenesis, leading to the development of diet-induced obesity and glucose intolerance.

This model provides important implications in the regulation of systemic BCAA metabolism under an obese or diabetic state in which impaired BAT activity and increased circulating BCAA levels are observed in humans and rodents. It has been suggested that the accumulation of incompletely oxidized intermediates derived from BCAA oxidation, such as 3-hydroxyisobutyrate (3-HIB), cause insulin resistance9,23,24. Conversely, lowering circulating BCAA levels by inhibiting the kinase BDK or overexpression of the phosphatase PPM1K in the liver improves glucose tolerance independently from body weight loss in rats25. Furthermore, reduced mitochondrial BCAA oxidation and subsequent accumulation of intracellular BCAA concentration leads to constitutive activation of mTOR signaling, resulting in persistent IRS-1 phosphorylation by mTORC1 and inhibition of insulin signaling6,23,26. The present study suggests a distinct yet non-mutually exclusive mechanism in which impaired BAT activity under an obese or diabetic state reduces systemic BCAA clearance, while active BAT acts as a significant metabolic-filter for circulating BCAA and protects against obesity and insulin resistance. It is conceivable that enhanced mitochondrial BCAA catabolism via SLC25A44 may serve as a promising strategy to improve systemic BCAA clearance and glucose homeostasis.

Lots more of interest in the paper methodology details ( you are all now reading the papers, right? 😉)

(1) Yoneshiro, T., Wang, Q., Tajima, K., Matsushita, M., Maki, H., Igarashi, K., Dai, Z., White, P. J., McGarrah, R. W., Ilkayeva, O. R., Deleye, Y., Oguri, Y., Kuroda, M., Ikeda, K., Li, H., Ueno, A., Ohishi, M., Ishikawa, T., Kim, K., Chen, Y., … Kajimura, S. (2019). BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature, 572(7771), 614–619.  https://doi.org/10.1038/s41586-019-1503-x

Edited by Mechanism

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18 hours ago, Mechanism said:

( you are all now reading the papers, right? 😉)

Yep!  Read 'em while watching the Carlsen-Nakamura chess match last night.  Interesting.  Thanks!

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On 8/6/2020 at 2:32 PM, Kenton said:

NMN

Another factor that may play a role in brown fat activity is NMN (nicotinamide mononucleotide), a precursor to the coenzyme NAD+. Research has found that adequate levels of NAD+ in adipose tissue are necessary for thermogenesis. For example, administering NMN to mice with low levels of NAD+ led to restored thermogenesis and brown fat activity. Quality NMN products are available in powder, lozenges, sustained-release, and capsule forms.

 Anyone (Dean?) have more info/thoughts/analysis on NMN (evidence it plays a legit role in thermogenesis / brown fat activation)? Do any of you supplement it, why or why NOT and if so, any specific recommendations? In a quick search I’ve seen it come up numerous times but I get the impression people here are not impressed with the evidence and most don’t take it or stopped taking it.  Sinclair still seems to be enthusiastic about it in (see: this interview).

Edited by Gordo

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On 8/21/2020 at 6:44 AM, Gordo said:

 Anyone (Dean?) have more info/thoughts/analysis on NMN (evidence it plays a legit role in thermogenesis / brown fat activation)? Do any of you supplement it, why or why NOT and if so, any specific recommendations? In a quick search I’ve seen it come up numerous times but I get the impression people here are not impressed with the evidence and most don’t take it or stopped taking it.

Hi, Gordo.  I took a couple of bottles of NMN, with some planned time lapses between each batch, but as I read more, I decided to pause for now.

There are some suggestions that it may increase cancer proliferation, at least if one is susceptible, so on balance, the potential risks outweighed the potential benefits, for me.

See this, for example:

Cancer Research Points to Key Unknowns about Popular “Antiaging” Supplements

 

Indeed, Zhang’s study is one of the first to directly show that providing supplemental NAD+, via the precursor NMN, was associated with increased cancerous growths in mice. But Elysium’s Guarente is skeptical of the data, arguing that Zhang’s study showed a small effect in a small number of animals and that it has yet to be replicated by other groups. “I don’t think the evidence is there at all to say that raising NAD+ levels would favor cancer,” Guarente says.

At the moment, the idea that elevating NAD+ levels could fuel cancer growth remains a hypothesis, but it is one that has attracted considerable attention. Cancer cells have high metabolic needs, including processes requiring NAD+. And many types of cancer cells boost NAD+-making enzymes and then die when those enzymes are blocked by drugs. “We know that they like NAD+, but it’s too early to say, if you add NAD+, whether they will grow really fast,” says Shashi Gujar, a cancer immunologist at Dalhousie University. “Many labs are working to figure that out.”

The answer may not be a single or straightforward one. NAD+ is a ubiquitous and fundamental molecule, involved in many biological pathways and cellular operations. Its ingestion could lead to a mix of positive and negative outcomes, the balance of which might depend on context. NAD+ precursors, consumed orally, may be taken up by some tissues more than others. And different cell types are known to employ distinct metabolic programs, which could lead to tissue-specific responses to NAD+.

Like the tissues from which they arise, cancers are diverse in their cellular ways—and at least some run counter to the “cancer fuel” hypothesis of NAD+. A 2014 study, for instance, reported that in a mouse model of liver cancer, inhibiting NAD+ production was a key step by which an errant gene caused DNA damage and tumor formation. In this case, feeding NR to the mice actually helped protect against these harmful effects.

Together these findings do not necessarily point to ready answers for consumers interested in NR or NMN supplements, so much as they highlight questions for scientists to address in the coming years. “I would say that given that many people are taking these supplements for health benefits, a study of what these do to cancer risk or existing cancer biology is warranted,” says Matthew Vander Heiden, a clinician-scientist at the Massachusetts Institute of Technology’s Koch Institute for Integrative Cancer Research.

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