Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance

The obesogenic effect of a high-fat (HF) diet is counterbalanced by stimulation of energy expenditure and lipid oxidation in response to a meal. The aim of this study was to reveal whether muscle nonshivering thermogenesis could be stimulated by a HF diet, especially in obesity-resistant A/J compared with obesity-prone C57BL/6J (B/6J) mice. Experiments were performed on male mice born and maintained at 30 degrees C. Four-week-old mice were randomly weaned onto a low-fat (LF) or HF diet for 2 wk. In the A/J LF mice, cold exposure (4 degrees C) resulted in hypothermia, whereas the A/J HF, B/6J LF, and B/6J HF mice were cold tolerant. Cold sensitivity of the A/J LF mice was associated with a relatively low whole body energy expenditure under resting conditions, which was normalized by the HF diet. In both strains, the HF diet induced uncoupling protein-1-mediated thermogenesis, with a stronger induction in A/J mice. Only in A/J mice: 1) the HF diet augmented activation of whole body lipid oxidation by cold; and 2) at 30 degrees C, oxygen consumption, total content, and phosphorylation of AMP-activated protein kinase (AMPK), and AICAR-stimulated palmitate oxidation in soleus muscle was increased by the HF diet in parallel with significantly increased leptinemia. Gene expression data in soleus muscle of the A/J HF mice indicated a shift from carbohydrate to fatty acid oxidation. Our results suggest a role for muscle nonshivering thermogenesis and lipid oxidation in the obesity-resistant phenotype of A/J mice and indicate that a HF diet could induce thermogenesis in oxidative muscle, possibly via the leptin-AMPK axis.     

Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans

The influence of a thermogenic mixture of ephedrine- (1 mg/kg) caffeine (2.5 mg/kg) on cold tolerance was investigated in nine healthy young male subjects during two seminude exposures to cold air (3 h at 10 degrees C). The drug ingestion reduced the total drop in core, mean skin, and mean body temperatures (P less than 0.01), thus producing significantly warmer final core, mean skin, and mean body temperatures compared with the placebo ingestion. The drug ingestion increased the total 3-h energy expenditure by 18.6% compared with that of the placebo ingestion in the cold (P less than 0.01). By means of the nonprotein respiratory exchange ratio to calculate the rates of substrate oxidation, it was found that the drug ingestion increased carbohydrate oxidation by as much as 41.7% above that of the placebo (P less than 0.05). In contrast, the drug mixture had no significant influence on lipid or protein metabolism. The results demonstrate that the ingestion of an ephedrine-caffeine mixture improves cold tolerance in humans by significantly increasing body temperatures in the cold. These improvements were not caused by an increased conservation of heat but by a greater energy expenditure, which appears to be dependent on an enhanced carbohydrate utilization.     

Effect of cold exposure on fuel utilization in humans: plasma glucose, muscle glycogen, and lipids.

The relative roles of circulatory glucose, muscle glycogen, and lipids in shivering thermogenesis are unclear. Using a combination of indirect calorimetry and stable isotope methodology ([U-13C]glucose ingestion), we have quantified the oxidation rates of these substrates in men acutely exposed to cold for 2 h (liquid conditioned suit perfused with 10 degrees C water). Cold exposure stimulated heat production by 2.6-fold and increased the oxidation of plasma glucose from 39.4 +/- 2.4 to 93.9 +/- 5.5 mg/min (+138%), of muscle glycogen from 126.6 +/- 7.8 to 264.2 +/- 36.9 mg glucosyl units/min (+109%), and of lipids from 46.9 +/- 3.2 to 176.5 +/- 17.3 mg/min (+376%). Despite the observed increase in plasma glucose oxidation, this fuel only supplied 10% of the energy for heat generation. The major source of carbohydrate was muscle glycogen (75% of all glucose oxidized), and lipids produced as much heat as all other fuels combined. During prolonged, low-intensity shivering, we conclude that total heat production is unequally shared among lipids (50%), muscle glycogen (30%), plasma glucose (10%), and proteins (10%). Therefore, future research should focus on lipids and muscle glycogen that provide most of the energy for heat production.     

The role of the liver in lipid metabolism during cold acclimation in non-hibernator rodents

Cold exposure increases the demand for energy substrates. Cold acclimation of rats led to a 3-fold increase in fatty acid (FA) beta-oxidation (P<0.01) for ex vivo livers perfused at 37 degrees C. This increase was preserved following perfusion at 25 degrees C (P<0.001). In vitro measurement of absolute rates of hepatic beta-oxidation revealed no significant difference following cold acclimation, implying changes in fatty acid flux through beta-oxidation rather than increased oxidation capacity. Total FA uptake was increased one-third following perfusion at 25 degrees C (P<0.001) and cold acclimation (P<0.05) and cold acclimation led to diversion of tissue FA from storage to beta-oxidation (P<0.01). In separate experiments, in vivo hepatic lipogenesis rates for saponifiable lipids doubled (P<0.01) and cholesterol synthesis increased one-third (P<0.001). Taken together these data suggest the oxidation and synthesis of lipids occur simultaneously in hepatic tissue possibly to increase prevailing tissue FA concentrations and to generate heat through increased metabolic flux rates.     

温度和高脂食物对黑线仓鼠代谢产热和体脂累积的影响

能量代谢的适应性调节是小型哺乳动物应对环境季节性变化的主要策略之一。为探讨不同温度下动物在代谢产热能量支出与脂肪累积之间的权衡策略,以成年雄性黑线仓鼠为研究对象开展了3 个实验:实验1 将动物驯化于高脂和低脂食物;实验2 将动物暴露于低温(5℃)和暖温(30℃);实验3 将饲喂高脂食物的动物暴露于低温。以食物平衡法测定摄食量、摄入能和消化率,以开放式氧气分析仪测定代谢产热,以索氏抽提法测定脂肪含量。结果发现,取食高脂食物的黑线仓鼠摄食量显著减少,但脂肪累积显著增加;暖温下摄食量显著减少,但体脂含量显著增加,低温下摄食量显著升高,但体脂含量显著减少;饲喂高脂食物的黑线仓鼠在低温下摄入能显著增加,非颤抖性产热增强,但体脂含量显著降低。结果表明高脂食物对黑线仓鼠体脂累积的影响与环境温度有关,低温诱导脂肪动员,暖温促进脂肪贮存;低温下黑线仓鼠增加能量摄入不能完全补偿用于产热的能量支出,导致脂肪动员增加;暖温下代谢产热降低是脂肪累积的主要因素;与能量摄入相比代谢产热的能量支出在体脂累积的适应性变化中发挥更重要的作用。     

Influence of caffeine on metabolic responses of men at rest in 28 and 5 degrees C

Cold stress and caffeine ingestion are each reported to increase plasma catecholamines, free fatty acid (FFA) concentrations, and energy metabolism. This study examined the possible interaction of these two metabolic challenges in four double-blind counterbalanced trials. Young adult men (n = 6) ingested caffeine (5 mg/kg) or placebo (dextrose, 5 mg/kg) and rested for 2 h in 28 or 5 degrees C air. Cold stress alone elevated (P less than 0.05) plasma norepinephrine, metabolism (O2 consumption, VO2), and respiratory exchange ratio (RER). Caffeine alone increased (P less than 0.05) plasma epinephrine and FFA but not RER. When the two challenges were combined (caffeine plus 5 degrees C for 2 h) norepinephrine and epinephrine were increased (P less than 0.05) as was FFA. However, VO2, RER, and skin and rectal temperatures were not different from the responses observed at 5 degrees C after placebo ingestion. The data suggest that caffeine selectively increases plasma epinephrine, whereas cold air increases norepinephrine. During the cold exposure, increasing epinephrine and FFA above normal levels did not appear to influence the metabolic or thermal responses to the cold stress. In fact the increase in RER suggested a greater carbohydrate oxidation.     

Changes in environmental temperature influence leptin responsiveness in low- and high-fat-fed mice

Loss of body fat in leptin-treated animals has been attributed to reduced energy intake, increased thermogenesis, and preferential fatty acid oxidation. Leptin does not decrease food intake or body fat in leptin-resistant high-fat (HF)-fed mice, possibly due to a failure of leptin to activate hypothalamic receptors. We measured energy expenditure of male C57BL/6 mice adapted to low-fat (LF) or HF diet and infused them for 13 days with PBS or 10 mug leptin/day from an intraperitoneal mini-osmotic pump to test whether leptin resistance prevented leptin-induced increases in energy expenditure and fatty acid oxidation. There was no effect of low-dose leptin infusions on either of these measures in LF-fed or HF-fed mice, even though LF-fed mice lost body fat. Experiment 2 tested leptin responsiveness in LF-fed and HF-fed mice housed at different temperatures (18 degrees C, 23 degrees C, 27 degrees C), assuming that the cold would increase and the hot environment would inhibit food intake and thermogenesis, which could potentially interfere with leptin action. LF-fed mice housed at 23 degrees C were the only mice that lost body fat during leptin infusion, suggesting that an ability to modify energy expenditure is essential to the maintenance of leptin responsiveness. HF-fed mice in cold or warm environments did not respond to leptin. HF-fed mice in the hot environment were fatter than other HF-fed mice, and, surprisingly, leptin caused a further increase in body fat, demonstrating that the mice were not totally leptin resistant and that partial leptin resistance in a hot environment favors positive energy balance and fat deposition.     

Effects on energy expenditure of facial cooling during exercise.

Estimated energy expenditures for men during Arctic manhauling expeditions were 29-33 MJ day-1, higher than those documented for other hard-working groups and exceeding predicted energy costs for such activities. Although physiological effects from generalised cooling were unlikely, cold exposure of the face could have influenced exercise metabolism via autonomic stimulation. This hypothesis was examined by measuring oxygen consumption, energy expenditure, respiratory exchange ratio (R) and cardiovascular changes during rest and exercise, with and without exposure of the face to air at--20 degrees C. Measurements were made in five subjects during 15 min of rest followed by continuous exercise on a cycle ergometer consisting of 15-min periods at 75, 100, 125 and 150 W external work. The cold air caused a profound fall in facial temperatures and small falls in mean skin and rectal temperatures (P less than 0.001). These changes were associated with a small increase in the mean oxygen consumption over all levels of rest and exercise (0.86 l min-1 vs 0.82 l min-1, P less than 0.001) and a corresponding increase in mean energy expenditure (294 W vs 283 W, P less than 0.05). Cold air also caused an increase in mean resting R values (1.00 vs 0.88, P less than 0.01) but a decrease in the mean R value for all levels of exercise (0.85 vs 0.91, P less than 0.05). Pulse rates were unchanged but systolic and diastolic blood pressures were relatively elevated throughout the cold face experiments (P less than 0.001).     

Plasma glucose and insulin responses to oral and intravenous glucose in cold-exposed humans

Although glucose tolerance and skeletal muscle glucose uptake are markedly improved by cold exposure in animals, little is known about such responses in humans. This study used two variations of a glucose tolerance test (GTT) to investigate changes in carbohydrate metabolism in healthy males during nude exposure to cold. In experiment 1, an oral GTT was performed in the cold and in the warm (3 h at 10 or 29 degrees C). To bypass the gastrointestinal tract, and to suppress hepatic glucose output, a second experiment was carried out as described above, using an intravenous GTT. Even though cold exposure raised metabolic rate greater than 2.5 times, plasma glucose and insulin responses to an oral GTT remained unaltered. In contrast, cold exposure reduced the entire plasma glucose profile as a function of time during the intravenous GTT (P less than 0.05), as plasma glucose was returned to basal levels within 1 h in comparison to a full 2 h in the warm, despite low insulin levels. The results of the intravenous GTT demonstrate that even with low insulin levels, carbohydrate metabolism is increased in cold-exposed males. This effect could be masked in the oral GTT by gastrointestinal factors and a high hepatic glucose output. Cold exposure may enhance insulin sensitivity and/or responsiveness for glucose uptake, mainly in shivering skeletal muscles.     

Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections

Hypothalamic neurons are regarded as essential for integrating thermal afferent information from skin and core and issuing commands to autonomic and behavioral effectors that maintain core temperature (T(c)) during cold exposure and for the control of energy expenditure more generally. Caudal brain stem neurons are necessary elements of the hypothalamic effector pathway and also are directly driven by skin and brain cooling. To assess whether caudal brain stem processing of thermal afferent signals is sufficient to drive endemic effectors for thermogenesis, heart rate (HR), T(c), and activity responses of chronic decerebrate (CD) and control rats adapted to 23 degrees C were compared during cold exposure (4, 8, or 12 degrees C) for 6 h. Other CDs and controls were exposed to 4 or 23 degrees C for 2 h, and tissues were processed for norepinephrine turnover (NETO), a neurochemical measure of sympathetic drive. Controls maintained T(c) for all temperatures. CDs maintained T(c) for the 8 and 12 degrees C exposures, but T(c) declined 2 degrees C during the 4 degrees C exposure. Cold exposure elevated HR in CDs and controls alike. Tachycardia magnitude correlated with decreases in environmental temperature for controls, but not CDs. Cold increased NETO in brown adipose tissue, heart, and some white adipose tissue pads in CDs and controls compared with their respective room temperature controls. These data demonstrate that, in neural isolation from the hypothalamus, cold exposure drives caudal brain stem neuronal activity and engages local effectors that trigger sympathetic energetic and cardiac responses that are comparable in many, but not in all, respects to those seen in neurologically intact rats.     

Energy balance and diabetes. The effects of cold exposure, exercise training, and diet composition on glucose tolerance and glucose metabolism in rat peripheral tissues

The effects of cold exposure, exercise training, and diet (high fat versus high carbohydrate) on glucose tolerance and glucose metabolism in rat peripheral tissues will be briefly reviewed. Stimulation of energy expenditure by cold exposure (4 degrees C) or exercise training generally leads to decreased plasma insulin levels and to an improvement in glucose tolerance, suggesting that insulin action on peripheral tissues is increased when energy expenditure is stimulated. On the contrary, feeding high-fat diets to sedentary rats living in the warm (25 degrees C) induces hyperinsulinemia and insulin resistance resulting in a marked deterioration of glucose tolerance. Nevertheless, cold exposure reverses the diabetogenic effects of high-fat feeding, demonstrating that nutrition-induced insulin resistance is amplified in sedentary animals living at temperatures close to thermoneutrality. Radioactive tracer studies of 2-deoxyglucose uptake in peripheral tissues revealed that cold exposure synergistically potentiates the effects of insulin on glucose uptake in skeletal muscles as well as in white and brown adipose tissues. However, more recent data showed that cold exposure improves glucose tolerance and stimulates glucose uptake in starved animals (ie., in the virtual absence of circulating insulin) nearly by the same order of magnitude as in fed animals. It is therefore concluded that cold exposure, and possibly also exercise, improve glucose tolerance and stimulate glucose uptake in peripheral tissues primarily by enhancing glucose oxidation via insulin-independent pathways, and secondarily by increasing the responsiveness of peripheral tissues to insulin.     

Effects of acute cold exposure on rectal temperature, blood glucose and plasma free fatty acids in alloxan-diabetic rats

These experiments were carried out to study the effects of acute cold exposure (0-2 degrees C/4 hr) on rectal temperature, blood glucose and plasma free fatty acids (FFA) in alloxan-diabetic rats. Male Wistar rats weighing 170-190 g were used and diabetes was induced by i.v. alloxan injection (40 mg/kg body wt). Cold exposure produced severe hypothermia in diabetic rats. After 4 hr of cold, blood glucose of diabetic rats was reduced from 296 +/- 16 to 86 +/- 12 mg/dl (P less than 0.01), and FFA increased slightly, but was not statistically different (P greater than 0.05) from the initial value. As expected, interscapular brown adipose tissue (IBAT) and retroperitoneal and epididymal white adipose tissues were significantly lower in diabetic than in control rats. Cold exposure reduced total IBAT lipids in control but not in diabetic animals. The results of this experiment suggest that diabetic rats were unable to maintain body temperature in the cold, probably because of a failure to generate an adequate amount of heat by nonshivering thermogenesis in brown adipose tissue.     

Functional evolution of leptin of Ochotona curzoniae in adaptive thermogenesis driven by cold environmental stress

Background

Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism''s fitness to challenging environments. Plateau pika (Ochotona curzoniae), an endemic and keystone species on Qinghai-Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress.

Methodology/Principal Findings

To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23±1°C) and cold (5±1°C) acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced β-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment.

Conclusions/Significance

These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau.     

Impaired activation of thermogenesis in the corpulent rat

The capacity for non-shivering thermogenesis was measured in groups of 12 week-old congenic lean and corpulent LA/N-cp rats of both sexes to determine if their obese state might be associated with an impairment in energy expenditure via non-shivering thermogenesis. Body weights of the corpulent phenotypes were 1.6 to 1.8 times greater than those of the lean phenotype. Measurements of resting oxygen consumption were similar in lean and in corpulent rats, and were greater in female than in male rats. Isoproterenol stimulation resulted in a significant increase in oxygen consumption in lean rats, while the rates of oxygen consumption of isoproterenol-stimulated corpulent rats were unchanged. Acute exposure of male rats to a 5 degrees C cold environment resulted in significant decreases in colonic and in rectal temperature in both phenotypes, but body temperatures recovered more rapidly in lean than in corpulent rats. Urinary VMA excretion was greater in lean than in corpulent rats and increased following cafeteria-feeding in lean but not in corpulent rats. These observations are consistent with an impaired mechanism of sympathetically-mediated thermogenesis in the corpulent phenotype of the LA/N-cp rat, and which may be a contributing factor in the development of their obese state via a decreased capacity for energy expenditure.     

Cold exposure increases glucose utilization and glucose transporter expression in brown adipose tissue.

When rats were exposed to a cold environment (4 degrees C) for 10 days, tissue glucose utilization was increased in brown adipose tissue (BAT), a tissue specified for non-shivering thermogenesis, but not in skeletal muscle. Cold exposure also caused an increase in the amount of GLUT4, an isoform of glucose transporters expressed in insulin-sensitive tissues, in parallel with an increased cellular level of GLUT4 mRNA. In contrast to BAT, no significant effect of cold exposure was found in skeletal muscle. The results suggest the cold-induced increase in glucose utilization by BAT is attributable, at least in part, to the increased expression of GLUT4.     

Effect of food restriction on cold adaptability of rats

To determine the role of the nutritional state in nonshivering thermogenesis during cold adaptation, cold adaptability was compared between cold-adapted (5 degrees C for 4-5 weeks) rats fed ad libitum and cold-adapted rats pair fed with warm controls having the same food intake. Cold-adapted pair-fed rats suffered a significant loss in body weight during cold exposure. However, brown adipose tissue (BAT) in both cold-adapted ad libitum fed and cold-adapted pair-fed rats was enlarged to the same extent as compared with that in control rats. Fat-free dry matter in BAT also increased in cold-adapted ad libitum fed and cold-adapted pair-fed rats to the same extent. Cold tolerance as assessed by the change in the colonic temperature at -5 degrees C was improved relative to control rats and was the same for cold-adapted ad libitum fed and cold-adapted pair-fed rats. Nonshivering thermogenesis as estimated by the noradrenaline-induced increase in oxygen consumption was significantly greater in the cold-exposed rats and there was no significant difference between cold-adapted ad libitum fed and cold-adapted pair-fed rats. These results suggest that an improved cold tolerance by means of nonshivering thermogenesis in brown adipose tissue is closely related to the low temperature itself but not the increased food intake which occurred in the cold.     

Influence of environmental temperature and energy intake on skeletal muscle respiratory enzymes and morphology

Influence of a cold (10 degrees C) or warm (35 degrees C) environment and a high or low level of energy intake on respiratory enzyme activities has been investigated in porcine skeletal muscle. Scanning microdensitometry was used to measure the reaction products from mitochondrial enzymes in individual slow- and fast-twitch muscle fibres. A cold environment was found to increase the activity of succinate dehydrogenase in both types of muscle fibre (P less than 0.001 for dark fibres, P less than 0.01 for light fibres) from young growing animals. Enzyme activity was also increased in animals on a low compared with a high energy intake (P less than 0.01) when living at 10 degrees C but not at 35 degrees C. Similar findings were obtained for NADH diaphorase and cytochrome oxidase aa3. The numbers of slow-twitch muscle fibres also increased after exposure to cold (P less than 0.01) and as a result of a low energy intake (P less than 0.01). These results are similar to those obtained in other species after exercise or as a result of peripheral arterial insufficiency. The extent to which they could be related to local tissue hypoxia or to changes in metabolic hormones is discussed.     

Increased nonshivering thermogenesis, brown fat cytochrome-c oxidase activity, GDP binding, and uncoupling protein mRNA levels after short daily cold exposure of Phodopus sungorus

In their natural environment, burrowing rodents experience rather fluctuating ambient temperatures and are acutely cold exposed only for short periods outside their burrows. The effect of short daily cold exposure on basal metabolic rate, nonshivering thermogenesis, brown fat thermogenesis, and uncoupling protein mRNA was studied in the Djungarian hamster, Phodopus sungorus. They were kept at 23 degrees C and exposed to 5 degrees C daily either for one 4-h period or twice for 2 h (in 12-h intervals). At the same time control hamsters were kept continuously either at thermoneutrality (23 degrees C) or at 5 degrees C. Two 2-h cold exposures daily were sufficient to increase basal metabolic rate and nonshivering thermogenesis to the same level as continuous cold exposure, whereas one 4-h cold period per day did not result in a significant increase of both parameters. Brown fat thermogenesis (as measured by cytochrome-c oxidase activity and GDP binding to the mitochondrial uncoupling protein) increased to the same extent by both treatments with short daily cold exposure. However, this increase was less than in the chronically cold-exposed hamsters. A similar result was found for uncoupling protein mRNA: both short-term cold-exposed hamsters increased uncoupling protein mRNA levels to a similar extent, but less than after chronic cold treatment. It is concluded that short daily cold exposures are sufficient to cause adaptive increases of the capacity of metabolic heat production as well as brown fat thermogenic properties.     

Cold‐Induced Adaptive Thermogenesis in Lean and Obese

On entering a cold environment, people react by increasing insulation and energy expenditure (EE). However, large interindividual differences exist in the relative contribution of each mechanism. Short‐term studies revealed that obese subjects increase EE (i.e., adaptive thermogenesis) less than lean subjects, which might have implications for the predisposition to obesity. In this study, we validate the differences in adaptive thermogenesis between lean and obese upon midterm mild cold exposure. Therefore, 10 lean and 10 obese subjects were exposed for 48 h to mild cold (16 °C) in a respiration chamber. The preceding 36 h they stayed in the same chamber at a neutral temperature (22 °C) for the baseline measurements. EE, physical activity, skin temperature, and core temperature have been measured for the last 24 h of both parts. Mean daytime EE increased significantly in the lean subjects (P < 0.01), but not in the obese. Physical activity decreased significantly in the lean (P < 0.01) and the obese (P < 0.001) subjects. The change in EE was related to the change in physical activity in both groups (respectively R² = 0.673, P < 0.01 and R² = 0.454, P < 0.05). Upon mild cold exposure, lean subjects decreased proximal skin temperature less, but distal skin temperature more than obese. In conclusion, the interindividual differences in cold‐induced thermogenesis were related to changes in physical activity in both lean and obese, pointing at the existence of individual variation in physical activity to compensate for cold‐induced thermogenesis. Furthermore, although a large part of the lean subjects counteracted the cold by increasing EE, most obese subjects changed temperature distribution, and therefore, increased insulation.     

Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis

Background

Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle.

Methodology/Principal Findings

The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32 MJ/day, range of −0.21 to 1.66 MJ/day, p<0.05). The individual increases in energy expenditure correlated to state 4 respiration (p<0.02, R² = 0.50).

Conclusions/Significance

This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilities for mitochondrial uncoupling as an alternative therapeutic target in the treatment of obesity.