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 20.21 to 1.66 MJ/day, p,0.05). The individual increases in energy expenditure correlated to state 4 respiration (p,0.02, R 2 = 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 possibilitie

A sample trace of the Oxygraph-2K.

<p>The blue line indicates the oxygen concentration in the sample. The red line indicates its derivative, the oxygen consumption by the sample in the respiration medium. The responses to the addition of malate (5 mM), ADP (2 mM), glutamate (10 mM), succinate (10 mM), and oligomycin (1 µg/ml) can be seen. After succinate addition, state 3 was achieved. After oligomycin addition, state 4 was achieved.</p

protein expression data

<p>AU, arbitrary units</p

Differential response of UCP3 to medium versus long chain triacylglycerols; manifestation of a functional adaptation

AbstractWe compared UCP3 protein in rat cardiac, glycolytic and oxidative skeletal muscle and examined the effect of high-fat medium chain vs. long chain triacylglycerol feeding on UCP3 content in these tissues. Cardiac muscle displays the lowest basal levels of UCP3 protein. Increasing long chain – but not medium chain – fatty acid supply upregulates UCP3 in all muscles. Since plasma non-esterified fatty acids and the expression of two peroxisome proliferator-activated receptor (PPAR)-responsive genes, were not different between groups, we conclude that the differential upregulation of UCP3 is not merely PPAR-mediated. This study supports a role of UCP3 in export of non-metabolizable fatty acids

Baseline and mild cold values of a) total daily energy expenditure, b) activity, c) state 4 respiration, and d) state 3 respiration.

<p>The figures show mean (±SEM) in both situations. * p<0.05, ** p<0.01</p

Regression of increases in total daily energy expenditure (MJ/day) and state 4 respiration (pmol O₂/(s·mg muscle·CS activity)) (p<0.02, R² = 0.50).

<p>Regression of increases in total daily energy expenditure (MJ/day) and state 4 respiration (pmol O₂/(s·mg muscle·CS activity)) (p<0.02, R² = 0.50).</p