Non-shivering thermogenesis can promote negative energy balance and weight loss. In this study, we identify a contextual stimulus that induces rapid and robust thermogenesis in skeletal muscle. Rats exposed to the odor of a natural predator (ferret odor) show elevated skeletal muscle temperatures detectable as quickly as 2 min after exposure, reaching maximum thermogenesis of >1.5 °C at 10-15 min. Mice exhibit a similar thermogenic response to the same odor. Ferret odor induces a significantly larger and qualitatively different response than do novel or aversive odors, fox odor, or moderate restraint stress. Exposure to predator odor increases energy expenditure, and both the thermogenic and energetic effects persist when physical activity levels are controlled. Predator odor-induced muscle thermogenesis is subject to associative learning as exposure to a conditioned stimulus provokes a rise in muscle temperature in the absence of the odor. The ability of predator odor to induce thermogenesis is predominately controlled by sympathetic nervous system activation of β-adrenergic receptors, as unilateral sympathetic lumbar denervation and a peripherally acting β-adrenergic antagonist significantly inhibit predator odor-induced muscle thermogenesis. The potential survival value of predator odor-induced changes in muscle physiology is reflected in an enhanced resistance to running fatigue. Lastly, predator odor-induced muscle thermogenesis imparts a meaningful impact on energy expenditure as daily predator odor exposure significantly enhances weight loss with mild calorie restriction. This evidence signifies contextually provoked, centrally mediated muscle thermogenesis that meaningfully impacts energy balance.

Previously, our laboratory reported that weight-cycled mice outlive their obese counterparts. To gain a better mechanistic understanding of these results, we evaluated cellular senescence in white adipose tissue (WAT) of lean, obese, and weight cycled mice. Our results show that at the end of a 28 day weight loss cycle cellular senescence is significantly reduced in multiple WAT depots compared to obese mice, which also corresponds to a reduction in circulating activin A (a marker of senescence). These findings suggest that a previously undescribed benefit to weight loss may be a reduction of cellular senescence in WAT.

We have previously identified predator odor as a potent stimulus activating thermogenesis in skeletal muscle in rats. As this may prove relevant for energy balance and weight loss, the current study investigated whether skeletal muscle thermogenesis was altered with negative energy balance, obesity propensity seen in association with low intrinsic aerobic fitness, and monogenic obesity. First, weight loss subsequent to 3 wk of 50% calorie restriction suppressed the muscle thermogenic response to predator odor. Next, we compared rats bred based on artificial selection for intrinsic aerobic fitness – high- and low-capacity runners (HCR, LCR) – that display robust leanness and obesity propensity, respectively. Aerobically fit HCR showed enhanced predator odor-induced muscle thermogenesis relative to the less-fit LCR. This contrasted with the profound monogenic obesity displayed by rats homozygous for a loss of function mutation in Melanocortin 4 receptor ( Mc4r K3a,4X/K314X rats), which showed no discernable deficit in thermogenesis. Taken together, these data imply that body size or obesity per se are not associated with deficient muscle thermogenesis. Rather, the physiological phenotype associated with polygenic obesity propensity may encompass pleiotropic mechanisms in the thermogenic pathway. Adaptive thermogenesis associated with weight loss also likely alters muscle thermogenic mechanisms.