Reduced contextually induced muscle thermogenesis in rats with calorie restriction and lower aerobic fitness but not monogenic obesity.

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 (Mc4rK3a,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.

Enhanced weight and fat loss from long-term intermittent fasting in obesity-prone, low-fitness rats.

BACKGROUND: Intermittent fasting (IF) strategies have emerged as viable alternatives to traditional calorie-restricted diets. A key predictor of metabolic health and response to diet is cardiometabolic fitness, including intrinsic aerobic capacity. In a contrasting rat model of aerobic capacity-high- and low-capacity runners (HCR, LCR)-we found that the lean and physically active HCR were also more responsive to a standard calorie-restricted diet. Here, we assessed the ability of IF to induce weight loss on a background of high and low aerobic fitness accompanied by different levels of daily physical activity. METHODS: Female HCR and LCR (8 per line) were subjected to IF (alternate-day fasting) for 14 weeks. Outcomes included changes in body weight, fat and lean mass, daily physical activity, and food and water intake. After initial measurements, IF was continued, and measurements were repeated after one year of IF. RESULTS: All rats lost weight with IF, and LCR lost significantly more weight than HCR. This difference was primarily due to differential fat loss; loss of lean mass, on the other hand, was similar between HCR and LCR. Total food intake decreased with IF, and LCR showed lower intake than HCR only during the first 5 weeks of IF. Physical activity was suppressed by long-term IF. Physical activity increased on fed days compared to fasted days, and this pattern was more pronounced in HCR. The differential effects of IF in HCR and LCR persisted after one year of IF, with IF preventing the marked weight gain seen in ad libitum fed LCR during this time. CONCLUSION: Weight and fat loss from IF was more pronounced in obesity-prone, low-aerobic capacity LCR, despite the low activity levels seen in these rats. The possibility that aerobic capacity modulates response to IF in human participants remains unexplored.

Skeletal muscle thermogenesis induction by exposure to predator odor.

Non-shivering thermogenesis can promote negative energy balance and weight loss. In this study, we identified a contextual stimulus that induces rapid and robust thermogenesis in skeletal muscle. Rats exposed to the odor of a natural predator (ferret) showed elevated skeletal muscle temperatures detectable as quickly as 2 min after exposure, reaching maximum thermogenesis of >1.5°C at 10-15 min. Mice exhibited a similar thermogenic response to the same odor. Ferret odor induced a significantly larger and qualitatively different response from that of novel or aversive odors, fox odor or moderate restraint stress. Exposure to predator odor increased energy expenditure, and both the thermogenic and energetic effects persisted when physical activity levels were controlled. Predator odor-induced muscle thermogenesis is subject to associative learning as exposure to a conditioned stimulus provoked a rise in muscle temperature in the absence of the odor. The ability of predator odor to induce thermogenesis is predominantly controlled by sympathetic nervous system activation of ß-adrenergic receptors, as unilateral sympathetic lumbar denervation and a peripherally acting ß-adrenergic antagonist significantly inhibited 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 enhanced weight loss with mild calorie restriction. This evidence signifies contextually provoked, centrally mediated muscle thermogenesis that meaningfully impacts energy balance.