Potential Mechanisms Underlying Adaptive Thermogenesis in Lean and Obesity-Prone Rats

Obesity is an epidemic in today's society. Weight loss requires negative energy balance, which can induce adaptive thermogenesis-the reduction of energy expenditure (EE) beyond that accounted for by the weight lost. Adaptive thermogenesis varies between individuals. Here, I investigated the underlying mechanisms responsible for the interindividual variation in adaptive thermogenesis.;First, I examined EE and physical activity before and after 21 days of 50% calorie restriction in male and female rats with lean and obesity prone phenotypes-rat strains selectively bred for high and low intrinsic aerobic capacity (HCR and LCR, respectively). My data suggest that calorie restriction decreased EE more than was predicted by loss of weight and lean mass, demonstrating adaptive thermogenesis. Both groups showed similar suppression in resting EE. The calorie restriction-induced suppression in non-resting EE, which includes activity EE, was significantly greater in HCR than in LCR in both male and female rats. Calorie restriction also significantly suppressed physical activity in HCR but not LCR, but physical activity was still higher in HCR than in LCR even after calorie restriction. Weight loss did not differ between groups. These results suggest that individual differences in calorie restriction-induced adaptive thermogenesis may be accounted for by variation in aerobic capacity. Moreover, it is likely activity EE, not resting or basal metabolism, accounts for the individual variation in adaptive thermogenesis.;Next, I examined how calorie restriction impacts the molecular mechanisms of skeletal muscle work efficiency and how the suppression in activity EE relates to these changes in molecular pathways in skeletal muscle at the gene and protein levels. I tested the hypotheses that (1) muscle molecular pathways important for thermogenesis decrease after calorie restriction, (2) calorie restriction enhances pathways important for energy conservation and lipid handling, and (3) these muscle responses are dependent on aerobic capacity. These muscle pathways were compared between HCR and LCR at baseline and after 2 and 21 days of calorie restriction. The data suggest potential roles of UCPs, ATP-gated K-channels and MED1 in the differential adaptive thermogenesis observed between HCR and LCR. One or more of the changes observed in the HCR may contribute to increased muscle efficiency and therefore suppressed non-resting EE. There were differences seen between short-term (2-day) vs. long-term (21-day) expression levels suggesting possible adaptations leading to restricted weight loss. No one particular protein stands out that may play a singular role in the muscle adaptive thermogenesis induced by calorie restriction.;Finally, using micropunched brain samples collected from the same animals, I observed region-specific changes in brain MC3R, MC4R, and AgRP. Calorie restriction-induced changes in melanocortin vs. AgRP signaling may serve to counteract energy shortage by inducing adaptive thermogenesis and suppressing physical activity, promoting energy conservation during food shortages.;In conclusion these results suggest that differential adaptive thermogenesis depends more on activity (non-resting) energy expenditure and varies with changes seen in molecular mechanisms in the skeletal muscle and opposing MCR-AgRP signaling during calorie restriction.