A Matter of Time and Taste: Circadian and Seasonal Regulation of Mammalian Energetics

Daily and seasonal rhythms in the brain and behavior are reciprocally linked to energy balance, but this relationship is often studied under laboratory conditions that may not fully resemble the environmental conditions under which these systems evolved. This dissertation probed this bidirectional relationship using two preclinical rodent models studied under deliberately ecological conditions: mice with a circadian clock destabilizing gene mutation (Per2^m/m) permitted to express their disrupted circadian chronotype in constant darkness, and Siberian hamsters allowed to self-select macronutrients over seasonal time scales rather than merely regulate total calories. Clock mutant mice exhibited obesity and increased food intake, but obesity was exacerbated and blood glucose levels were elevated in the subset of mutants with disrupted circadian rhythms—indicating that the circadian clock genes affect behavior and metabolism via circadian-dependent and -independent mechanisms, and linking obesity to circadian pacemaker stability in this circadian clock mutant model system. We next examined the causal effects of obesity and macronutrient intake on circadian pacemaker stability by testing whether high fat diet-induced obesity could induce circadian rhythm disruption in Per2 mutant mice. Diet-induced obese mice were no more likely to become circadian disrupted than lean mutants; however, circadian disruption exacerbated the obesity phenotype. Confirming prior studies, a high fat diet alone shifted gut microbial community structure, but the microbiome was further altered in mice that exhibited severe circadian disruption -- pointing to the microbiome as a potential mediator linking diet and host circadian behavior. In the seasonal domain, we showed that winter reductions in food intake reflected the selective avoidance of dietary fat rather than uniform calorie restriction. Hamsters prevented from reducing fat intake showed attenuated seasonal responses, changes in circadian clock period, and aberrant entrainment to the environmental light:dark cycle. Moreover, these effects were driven partly by gonadal hormones, as testosterone promoted fat preference. In addition to day length, macronutrient intake may be a potent seasonal environmental cue that animals perceive via ingestion and use to modulate circadian clock function and the gonadal regression that defines seasonal breeding. Together, these findings confirm and extend our understanding of biological timekeeping and energy homeostasis as tightly interdependent systems bound by reciprocal regulation, with the gut microbiome as a candidate nexus. Standard laboratory paradigms often obscure the mechanisms that this reciprocity relies on.