Circadian Neurocircuit Mechanism in Metabolism and Time Restricted Feeding

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

PROJECT SUMMARY The circadian rhythm is an intrinsic 24-hour cycle which regulates the sleep/wake cycle, energy expenditure and storage, and body temperature in anticipation of the needs of the day. Disruption of the circadian cycle can occur through jetlag, sleep loss, shiftwork, feeding at the wrong time of day, and with experimental genetics. The dysregulation of the circadian rhythm is associated with insulin resistance, susceptibility to diet-induced obesity, and decreased ability to regulate body temperature through mechanisms that remain incompletely understood. Recent research from our lab has demonstrated that feeding animals a high-fat diet (HFD) during the inactive period of the 24-hour cycle exacerbates diet-induced obesity and metabolic syndrome through reduced futile creatine cycling in thermogenic brown adipose tissue (BAT). Further, our lab has identified a neural circuit from arginine vasopressin-expressing neurons of the suprachiasmatic nucleus (SCNAVP) to neurons of the dorsomedial hypothalamus (DMH) as an important mediator of time-of-day appropriate energy expenditure: chemogenetically activating the normally silent SCNAVP → DMH circuit during the active period of mice induces a significant decrease in thermogenesis and body temperature during the active period. Combined with recent research indicating that sympathetic adrenergic signaling within brown adipose tissue exerts control over creatine-mediated thermogenesis, I seek to unravel the relationship between time-restricted feeding and SCNAVP → DMH in the control of thermogenesis. The interaction between feeding time and the circadian clock in regulating brown adipose thermogenesis, remain an open question. In this proposal, I aim to test the novel hypotheses that the circadian clock integrates feeding time and brown adipose thermogenesis through rhythmic activity within the SCNAVP → DMH circuit (i), and that both SCNAVP → DMH signaling and meal time exert molecular control over thermogenesis through the brain-adipose axis (ii). In Aim 1, I will determine the roles of feeding time and the molecular clock in SCNAVP → DMH control of thermogenesis. I will evaluate the role of active-period time-restricted chow and HFD feeding after mistimed chemogentic activation, as well as genetic ablation of the molecular clock, in the SCNAVP → DMH circuit to determine how meal timing affects the neural-mediated thermogenesis in absence of the molecular rhythm. In Aim 2, I will test the hypothesis that both SCNAVP → DMH signaling and feeding time regulate peripheral thermogenesis in BAT. I will determine the mechanism by which the activity of the SCNAVP → DMH circuit regulates diet-induced thermogenesis via cold challenge and brown fat molecular function. I will also examine the effect of time-restricted feeding on BAT thermogenesis in response to autonomic catecholamine signaling from the sympathetic nervous system. The work presented in this proposal will dissect the contributions of meal timing and the molecular circadian clock to the function of a neural circuit and its peripheral projections in regulating diet-induced thermogenesis and metabolic health.