Bioenergetics of time-restricted feeding within the brain-adipose axis

Project Summary: The increased risk of metabolic disorders in individuals subjected to shiftwork and those experiencing sleep loss indicate that disruption of day/night behavioral rhythms represents an emerging factor in the linked epidemics of obesity and diabetes. In mice, consumption of a high fat diet (HFD) leads to increased feeding during the light period (the normal sleep phase) and disrupted circadian and metabolic rhythms. Conversely, nighttime-restricted feeding (the normal active phase) has emerged as a dietary strategy to combat obesity and diabetes. We have recently shown that time-restricted feeding (TRF) with HFD provided only during dark period mitigates obesity due to increased metabolism of food to produce heat. We have further shown that the molecular clock controls the synthesis of creatine within adipocytes, fueling a futile cycle of ATP consumption which is required for the metabolic benefits of nighttime-restricted feeding. However, we have not yet identified the brain signals that promote increased diet-induced thermogenesis during nighttime-restricted feeding, nor the epigenetic mechanisms at the level of the adipocyte that are required for circadian control of futile creatine cycling in response to time-restricted feeding. Here we propose to exploit integrative neurogenetic and circuit-based approaches in combination with behavioral, bioenergetic, metabolomic, and genomic strategies to examine the interorgan mechanisms by which the brain-adipose axis drives the health benefits of TRF. Aim 1 will test the hypothesis that the circadian SCNAVPàDMH neurocircuit drives energy expenditure rhythms to maximize health with nighttime-restricted feeding. This aim builds upon our finding that AVP cells within the SCN project to DMH neurons which are important in regulation of energy expenditure and thermogenesis. We will examine the effect of time-restricted feeding on energy expenditure and thermogenesis following (a) chemogenetic manipulation of the activity of DMH-projecting AVP neurons and (b) after genetic manipulation of molecular clock activity within these cells. These studies will identify specific cells mediating communication between the SCN and the DMH that determine the metabolic benefits of nighttime-restricted feeding. Aim 2 will test the hypothesis that the adipocyte circadian clock synchronizes thermogenic rhythms with the light cycle through the epigenetic control of creatine synthesis. We will determine how the brain clock aligns adipocyte circadian cycles with the light-dark cycle through autonomic stimulation of adipose thermogenesis, and we will elucidate the epigenetic mechanisms that link clock transcription cycles to rhythms of creatine synthesis. Collectively, these studies will define the mechanisms through which the brain-adipose axis integrates environmental and intrinsic circadian signals underlying the healthful response to time-restricted feeding.