Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network

PROJECT SUMMARY Circadian rhythms are autonomous cycles of behavior and physiology that undergo routine disruption in modern society due to the rise in shift work, exposure to blue light at night, disrupted sleep, and consumption of highly- palatable high-fat diet. Molecular clocks are encoded by transcription feedback loops that drive the 24-hr sleep- wake cycle and physiological rhythms in hormone levels, glucose metabolism, and energetics. In the previous grant period, we revealed an essential function for both brain and peripheral clocks in rhythmic energy homeostasis and glucose metabolism. We showed that morning/evening variation in chromatin conformation controls -cell insulin secretion. We also showed that clock ablation in neurons of forebrain and midbrain impairs appetitive drive, sleep/wake rhythms, energy balance, glucose tolerance, and transcription, although a gap remains in our understanding of the mechanisms underlying rhythmic integration of behavior and metabolism. Here we seek to extend our insight into circadian mechanisms linking behavior and metabolism. (i) In our first aim, we will dissect the cell and molecular basis for genomic rhythms driving -cell function important in glucose constancy across the sleep-wake cycle. (ii) In our second aim, we will identify the neurocircuit basis for rhythms of hedonic and homeostatic feeding coordinating appetitive drive with glucose homeostasis. An innovation of our work is the multidimensional integration of genetics, genomics, and behavioral analyses to gain molecular insight into rhythmic -cell function and neuronal control of hunger. Ultimately, we are poised to uncover new insight into how central and peripheral clocks impact physiology, findings which have broad implications for the treatment and prevention of obesity and metabolic syndrome.