Vagal REV-ERB as a Circadian Regulator of Satiation Signaling

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Project Summary Obesity is an international epidemic with significant health and economic consequences. Excess caloric intake and dysregulated feeling of hunger/fullness largely contribute to the failure of lifestyle modifications to maintain weight loss. Accordingly, basic science research investigating the physiological mechanisms regulating feeding behavior and energy homeostasis for the development of effective anti-obesity therapeutics is more pertinent than ever. The normal diurnal patterns of food intake (high during the active phase, low during the inactive phase) are muted in obesity. Gastric vagal afferent nerves convey nutritional information from the gastrointestinal (GI) tract (mechanical distension of the stomach and GI-released neuropeptides) to the brain to regulate feeding behavior. Interestingly, vagal afferents are more sensitive to gastric distension during the inactive phase and similarly the GI-neuropeptide cholecystokinin (CCK) is more satiating during the inactive phase. We propose that diurnal variations in the potency of postprandial satiety mechanisms reinforces diurnal patterns of food intake. Obesity, however, eliminates the circadian rhythms of vagal nerve sensitivity to gastric distension and diminishes the satiating effects of GI satiety factors through incompletely understood mechanisms, leading to the hypothesis that obesity-induced hyperphagia is due in part to dysregulated circadian patterns of ingestive behavior. Clock genes are molecular regulators of circadian dependent processes and our preliminary data show that vagal afferent nerves express the clock genes REV-ERBα and β. REV-ERBα/β uniquely coordinate energy homeostasis with circadian cues, yet their role in peripheral satiation signaling and diurnal control of food intake is completely unexplored. The research proposed in this application utilizes the novel model of vagal REV- ERBα/β double knockdown (DKD) mice to test the hypothesis that vagal REV-ERBα/β regulate diurnal sensitivity to GI-derived satiation signals. Specific Aim 1 will assess the impact of vagal REV-ERB DKD on meal patterning using a BioDAQ Food Intake Monitoring System and the satiating effect of CCK, glucagon-like peptide-1, and gastric distension at 4 different circadian timepoints. Diurnal patterns of eating and wakefulness are highly coupled, and obesity disrupts sleep patterns in addition to feeding behavior. Accordingly, Specific Aim II will use CLAMS metabolic cages to investigate the role of vagal REV-ERB DKD on diurnal patterns of locomotor activity, and indicator of sleep behavior. Additionally, we will use RNA-seq to analyze circadian patterns of vagal gene expression and identify REV-ERBα/β regulated genes in satiation signaling and neurotransmission. As we propose that altered vagal REV-ERBα/β signaling underlies obesity-induced dysregulations in feeding behavior, we expect that vagal REV-ERB DKD will blunt diurnal variations in food intake, sensitivity to satiation signals, and locomotion. This work will enhance our understanding of the molecular mechanisms regulating circadian rhythms of feeding behavior with the goal of identifying new pharmacologic targets to treat the circadian misalignment, hyperphagia, and weight gain associated with obesity.