The central melanocortin system mediates the benefits of time-restricted feeding on energy balance

Abstract Objective Recent decades have seen a marked increase in the prevalence of obesity and its associated comorbidities. This increase correlates with greater access to calorie-dense food that is often consumed later in the active phase of the day. Studies in high-fat diet-induced obese (DIO) mice indicate that restricting food access to their active (dark) phase is sufficient to reduce obesity. However, the specific mechanisms mediating these beneficial metabolic effects of dark restricted feeding (DRF) remain unknown. Methods We examined the impact of DRF on the response to peripheral signals regulating the central melanocortin system of DIO mice and on Mc4r−/− mice. Results The body weight loss following DRF has an acute onset that is sustained over time. This effect is contributed by a reduction on food intake that requires a functional central melanocortin system. Specifically, DRF impacts the circadian expression of melanocortin system genes in the arcuate nucleus of the hypothalamus (ARC). Consistent with this, DRF significantly increases the effectiveness of the fasting-feeding signals ghrelin and leptin that interact with the melanocortin system to regulate energy balance. Importantly, DRF did not reduce or prevent obesity in Mc4r−/− mice. Conclusions Taken together, our data reveal a critical role of brain melanocortin signaling in mediating the beneficial effects of timed feeding on metabolic control, supporting potential meaningful benefits in combining timed feeding with pharmacological targeting of the melanocortin signaling for the treatment of obesity.