Regulation of satiation centers in health and obesity

PROJECT SUMMARY
The prevalence of obesity and associated comorbidities is a major public health concern with significant
personal and societal consequences. Weight loss pharmacotherapies that target known food intake-inhibitory
mechanisms (e.g., hindbrain and hypothalamic circuits) have been largely unsuccessful at promoting sustained
weight loss. This suggests the existence of yet-to-be-identified nodes that regulate food intake, and uncovering
such mechanisms holds promise for the development of more effective obesity treatments. To this end, we
recently used a “reverse translational” approach to identify and characterize a novel population of cerebellar
neurons and their importance to feeding behavior. Starting with human subjects and following up with
mechanistic experiments in mice, we discovered that glutamatergic neurons in the anterior, lateral deep
cerebellar nuclei (aDCN-lat) are activated by food and have the ability to dramatically reduce meal size. These
data demonstrate that glutamatergic aDCN-lat neurons are critical regulators of feeding behavior, and highlight
this population as a potential target for obesity therapeutics. Here, we leverage these findings to understand
how activity in these cerebellar neurons is regulated and how it is altered in obesity. The goals of this proposal
are to (1) reveal the sensory, nutritive, and gut-brain pathways that activate cerebellar satiation neurons, (2)
determine how activity in these neurons changes in obesity, and (3) test whether chronic activity in these
neurons is sufficient to prevent or reverse diet-induced obesity in mice. These results will provide a
comprehensive understanding of cerebellar mechanisms for feeding behavior, illuminating a novel satiation
center in the brain that may be targeted for the development obesity therapeutics.

Grant Number: 5R01DK133399-04
NIH Institute/Center: NIH
Principal Investigator: John Betley