MON-605 - A Novel Population of VMH Neurons as Critical Mediators of Glucose Homeostasis and Hepatic Insulin Sensitivity

The brain plays a key role in glucose homeostasis across a variety of physiological states, including fasting, stress, and hypoglycemia. However, attempts to target brain function to improve glucose metabolism in diabetes are limited by our incomplete understanding of how the brain controls organ-specific peripheral metabolic functions. We recently found that the ventromedial hypothalamus (VMH), a brain region with a long-documented role in glucose metabolism, regulates glucose across multiple different conditions and is comprised of many different neuronal populations, raising the possibility that different neuronal populations may control different aspects of glucose homeostasis. Here, we identify a transcriptionally and anatomically distinct population of VMH neurons marked by vesicular glutamate transporter 3 (VMH-Vglut3 neurons) that regulate glucose homeostasis through a liver-centered mechanism. In contrast to previously studied VMH neurons, chronic silencing of VMH-Vglut3 neurons lowers ad libitum and short-term fasting blood glucose without altering pancreatic hormones or circulating gluconeogenic substrates. Using hyperinsulinemic–euglycemic clamp studies, we demonstrate enhanced insulin-mediated suppression of hepatic glucose production, indicating that these mice have improved hepatic insulin sensitivity, but no change in whole body glucose disposal. Chronic silencing of VMH-Vglut3 neurons improves glucose tolerance in insulin-resistant states, including both diet-induced-obesity and leptin-deficient ob/ob mice. Although the VMH controls glucose across a broad range of metabolic conditions, VMH-Vglut3 neurons are only required to maintain euglycemia during normal physiology and maximize restraint stress–induced glucose mobilization, but do not mediate counter-regulatory response to hypoglycemia. Thus, these findings demonstrate that the VMH contains parallel, functionally specialized glucoregulatory circuits that differentially regulate different peripheral metabolic tissues in a context-dependent manner, providing a circuit-level framework for central control of glucose metabolism that can be leveraged in the search for new diabetes treatments.

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