313-OR: PACAP from the Ventromedial Hypothalamic Nucleus Controls Both Energy Balance and Glucose Homeostasis

Abstract

Obesity results from energy imbalance, due, at least in part, to suppressed energy expenditure. While the brain tunes energy expenditure, the neurocircuits, and essential components within these circuits, that can accelerate and decelerate energy consumption have not yet been revealed in great detail. The ventromedial hypothalamic nucleus (VMN) is a critical site for the control of sympathetic tone, which controls a range of physiologic indices including energy expenditure. While the VMN contains, almost exclusively, glutamatergic neurons, neuropeptides are also expressed within the nucleus. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is the most abundant neuropeptide in the VMN. Since previous studies have implicated PACAPVMN in responses to energy status, we hypothesized that PACAPVMN is necessary for energy balance by promoting energy expenditure. We acquired a PACAPflox mice that, in the presence of cre, results in a truncated protein, preventing communication downstream by PACAP. Because PACAP is expressed in the periphery, we administered a VMN injection of AAVcre in PACAPflox mice. Bilateral AAVcre administration ablated dmVMN PACAP expression. We found that, in both male and female mice, loss of PACAPVMN results in massive obesity, adiposity, and hyperglycemia. Surprisingly, food intake only increased once body weight had almost doubled. In support of this notion, PACAPVMNKO suppressed VO2 and not activity, despite massive obesity. In addition to energy imbalance, PACAPVMNKO induced hyperinsulinemia and suppressed glucose clearance to brown adipose tissue, heart, and muscle during hyperinsulinemic/euglycemic clamp. Our data demonstrate that PACAP is an essential component for the promotion of energy expenditure and glucose clearance by the VMN. Future studies will reveal both the VMN cells that use PACAP for these functions, as well as the downstream cells that control energy balance and glucose homeostasis. Disclosure N. Bozadjieva: None. R.A. Ross: None. B. Lowell: None. J.N. Flak: Research Support; Self; Novo Nordisk Inc. Funding American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-15 to J.N.F.)