1154-P: Mediobasal Hypothalamic PACAP Is Essential for Energy Balance by Stimulating Energy Expenditure

Body energy homeostatic mechanisms dynamically balance energy expenditure with energy intake, and the brain plays a critical role in this process. While mediobasal hypothalamic (MBH) signaling is essential for natural elevations in energy expenditure, the downstream anatomical mechanisms are not clear at this point. The MBH contains several important nuclei for energy expenditure control, such as the Ventromedial Hypothalamus (VMN). Because VMN-specific expression of pituitary adenylate cyclase-activating polypeptide (PACAP) decreases with both under-nutrition and loss of leptin action, we tested the hypothesis that MBH PACAP controls energy expenditure. To test this hypothesis, we administered local AAVCre injections into Adcyap1flox (gene that encodes for PACAP) mice. While our approach ensured that peripheral PACAP expression was completely intact, AAV injections did spread into nearby hypothalamic regions, resulting in a MBH loss of function (PACAPMBHKO), rather than a purely VMN knockout. However, all mice exhibited a near complete bilateral ablation of PACAP mRNA in the VMN without interfering with PACAP mRNA in nearby populations that highly express PACAP (e.g., preoptic area (POA) and medial amygdala). In both male and female mice, PACAPMBHKO induced obesity and more than a two-fold increase in adipose mass. VO2, expressed as a function of lean mass, was decreased particularly in the first few hours of the dark cycle, when the mice consume food. Because MBH PACAP cells do not directly project to the spinal cord, PACAP must activate a circuit via a downstream site to stimulate energy expenditure. PAC1r cells primarily overlay with VMN, the primary MBH site containing PACAP, projections in the POA and to a lesser extent in the periaqueductal grey and bed nucleus of the stria terminalis. MBH PACAP, as well as associated signaling targets, are critical components to the control of energy balance by activating energy expenditure.