Body energy homeostatic mechanisms dynamically balance energy expenditure with energy intake, and the brain plays a critical role in this process. However, the specific circuits responsible for controlling energy expenditure are only superficially understood. Because Ventromedial Hypothalamic (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 VMN PACAP controls energy expenditure. Since PACAP is expressed in the periphery, we administered a VMN-targeted injection of AAVcre in PACAPflox mice to remove VMN PACAP (PACAPVMNKO), which resulted in a near complete bilateral ablation of PACAP mRNA in the VMN without interfering with PACAP mRNA in nearby sites (e.g., preoptic area (POA) and medial amygdala). In both male and female mice, PACAPVMNKO induced massive obesity and more than a two-fold increase in adipose mass. This induced obesity, similar to other VMN loss of function studies, is due to chronically suppressed energy expenditure because VO2, but not activity, was decreased in these mice. PACAPVMNKO mice were also hyperinsulinemic, hyperglycemic, and exhibited impaired glucose clearance in the hyperinsulinemic/hyperglycemic clamp. However, PACAPVMNKO mice were normoglycemic 4 weeks post-injection (prior to obesity), indicating that glycemic effects were secondary to obesity. Because the VMN does not contain directly pre-autonomic neurons, PACAP must activate a circuit via a downstream site to stimulate energy expenditure. PAC1r cells primarily overlay with VMN projections in the POA and to a lesser extent in the periaqueductal grey and bed nucleus of the stria terminalis. VMN PACAP, as well as associated signaling targets, are critical components to the control of energy balance by activating energy expenditure.
D.Q. Johnson: None. J. Flak: None.
American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-15 to J.F.); National Institutes of Health (DK020572)