Payne, Geoffrey

Obesity is adetrimental health condition that occurs when energy intake, exceeds energy expenditure. Pituitary adenylatecyclase-activating polypeptide (PACAP) regulates energy expenditure, including adaptive thermogenesis, through the hypothalamic-sympatheticnervous system-brown adipose tissue axis. We hypothesize that PACAP expression in the ventromedial nucleus (VMN) is required for adaptive thermogenesis. To assess this, our goal is to develop an animal model that expresses PACAP specifically in the VMN of the hypothalamus. As a first step to achieving this goal, we established a protocol to deliver an adeno-associatedvirus (AAV) expressing the visible protein eGFP under the control of a VMN-specific promoter, steroidogenic factor 1 (SF1) using stereotaxic surgery. A second step was to develop a protocol to detect PACAP mRNA in the brain using in situ hybridization. Our results showed that the stereotaxic protocol was successful and provides significant progress towards achieving PACAP-specific expression in the VMN.

Obesity results when energy intake chronically exceeds energy expenditure, driving accumulation and malfunctioning of white adipose tissue and increasing risk for comorbidity. Brown adipose tissue (BAT) burns energy via adaptive thermogenesis, a process gaining therapeutic interest to restore energy balance in obesity. PACAP regulates energy expenditure including thermogenesis in BAT, but the neuronal circuits involved are not well known. Thus, we aim to develop a tool to safely restore PACAP in the hypothalamic ventromedial nucleus (VMN) of PACAP-null mice to assess the VMN’s contribution. We also investigated whether PACAP directly regulates BAT function by binding at adipocytes. We discovered PACAP receptor expression in BAT and genetic regulation of receptor expression with cold acclimation. Acute in vitro studies did not show PACAP-stimulated thermogenesis in BAT. Studying adaptive thermogenesis and its hypothalamic regulation will contribute to the field of energy metabolism, and the pathophysiology of obesity and type 2 diabetes.