The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism
Year: 2021
Type: article
Abstract: Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis.
Source: Endocrinology
Institutions: University of Michigan, Albert Einstein College of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Indiana Biosciences Research Institute, University of Cologne, Max Planck Institute for Metabolism Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Indiana University School of Medicine, Michigan Medicine
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: American Diabetes Association, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Boston Area Diabetes Endocrinology Research Center, The AgRP / POMC -> Paraventricular (PVH) -> Parabrachial (PBN) -> Limbic/Reward Satiety Circuit, G2513047960, Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance, Boston Nutrition Obesity Research Center, G4112104809, Training Program in Cardiovascular Research, Obesity & Gastrointestinal Surgery Research Training Program, Glutamatergic Neurons in the Arcuate Nucleus (ARC) and Regulation of Satiety, G6760362721, AgRP neurons: circadian control and interactions with the HPA axis, Michigan Institute for Clinical and Health Research (MICHR), Dissecting a novel prefrontal cortical pathway regulating feeding behavior, G9000104193, G9000137030, G9000299033, Michigan Diabetes Research Center (MDRC), Training Grant on Genetic Aspects of Alcoholism, Training in Basic and Translational Digestive Sciences, SUPPORT FOR THE ROSE F KENNEDY IDDRC P50, Indiana Diabetes Research Center
OpenAlex ID: W3124792749