A Physiological Role for Hypothalamic Proopiomelanocortin in the Intrinsic Regulation of Locomotor Activity and Stress.

Abstract

Proopiomelanocortin (POMC) produced in the hypothalamic arcuate nucleus (Arc) has been studied extensively for its roles in the regulation of food intake and energy expenditure. POMC-derived peptides signal satiation and contribute to meal termination, thus individuals lacking POMC exhibit hyperphagic obesity. Neural circuits regulating feeding cross-talk extensively with other neural and endocrine pathways and therefore could affect physiological systems not directly related to feeding. However, these potential functions of ArcPOMC have not been well characterized. We generated a genetic mouse model that lacks Pomc expression specifically in Arc neurons (ArcPomc-knockout (KO)) and used these mice to identify roles for POMC in regulation of locomotor activity and the hypothalamic-pituitary-adrenal (HPA) stress axis.

We assessed spontaneous home cage and voluntary wheel running activity in wildtype control mice, obese ArcPomc-KO mice, and ArcPomc-KO mice weight-matched to wildtype controls by caloric restriction. Obese ArcPomc-KO mice had decreased home cage activity that was normalized by weight-matching. In contrast, both obese and weight-matched ArcPomc-KO mice exhibited less voluntary wheel running activity than controls. These results indicate that spontaneous locomotor activity is not directly regulated by ArcPomc but can decrease secondary to obesity. However, ArcPomc intrinsically regulates voluntary wheel running behavior, which is known to be rewarding, independently of body weight, suggesting a reward deficit in ArcPomc-KO mice.

Additionally, we extensively characterized the HPA axis of ArcPomc-KO mice. Obese and weight-matched ArcPomc-KO mice developed adrenocortical hypertrophy, and obese ArcPomc-KO mice had elevated stress hormones as well as increased expression of hypothalamic and pituitary HPA axis related genes. We identified hypothalamic arginine vasopressin as a potential downstream effector of this dysregulation, but ArcPomc-KO mice crossed with vasopressin receptor 1b (Avpr1b)-KO mice did not exhibit a rescued HPA phenotype. Therefore, we conclude that ArcPomc tonically inhibits the HPA axis and vasopressin signaling is not necessary for the hyperactivity of the axis caused by POMC-deficiency.

Collectively, we have shown that in addition to its role in feeding behavior, ArcPOMC also regulates locomotor activity levels and the HPA stress axis. Both of these pathways are involved in body weight adjustment and may be additional mechanisms whereby POMC deficiency leads to obesity.