Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin

Abstract

Objective The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. D issipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Matherials/Methods Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Results Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916 ± 952 pg/ml vs. 23474 ± 1507 pg/ml, p<0.01) while no change was observed for insulin, IGF-1 or leptin. Conclusions GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of it down-regulation.

Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders

“…A shRNA viral mediated knockdown of GPR83 in the preoptic area of the anterior hypothalamus (POA) decreased core body temperature and increased body weight in mice with no changes in food intake. 45 As mentioned earlier, GPR83 is expressed in warm-sensitive neurons in the POA (Fig. 3B and F), which are responsible for maintaining core body temperature and fever responses.…”

“…In the hypothalamus, GPR83 is expressed in the arcuate nucleus and the preoptic area 43–45 (Fig. 3B, C, F, and H).…”

“…44 GPR83 expression in AgRP and warm-sensitive neurons suggests a significant role in regulating metabolism, energy expenditure and regulation of core body temperature, which will be discussed later in this review. 43,45 …”

Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83

“…Gpr83 is most abundantly expressed in the murine brain and the thymus [2, 3] and was found to play a regulatory role in thermogenesis and to participate in the control of circulating adiponectin levels [4]. The Gpr83 knock-out mouse is protected against diet-induced obesity and mGPR83 has been suggested to be a determinant in systemic energy metabolism [5].…”

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

“…Rodent studies show that this protein is expressed in multiple brain regions of relevance to OSA, including the hypoglossal nuclei, dorsal motor nucleus of vagus nerve, and the nucleus of solitary tract (36). Gpr83 down-regulation in mice leads to decreased core body temperature and increases in weight and circulating adiponectin (37). Gpr83 knockout mice display differences in expression of the sleep-and wake-related genes Npy and Hcrt in the hypothalamus (38).…”