Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding
Authors: Shijun Yan
Sharon L Wardlaw
Jason M Conley
Sunil K Panigrahi
Shudi Zhou
Austin M Reilly
Hongxia Ren
Patrick L Sheets
Journal: Nutrition & diabetes (2019)
Discipline: CLINICAL MEDICINE
Keywords: Proopiomelanocortin neurons; Gpr17; energy homeostasis; metabolism; knockout mice
Affiliations: Stark Neurosciences Research Institute, Medical Neuroscience Graduate Program, Indiana University School of Medicine, 320 W. 15th Street Indianapolis, Indianapolis, IN, 46202, USA., Department of Medicine, Division of Endocrinology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA., Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA., Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA., Department of Pharmacology & Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA., Stark Neurosciences Research Institute, Medical Neuroscience Graduate Program, Indiana University School of Medicine, 320 W. 15th Street Indianapolis, Indianapolis, IN, 46202, USA. ., Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA. ., Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA. ., Department of Pharmacology & Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA. ., Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA. ., Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA. .

Abstract:  Background: Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. Methods: In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). Results: Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p &lt; 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Conclusions: Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control. 

Retracted: No

PubPeer comments:
 yes, but Gpr17 exerts its metabolic effects via oligodendrocytes rather than neurons: PMID: 30865888 PMID 26329458 PMID: 25624481 , 
 62 sites of recombination throughout the adult brain have been identified using this pomc-cre line. See PMID: 22166984. ,