Dataset Information

PNOC^ARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding.

ABSTRACT: Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOC^ARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOC^ARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOC^ARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOC^ARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.

SUBMITTER: Jais A

PROVIDER: S-EPMC7303947 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding.

Jais Alexander A Paeger Lars L Sotelo-Hitschfeld Tamara T Bremser Stephan S Prinzensteiner Melanie M Klemm Paul P Mykytiuk Vasyl V Widdershooven Pia J M PJM Vesting Anna Juliane AJ Grzelka Katarzyna K Minère Marielle M Cremer Anna Lena AL Xu Jie J Korotkova Tatiana T Lowell Bradford B BB Zeilhofer Hanns Ulrich HU Backes Heiko H Fenselau Henning H Wunderlich F Thomas FT Kloppenburg Peter P Brüning Jens C JC

Neuron 20200416 6

Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the AR ...[more]

PMID: 32302532

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Project description:BackgroundProopiomelanocortin (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.MethodsIn 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).ResultsAdult 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 < 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.ConclusionsGpr17 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.

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Dataset Information

PNOC^ARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding.

Publications

PNOC<sup>ARC</sup> Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding.

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