Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis
- Authors
- Wu, Chia-Shan; Bongmba, Odelia Y. N.; Yue, Jing; Lee, Jong Han; Lin, Ligen; Saito, Kenji; Pradhan, Geetali; Li, De-Pei; Pan, Hui-Lin; Xu, Allison; Guo, Shaodong; Xu, Yong; Sun, Yuxiang
- Issue Date
- Apr-2017
- Publisher
- MDPI AG
- Keywords
- Agouti-related peptide (AgRP); ghrelin; growth hormone secretagogue receptor (GHS-R); diet-induced obesity (DIO); thermogenesis
- Citation
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.18, no.4
- Journal Title
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
- Volume
- 18
- Number
- 4
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6289
- DOI
- 10.3390/ijms18040832
- ISSN
- 1422-0067
- Abstract
- Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsr(f/f)). Our data showed that GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.
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