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Int. J. Mol. Sci. 2017, 18(4), 832; doi:10.3390/ijms18040832

Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis

1
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
2
United States Department of Agriculture/Agriculture Research Service Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
3
Reproductive Medical Center, Tongji affiliated Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
4
College of Pharmacy, Gachon University, Incheon 21936, Korea
5
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
6
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
7
Division of Anesthesiology and Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
8
Diabetes Center, University of California, San Francisco, CA 94143, USA
9
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Suzanne L. Dickson
Received: 1 March 2017 / Revised: 7 April 2017 / Accepted: 7 April 2017 / Published: 14 April 2017
(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)
View Full-Text   |   Download PDF [2111 KB, uploaded 14 April 2017]   |  

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;Ghsrf/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. View Full-Text
Keywords: Agouti-related peptide (AgRP); ghrelin; growth hormone secretagogue receptor (GHS-R); diet-induced obesity (DIO); thermogenesis Agouti-related peptide (AgRP); ghrelin; growth hormone secretagogue receptor (GHS-R); diet-induced obesity (DIO); thermogenesis
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Wu, C.-S.; Bongmba, O.Y.N.; Yue, J.; Lee, J.H.; Lin, L.; Saito, K.; Pradhan, G.; Li, D.-P.; Pan, H.-L.; Xu, A.; Guo, S.; Xu, Y.; Sun, Y. Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis. Int. J. Mol. Sci. 2017, 18, 832.

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