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

International Journal of Molecular Sciences - Tập 18 Số 4 - Trang 832
Chia‐Shan Wu1,2, Odelia Y. N. Bongmba2, Jing Yue3,2, Jong Eun Lee4,2, Ligen Lin5,2, Kenji Saito2, Geetali Pradhan6,2, De‐Pei Li7, Hui‐Lin Pan7, Allison Xu8, Shaodong Guo1, Yong Xu2, Yuxiang Sun1,9,2
1Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
2United States Department of Agriculture/Agriculture Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
3Reproductive Medical Center, Tongji affiliated Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
4College of Pharmacy, Gachon University, Incheon 21936, Korea
5State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
6Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
7Division of Anesthesiology and Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
8Diabetes Center, University of California, San Francisco, CA 94143, USA
9Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA

Tóm tắt

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.

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International Journal of Molecular Sciences

Tập 18 Số 4

832

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