Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling

Qin Tang; Yong Gao; Qinhui Liu; Xuping Yang; Tong Wu; Cuiyuan Huang; Ya Huang; Jinhang Zhang; Zijing Zhang; Rui Li; Shiyun Pu; Guorong Zhang; Yingnan Zhao; Jian Zhou; Hui Huang; Yanping Li; Wei Jiang; Yongsheng Chang; Jinhan He

Molecular Metabolism (Jul 2020)

Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling

Qin Tang,
Yong Gao,
Qinhui Liu,
Xuping Yang,
Tong Wu,
Cuiyuan Huang,
Ya Huang,
Jinhang Zhang,
Zijing Zhang,
Rui Li,
Shiyun Pu,
Guorong Zhang,
Yingnan Zhao,
Jian Zhou,
Hui Huang,
Yanping Li,
Wei Jiang,
Yongsheng Chang,
Jinhan He

Affiliations

Qin Tang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Yong Gao: Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
Qinhui Liu: Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Xuping Yang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Tong Wu: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Cuiyuan Huang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Ya Huang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Jinhang Zhang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Zijing Zhang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Rui Li: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Shiyun Pu: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Guorong Zhang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Yingnan Zhao: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Jian Zhou: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Hui Huang: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Yanping Li: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Wei Jiang: Molecular Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
Yongsheng Chang: Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China; Corresponding author. Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
Jinhan He: Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author. Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China.

Journal volume & issue: Vol. 37
p. 100994

Abstract

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Objective: Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. Methods: For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. Results: Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. Conclusions: Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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