Microglia Sirt6 modulates the transcriptional activity of NRF2 to ameliorate high-fat diet-induced obesity

Molecular Medicine

Research Article

Huiling Hu¹  Zhisen Pan²  Xiaoying Yang³  Qi Wang⁴  Xiaoxia Xiao⁴  Yong Gao⁴  Kaijia Tang⁴  Yingjian Chen⁴  Jiawen Huang⁴  Yadi Zhong⁴ 

[1] Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510289, Guangzhou, China;Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510289, Guangzhou, China;First Affiliated Hospital, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China;Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, 221004, Xuzhou, Jiangsu, China;Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China;

关键词: Sirt6;    Microglial activation;    Hypothalamic inflammation;    NRF2;    Obesity;   

DOI  :  10.1186/s10020-023-00676-9

 received in 2023-01-31, accepted in 2023-05-31,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMicroglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown.MethodsMicroglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity.ResultsWe found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity.ConclusionCollectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.

【 授权许可】

CC BY   
© The Feinstein Institute for Medical Research 2023

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