Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice

• Published in: Cell death discovery 2021-11, Vol.7 (1), p.338-12, Article 338
• Main Authors: Li, Xuan, Cai, You, Luo, Jiao, Ding, Jingyun, Yao, Guojun, Xiao, Xiaohua, Tang, Yizhe, Liang, Zhen
• Format: Article
• Language: English
• Subjects: 631/378/2596/1953; 692/699/2743/393; Antidiabetics; Apoptosis; Biochemistry; Biomedical and Life Sciences; Body weight gain; Cell Biology; Cell Cycle Analysis; Cell death; Diabetes mellitus; Enzyme inhibitors; High fat diet; Hypothalamus; IL-1β; Inflammation; Kinases; Life Sciences; Metformin; Microglia; Necroptosis; Obesity; Phenotypes; Protein kinase; Remission; Stem Cells; Tumor necrosis factor-α
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-021-00732-5

Necroptosis, a form of programmed cell death, accounts for many inflammations in a wide range of diseases. Diet-induced obesity is manifested by low-grade inflammation in the mediobasal hypothalamus (MBH), and microglia are implicated as critical responsive components for this process. Here, we demonstrate that microglial necroptosis plays a pivotal role in obesity-related hypothalamic inflammation, facilitating proinflammatory cytokine production, such as TNF-α and IL-1β. Treatment with the anti-diabetic drug metformin effectively reduces the obese phenotypes in the high-fat diet (HFD)-fed mice, attributing to remission of hypothalamic inflammation partly through repressing microglial necroptosis. Importantly, using the receptor-interacting protein kinase 1 inhibitor, necrostatin-1s, could not suppress the microglial inflammation nor prevent body weight gain in the obese mice, indicating that the microglial necroptosis is RIPK1-independent. Altogether, these findings offer new insights into hypothalamic inflammation in diet-induced obesity and provide a novel mechanism of action for metformin in obesity treatment.