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

Xuan Li,Yizhe Tang,Xiaohua Xiao,Guojun Yao,You Cai,Jingyun Ding,Zhen Liang,Jiao Luo

doi:10.1038/s41420-021-00732-5

Abstract

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.

Highlights

Diet-induced obesity (DIO) has emerged as a major health problem provoking the interests of researchers worldwide
RNA-Seq analysis reveals necroptosis arises in the mediobasal hypothalamus (MBH) of DIO mice, and metformin treatment dampens this process To investigate potentially altered gene expression underlying the DIO mice, RNA-sequence (Seq) analysis was performed on the hypothalamus of the chow mice (Chow), high-fat feeding mice (HFD), and the metformin-treated high-fat diet (HFD) mice (HM) (Fig. 1A)
In the present study, we first delineate a novel picture that microglial necroptosis facilitated metabolic inflammation in the MBH of DIO mice

Summary

Introduction

Diet-induced obesity (DIO) has emerged as a major health problem provoking the interests of researchers worldwide. Many studies have demonstrated that obesity-induced chronic low-grade inflammation in the area of the hypothalamus (mediobasal hypothalamus, MBH), including the arcuate nucleus (ARC), plays a pivotal role in metabolic disorder and body weight gain [1]. Necroptosis, a newly defined wellregulated necrosis, is critical for inflammation regulation. Receptorinteracting protein kinase 1 (RIPK1) and RIPK3 are two key initiators of necroptosis. Their downstream molecule mixed lineage kinase domain-like protein (MLKL) is a critical effector of the pathway. Necroptosis initiation requires RIPK1, which binds to its partner RIPK3 to form necrosome. Increasing evidence has indicated that RIPK3 can mediate RIPK1-independent necroptosis [3]. It is noteworthy to examine the functional roles of necroptosis in hypothalamic inflammation in DIO

Methods

Results

Conclusion