Yong Liu Group Discovered New Mechanism of Overnutrition Inducing Obesity and Metabolic Diseases
Source：Yong Liu
2017-05-02
Obesity is associated with adipose inflammation and endoplasmic reticulum (ER) stress that are believed to promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players in orchestrating metabolic inflammation. ATM M1 polarization is thought to promote insulin resistance and type 2 diabetes, whereas M2 polarization has been shown to enhance the activation of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT). ER stress activates three unfolded protein response (UPR) pathways that act coordinately to restore ER homeostasis. Although ER stress is able to enhance macrophage activation, the role of individual UPR pathways in M1/M2 polarization and ATM regulation of glucose and energy homeostasis remains poorly understood.
A research team led by Dr. Yong Liu from Wuhan University and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, has identified theinositol-requiring enzyme 1α(IRE1α) branch of the UPR acting as a critical switch that governs M1/M2 polarization and energy homeostasis. As reported in a Research Article entitled “The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity” in Nature Immunology, they found that the IRE1α-XBP1 pathway in ATMs was aberrantly activated in dietary obese mice. Utilizing a mouse model in which the gene encoding IRE1α was specifically deleted in myeloid cells including macrophages, they demonstrated that abrogation of myeloid IRE1α largely reversed high-fat diet (HFD)-induced M1/M2 imbalance in WAT and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Remarkably, myeloid IRE1α deficiency resulted in higher BAT activity and WAT browning, thereby enhancing energy expenditure and protecting against obesity and obesity-associated metabolic diseases. Ablation of IRE1α also cell-autonomously decreased M1 polarization and enhanced M2 polarization in response to IL-4, which was able to activate the IRE1-XBP1 pathway in macrophages. Thus, IRE1αcan act as a molecular sensor for protein unfolding, metabolic, and immunological states to guide ATM M1/M2 polarization. Their findings have revealed a new paradigm with respect to how metabolic ER stress leads to disruption of glucose and energy metabolism: in the state of overnutrition, obesogenic factors can activate macrophage IRE1α, which acts to promote M1, while repressing M2, polarization; such adipose M1/M2 imbalance in turn cripples the energy-burning capacity of both brown and beige fat. Targeting the IRE1α pathway in ATMs may open new avenues for developing brown/beige fat-enhancing therapeutics to combat obesity and metabolic diseases.
A research team led by Dr. Yong Liu from Wuhan University and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, has identified theinositol-requiring enzyme 1α(IRE1α) branch of the UPR acting as a critical switch that governs M1/M2 polarization and energy homeostasis. As reported in a Research Article entitled “The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity” in Nature Immunology, they found that the IRE1α-XBP1 pathway in ATMs was aberrantly activated in dietary obese mice. Utilizing a mouse model in which the gene encoding IRE1α was specifically deleted in myeloid cells including macrophages, they demonstrated that abrogation of myeloid IRE1α largely reversed high-fat diet (HFD)-induced M1/M2 imbalance in WAT and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Remarkably, myeloid IRE1α deficiency resulted in higher BAT activity and WAT browning, thereby enhancing energy expenditure and protecting against obesity and obesity-associated metabolic diseases. Ablation of IRE1α also cell-autonomously decreased M1 polarization and enhanced M2 polarization in response to IL-4, which was able to activate the IRE1-XBP1 pathway in macrophages. Thus, IRE1αcan act as a molecular sensor for protein unfolding, metabolic, and immunological states to guide ATM M1/M2 polarization. Their findings have revealed a new paradigm with respect to how metabolic ER stress leads to disruption of glucose and energy metabolism: in the state of overnutrition, obesogenic factors can activate macrophage IRE1α, which acts to promote M1, while repressing M2, polarization; such adipose M1/M2 imbalance in turn cripples the energy-burning capacity of both brown and beige fat. Targeting the IRE1α pathway in ATMs may open new avenues for developing brown/beige fat-enhancing therapeutics to combat obesity and metabolic diseases.
