Nature Immunology: Peking University researchers discovered a new mechanism for IRX3 protein to regulate obesity

On September 23, 2021, Qiu Yifu's team from the Institute of Molecular Medicine, Peking University Future Institute of Technology and Peking University-Tsinghua Life Sciences Joint Center published a research paper entitled " Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation " in Nature Immunology , For the first time reported that IRX3 in adipose tissue macrophages plays an important role in regulating obesity and metabolic inflammation, and clarified the specific molecular mechanism of IRX3 as a transcription factor promoting the expression of inflammatory genes .

Screenshot of the paper

Obesity not only causes a series of metabolic diseases such as diabetes, non-alcoholic fatty liver, and atherosclerosis, but also accelerates the occurrence and development of various diseases such as cancer and new coronary pneumonia.

The obesity epidemic has become a major burden on the global medical and health system

In order to explore the function of IRX3 in macrophages, the authors constructed myeloid-specific Irx3 knockout mice (Irx3 ^fl/fl Lyz2 ^Cre ), and found that the body weight of the knockout mice under the conditions of ordinary diet and high-fat diet Both are significantly lower than control mice (Irx3 ^fl/fl ), and are mainly due to the loss of fat and liver tissue weight
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It was further found that the oxygen consumption capacity of the knockout mice was significantly enhanced, and the expression of thermogenesis and lipolysis genes in the brown fat and subcutaneous fat was also significantly higher than that of the control mice

So, how does myeloid-specific knockout of Irx3 affect the function of adipocytes? After treating adipocytes with supernatants of macrophages cultured in vitro, the authors found that the supernatants of control mouse macrophages could significantly inhibit the thermogenesis and lipolysis process of adipocytes, while the supernatants of macrophages with Irx3 knocked out basically Releasing this inhibitory effect indicates that IRX3 in macrophages acts on fat cells by releasing certain factors
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Through high-throughput sequencing analysis, in vitro knockout and overexpression experiments, the authors found that IRX3 can promote the transcription of inflammatory factors Il6, Il1a, Il1b, etc.

How does IRX3 regulate the expression of inflammatory factors in macrophages? The authors found that LPS stimulation can significantly increase the amount of IRX3 protein in macrophages, mainly because the ubiquitination degradation of IRX3 protein is inhibited, and the ubiquitination site K409 of IRX3 protein has been identified
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In addition to increasing the amount of IRX3 protein, LPS can also increase the phosphorylation level of IRX3

Since macrophages and inflammatory factors play an important role in obesity and related metabolic diseases, the authors further explored whether the knockout of Irx3 in macrophages can alleviate the metabolic diseases caused by obesity
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After induction of obesity by a high-fat diet, control mice showed glucose intolerance and insulin resistance, while these symptoms of myeloid-specific Irx3 knockout mice were significantly improved, indicating that they have better blood glucose clearance and insulin response Ability

In summary, the study mainly found that IRX3 in macrophages, as a transcription factor, directly promotes the expression of inflammatory genes through the TLR4-JNK1/2-IRX3 signaling pathway, thereby inhibiting the thermogenic function of adipose tissue, leading to obesity and related metabolic inflammatory diseases Happened
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At the same time, the study also identified for the first time the ubiquitination and phosphorylation sites of IRX3 protein regulated by LPS, providing new clues for in-depth understanding of the protein function of IRX3 and the prevention and treatment of obesity-related diseases

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Yao Jingfei, a 2016 doctoral student at the Institute of Molecular Medicine, Peking University Future Institute of Technology, is the first author of the article, and researcher Qiu Yifu is the corresponding author
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