Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

Yuxiao Liu; Weitong Su; Zhengshuai Liu; Zhimin Hu; Jiaxin Shen; Zengpeng Zheng; Dong Ding; Wei Huang; Wenjing Li; Genxiang Cai; Shuang Wei; Ni Li; Xia Fang; Hong Li; Jun Qin; Haibing Zhang; Yichuan Xiao; Yan Bi; Aoyuan Cui; Chunxiang Zhang; Yu Li

doi:10.1002/advs.202306685

Advanced Science (Apr 2024)

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

Yuxiao Liu,
Weitong Su,
Zhengshuai Liu,
Zhimin Hu,
Jiaxin Shen,
Zengpeng Zheng,
Dong Ding,
Wei Huang,
Wenjing Li,
Genxiang Cai,
Shuang Wei,
Ni Li,
Xia Fang,
Hong Li,
Jun Qin,
Haibing Zhang,
Yichuan Xiao,
Yan Bi,
Aoyuan Cui,
Chunxiang Zhang,
Yu Li

Affiliations

Yuxiao Liu: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Weitong Su: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Zhengshuai Liu: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Zhimin Hu: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Jiaxin Shen: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Zengpeng Zheng: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Dong Ding: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Wei Huang: Department of Endocrinology and Metabolism The Affiliated Hospital of Southwest Medical University Metabolic Vascular Diseases Key Laboratory of Sichuan Province Luzhou Sichuan 646000 China
Wenjing Li: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Genxiang Cai: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Shuang Wei: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Ni Li: CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Xia Fang: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Hong Li: CAS Key Laboratory of Computational Biology Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai 200031 China
Jun Qin: CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Haibing Zhang: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Yichuan Xiao: CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Yan Bi: Affiliated Drum Tower Hospital Medical School of Nanjing University Nanjing Jiangsu 210008 China
Aoyuan Cui: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China
Chunxiang Zhang: Metabolic Vascular Disease Key Laboratory of Sichuan Province The Affiliated Hospital of Southwest Medical University Key Laboratory of Medical Electrophysiology Ministry of Education Southwest Medical University Luzhou 646000 China
Yu Li: CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China

DOI: https://doi.org/10.1002/advs.202306685
Journal volume & issue: Vol. 11, no. 13
pp. n/a – n/a

Abstract

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Abstract Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition‐induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance. CREBZF deficiency in macrophages, not in neutrophils, attenuates macrophage infiltration in adipose, proinflammatory activation, and hyperglycemia in diet‐induced insulin‐resistant mice. The coculture assays show that macrophage CREBZF deficiency improves insulin sensitivity in primary adipocytes and adipose tissue. Mechanistically, CREBZF competitively inhibits the binding of IκBα to p65, resulting in enhanced NF‐κB activity. In addition, bromocriptine is identified as a small molecule inhibitor of CREBZF in macrophages, which suppresses the proinflammatory phenotype and improves metabolic dysfunction. Furthermore, CREBZF is highly expressed in ATM of obese humans and mice, which is positively correlated with proinflammatory genes and insulin resistance in humans. This study identifies a previously unknown role of CREBZF coupling ATM activation to systemic insulin resistance and type 2 diabetes.

Published in Advanced Science

ISSN: 2198-3844 (Online)
Publisher: Wiley
Country of publisher: Germany
LCC subjects: Science
Website: https://onlinelibrary.wiley.com/journal/21983844

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