Regulation of adipogenic differentiation and adipose tissue inflammation by interferon regulatory factor 3

Peng Tang,Huipeng Jiao,Sam Virtue,Chin Wen Png,Jing Guo,Antonio Vidal-Puig,José-Manuel Fernández-Real,Jian Yi Gerald Goie,José Maria Moreno-Navarrete,Mark Campbell,Yongliang Zhang,Yen Leong Chua,Ying Li,Stephan Gasser,Henry Yang,David Michael Kemeny,Asim Shabbir

doi:10.1038/s41418-021-00798-9

Abstract

Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNβ-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.

Highlights

Obesity is a major contributing factor to the development of chronic medical conditions including type 2 diabetes (T2D), fatty liver, and cardiovascular diseases [1]
After HFD for 8 weeks, we observed a significant increase in mRNA expression of Interferon regulatory factor 3 (IRF3) in white adipose tissue (WAT), but not in skeletal muscle or the liver, compared to that in mice fed with chow (Supplementary Fig. 1a)
After 16 weeks of HFD, reduced IRF3 expression in both visceral WAT and subcutaneous WAT compared to that in chow-fed mice was observed (Supplementary Fig. 1C), whereas IRF3 activation was undetectable. These results suggest that the development of severe obesity in mice is associated with the loss of IRF3 function in WAT

Summary

Introduction

Obesity is a major contributing factor to the development of chronic medical conditions including type 2 diabetes (T2D), fatty liver, and cardiovascular diseases [1]. This energy balance disorder is characterized by excessive, and often dysfunctional, accumulation of white adipose tissue (WAT). During the development of obesity, these primary functions of adipocytes are dysregulated, contributing to the development of metabolic disorders including insulin resistance (IR) and T2D [4]. C/EBPα was found to regulate adipogenesis through PPARγ [7, 10] In addition to these central players, other factors including several KLFs, STAT5, and SREBP-1 promote adipogenesis, whereas GATA2/3, KLF2, HES-1, and TCF/LEF have inhibitory effects [8, 11]

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Results

Conclusion