DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-\u03b3 production

Haiyan Zhou,Feng Liu,Juli Bai,Liwen Wang,Xinyi Peng,Hairong Luo,Guobao Li,Yujiao Ji,Junyan Zhang,Meilian Liu,Yacheng Zhang,Jie Hu,Jingjing Zhang,Zhiguang Zhou

doi:10.1038/s41467-020-20665-4

Abstract

Adipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

Highlights

Adipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear
We show that high-fat diet (HFD) feeding greatly suppresses disulfide-bond A oxidoreductase-like protein (DsbA-L) expression in T cells, which correlates with reduced mitochondrial function in brown adipose tissue (BAT)-resident T cells
We quantified dysfunctional mitochondria (Fig. 1c) and found that HFD feeding increased the mitochondrial defective MMP-low cells in CD4+ T cells and to a lesser extent in CD8+ T cells of BAT (Fig. 1d), but increased MMP of T cells in inguinal white adipose tissue (iWAT) (Fig. 1e). These findings suggest that over-nutrition has a distinct effect on T cell mitochondrial function in mouse BAT and iWAT

Summary

Introduction

Adipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Both types of adaptive thermogenesis are sensed by the brain, and rely on the activation of β3 adrenergic receptor (β3AR) signaling and uncoupling protein 1 (UCP1) expression[2,3]. Several immune cell types such as Group 2 innate lymphoid cells (ILC2s), eosinophils, alternatively activated macrophages (AAMacs), and invariant natural killer T (iNKT) cells have been found to regulate adaptive thermogenesis in brown adipose tissue (BAT) and beige fat[4,5,6], both of which are specialized in the dissipation of energy in the form of heat. The mechanisms by which adiposeresident T cells regulate energy homeostasis remain largely unknown

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Results

Conclusion