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

• Published in: Nature communications 2021-01, Vol.12 (1), p.326-14, Article 326
• Main Authors: Zhou, Haiyan, Peng, Xinyi, Hu, Jie, Wang, Liwen, Luo, Hairong, Zhang, Junyan, Zhang, Yacheng, Li, Guobao, Ji, Yujiao, Zhang, Jingjing, Bai, Juli, Liu, Meilian, Zhou, Zhiguang, Liu, Feng
• Format: Article
• Language: English
• Subjects: 13/1; 14/19; 38/77; 38/88; 38/90; 631/250; 631/443/319/1642; 64/60; 692/163/2743/393; 82/51; 82/80; 96/106; 96/31; Adipocytes; Adipocytes, Brown - drug effects; Adipocytes, Brown - metabolism; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - drug effects; Adipose Tissue, White - metabolism; Animal tissues; Animals; Diet; Diet, High-Fat; Down-Regulation - drug effects; Energy balance; Energy expenditure; Energy Metabolism - drug effects; Feeding Behavior; Glutathione Transferase - deficiency; Glutathione Transferase - metabolism; High fat diet; Homeostasis; Humanities and Social Sciences; Insulin; Insulin Resistance; Interferon-gamma - administration & dosage; Interferon-gamma - biosynthesis; Interferon-gamma - pharmacology; Kinases; Lymphocytes; Lymphocytes T; Male; Metabolic disorders; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; Nutrition; Obesity; Obesity - genetics; Obesity - pathology; Oxidoreductase; Phosphodiesterase; Protein kinase A; Proteins; Science; Science (multidisciplinary); T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; Thermogenesis; Thermogenesis - drug effects; Thermogenesis - genetics; Uncoupling Protein 1 - metabolism; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20665-4

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. Adipose tissue-resident T cells are known to regulate thermogenesis and energy expenditure. Here the authors report that deletion of mitochondria-localized protein DsbA-L in T cells promotes diet-induced thermogenesis via suppressing IFN-γ production.