IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis

被引：53

作者：

Yan, Shuai ^{[1
]}

Kumari, Manju ^{[1
,2
]}

Xiao, Haopeng ^{[3
,4
]}

Jacobs, Christopher ^{[1
,5
]}

Kochumon, Shihab ^{[6
]}

Jedrychowski, Mark ^{[3
]}

Chouchani, Edward ^{[3
,4
]}

Ahmad, Rasheed ^{[6
]}

Rosen, Evan D. ^{[1
,4
,5
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA

[2] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, Hamburg, Germany

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA

[4] Harvard Med Sch, Boston, MA 02115 USA

[5] Broad Inst Harvard & MIT, Cambridge, MA USA

[6] Dasman Diabet Inst, Immunol & Microbiol Dept, Kuwait, Kuwait

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 07期

关键词：

COLD-INDUCED THERMOGENESIS; BROWN ADIPOCYTES; ENERGY-EXPENDITURE; ADAPTIVE THERMOGENESIS; INSULIN-RESISTANCE; ISG15; CONJUGATION; PROTEIN-KINASE; FATTY-ACIDS; KAPPA-B; TISSUE;

D O I：

10.1172/JCI144888

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Adipose thermogenesis is repressed in obesity, reducing the homeostatic capacity to compensate for chronic overnutrition. Inflammation inhibits adipose thermogenesis, but little is known about how this occurs. Here we showed that the innate immune transcription factor IRF3 is a strong repressor of thermogenic gene expression and oxygen consumption in adipocytes. IRF3 achieved this by driving expression of the ubiquitin-like modifier ISG15, which became covalently attached to glycolytic enzymes, thus reducing their function and decreasing lactate production. Lactate repletion was able to restore thermogenic gene expression, even when the IRF3/ISG15 axis was activated. Mice lacking ISG15 phenocopied mice lacking IRF3 in adipocytes, as both had elevated energy expenditure and were resistant to dietinduced obesity. These studies provide a deep mechanistic understanding of how the chronic inflammatory milieu of

引用

页数：19

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