期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 7, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI144888
关键词
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资金
- NIH [R01 DK085171, R01 DK102173, R01 DK102170, R01 DK1113669, R01 DK123095]
- Claudia Adams Barr Program
- American Heart Association [17SDG33660660]
- National Cancer Center postdoctoral fellowship
- Kuwait Foundation for the Advancement of Sciences (KFAS) [RA-AML-2014-016]
This study showed that the innate immune transcription factor IRF3 can inhibit thermogenic gene expression in adipocytes, potentially by driving ISG15 expression and reducing glycolytic enzyme function. Mice lacking ISG15 exhibited similar characteristics to mice lacking IRF3 in adipocytes, both showing increased energy expenditure and resistance to diet-induced obesity.
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
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