Journal
CELL REPORTS
Volume 20, Issue 3, Pages 641-654Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.06.069
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Funding
- Institute of Molecular Medicine, Peking University [UCP1 KO]
- National Natural Science Foundation of China [81471049, 81670749]
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Promoting development and function of brown and beige fat may reduce obesity. Here, we show that fat SIRT6 expression is markedly induced by cold exposure and a beta-adrenergic agonist. Deletion of SIRT6 in adipose tissue impairs the thermogenic function of brown adipocytes, causing a morphological whitening'' of brown fat, reduced oxygen (O-2) consumption, obesity, decreased core body temperature, and cold sensitivity. Fat SIRT6-deleted mice exhibit increased blood glucose levels, severe insulin resistance, and hepatic steatosis. Moreover, SIRT6 deficiency inhibits the browning of white adipose tissue (WAT) following cold exposure or beta 3-agonist treatment. Depletion of SIRT6 expression in brown adipocytes reduces expression of thermogenic genes, causing a reduction in cellular respiration. Conversely, SIRT6 overexpression in primary fat cells stimulates the thermogenic program. Mechanistically, SIRT6 interacts with and promotes phos-pho-ATF2 binding to the PGC-1 alpha gene promoter to activate its expression. The present study reveals a critical role for SIRT6 in regulating thermogenesis of fat.
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