SIRT2 suppresses adipocyte differentiation by deacetylating FOX01 and enhancing FOXO1's repressive interaction with PPAR gamma

Authors: WANG, FEI - Children'S Nutrition Research Center (CNRC); TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Biology of the Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2008
Publication Date: 2/1/2009
Citation: Wang, F., Tong, Q. 2009. SIRT2 suppresses adipocyte differentiation by deacetylating FOX01 and enhancing FOXO1's repressive interaction with PPAR gamma. Molecular Biology of the Cell. 20:801-808.

Interpretive Summary: Our previous research found long term dietary caloric restriction induces the expression of a longevity related gene, SIRT2. In this report, we found short term fasting is robust enough to stimulate SIRT2 expression in the white fat tissue. Because fat tissue is a key metabolic organ regulating whole body energy homeostasis, we went on to explore the function of SIRT2 in fat tissue. We found SIRT2 inhibits fat cell formation by modifying an important transcription factor, FOXO1 and enhances its inhibitory binding to the key adipogenic factor PPAR'. This finding provides knowledge of a novel pathway linking food intake and fat tissue function.

Technical Abstract: Sirtuin family of proteins possesses NAD-dependent deacetylase and ADP ribosyltransferase activities. They are found to respond to nutrient deprivation and profoundly regulate metabolic functions. We have previously reported that caloric restriction increases the expression of one of the seven mammalian sirtuins, SIRT2, in tissues such as white adipose tissue. Because adipose tissue is a key metabolic organ playing a critical role in whole body energy homeostasis, we went on to explore the function of SIRT2 in adipose tissue. We found short-term food deprivation for 24 h, already induces SIRT2 expression in white and brown adipose tissues. Additionally, cold exposure elevates SIRT2 expression in brown adipose tissue but not in white adipose tissue. Intraperitoneal injection of a beta-adrenergic agonist (isoproterenol) enhances SIRT2 expression in white adipose tissue. Retroviral expression of SIRT2 in 3T3-L1 adipocytes promotes lipolysis. SIRT2 inhibits 3T3-L1 adipocyte differentiation in low-glucose (1 g/l) or low-insulin (100 nM) condition. Mechanistically, SIRT2 suppresses adipogenesis by deacetylating FOXO1 to promote FOXO1's binding to PPARgamma and subsequent repression on PPARgamma transcriptional activity. Overall, our results indicate that SIRT2 responds to nutrient deprivation and energy expenditure to maintain energy homeostasis by promoting lipolysis and inhibiting adipocyte differentiation.