SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation.
The family of mammalian Sirtuin proteins comprises seven members homologous to yeast Sir2. Here we show that SIRT2, a cytoplasmic sirtuin, is the most abundant sirtuin in adipocytes. Sirt2 expression is downregulated during preadipocyte differentiation in 3T3-L1 cells. Overexpression of SIRT2 inhibits differentiation, whereas reducing SIRT2 expression promotes adipogenesis. Both effects are accompanied by corresponding changes in the expression of PPARgamma, C/EBPalpha, and genes marking terminal adipocyte differentiation, including Glut4, aP2, and fatty acid synthase. The mechanism underlying the effects of reduced SIRT2 in 3T3-L1 adipocytes includes increased acetylation of FOXO1, with direct interaction between SIRT2 and FOXO1. This interaction enhances insulin-stimulated phosphorylation of FOXO1, which in turn regulates FOXO1 nuclear and cytosolic localization. Thus, Sirt2 acts as an important regulator of adipocyte differentiation through modulation of FOXO1 acetylation/phosphorylation and activity and may play a role in controlling adipose tissue mass and function.
Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Enxuan
E
Jing
Stephane
S
Gesta
C Ronald
CR
Kahn
D041721:3T3-L1 Cells; D000107:Acetylation / Q000187:drug effects; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D020033:Protein Isoforms; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; D037761:Sirtuins