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Sci. Signal., 7 August 2012
Vol. 5, Issue 236, p. ec205
[DOI: 10.1126/scisignal.2003471]


Metabolism SIRT-ain to Become Brown Fat

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Whereas white adipose tissue acts as storage depots for energy, brown adipose tissue dissipates energy in the form of heat. White adipose tissue can acquire some of the characteristics of brown adipose tissue, such as the expression of brown fat–specific and thermogenic genes in a process called "browning." Stimulation of the nuclear receptor PPAR{gamma} (peroxisome proliferator–activated receptor {gamma}) leads to the transcription of genes that promote the transcription of brown adipose tissue–specific genes and suppresses that of visceral white adipose tissue–specific genes associated with insulin resistance. Because mice overexpressing the deacetylase SIRT1 (SirBACO mice) show increased insulin sensitivity, a response also induced by PPAR{gamma} ligands, Qiang et al. investigated whether deacetylation of PPAR{gamma} by SIRT1 affected its ability to promote the browning of white fat. Endogenous SIRT1 interacted with PPAR{gamma}, and the association of exogenously expressed PPAR{gamma} with SIRT1 was increased by the PPAR{gamma} agonist rosiglitazone and decreased by the PPAR{gamma} antagonist GW9662. Acetylation of exogenous expressed PPAR{gamma} was decreased by rosiglitazone, overexpression of SIRT1, or the SIRT1 activator resveratrol and was increased by the SIRT1 inhibitor nicotinamide. In vitro deacetylation assays revealed that PPAR{gamma} was deacetylated by wild-type SIRT1 but not a catalytically inactive mutant (H363Y). The expression of white adipose tissue–specific genes in 3T3-L1 white adipocytes was decreased by resveratrol treatment or overexpression of wild-type SIRT1 but not the H363Y mutant. Conversely, expression of brown adipose tissue–specific genes in HIB-1B brown adipocytes was increased by treatment with resveratrol or the PPAR{gamma} agonist troglitazone and decreased by treatment with GW9662 or nicotinamide. Browning of white fat can be induced by cold exposure (4°C), a process that was enhanced in mice deficient in the SIRT1 inhibitor Dbc-1 (Deleted in breast cancer) or SirBACO mice. PPAR{gamma} acetylation in inguinal white adipose tissue was decreased in cold-exposed mice. In contrast, PPAR{gamma} acetylation was increased in mice fed a high-fat diet, an effect that was accompanied by decreased association with SIRT1 and was reversed by rosiglitazone treatment and attenuated in Dbc1–/– and SirBACO mice. PPAR{gamma} was deacetylated at Lys268 and Lys293 after rosiglitazone treatment, and differentiation of Swiss 3T3 fibroblasts into adipocytes was increased by expression of a deacetylation-mimetic mutant (K268R/K293R; 2KR). Association with the transcriptional corepressor NCoR inhibits the activity of PPAR{gamma}, whereas association with the transcriptional coactivator Prdm16 is required for the browning of white fat. Rosiglitazone induced the association of exogenously expressed Prdm16 with PPAR{gamma} in a deacetylation-dependent manner, and the deacetylation-mimetic 2KR mutant showed constitutive association with Prdm16. Mutational analysis indicated that deacetylation of both lysine residues was required to attenuate the interaction of PPAR{gamma} with NCoR, whereas deacetylation of Lys293 was required for the interaction of PPAR{gamma} with Prdm16. Thus, deacetylation by SIRT1 promotes the ability of PPAR{gamma} to induce the browning of white adipose tissue.

L. Qiang, L. Wang, N. Kon, W. Zhao, S. Lee, Y. Zhang, M. Rosenbaum, Y. Zhao, Wei Gu, S. R. Farmer, D. Accili, Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppar{gamma}. Cell 150, 620–632 (2012). [Online Journal]

Citation: W. Wong, SIRT-ain to Become Brown Fat. Sci. Signal. 5, ec205 (2012).

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