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Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1 and UCP-1 gene expression in brown adipocytes

¹Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Osaka; ⁴ProteinExpress, Choshi, Chiba; ⁵Food and Nutrition, Senri Kinran University, Osaka; ⁶Faculty of Contemporary Human Life Science, Tezukayama University, Nara, Japan; ²Institut National de la Santé et de la Recherche Médicale, Unité 693, Le Kremlin-Bicêtre; and ³Faculté de Médecine Paris-Sud, UMR-S693, University Paris-Sud, Le Kremlin Bicêtre, France

Submitted 12 January 2009 ; accepted in final form 1 April 2009

Salt-inducible kinase 2 (SIK2) is expressed abundantly in adipose tissues and represses cAMP-response element-binding protein (CREB)-mediated gene expression by phosphorylating the coactivator transducer of regulated CREB activity (TORC2). Phosphorylation at Ser⁵⁸⁷ of SIK2 diminishes its TORC2 phosphorylation activity. In 3T3-L1 white adipocytes, SIK2 downregulates lipogenic gene in response to nutritional stresses. To investigate the impact of SIK2 on the function of brown adipose tissue (BAT), we used T37i brown adipocytes, mice with diet-induced obesity, and SIK2 mutant (S587A) transgenic mice. When T37i adipocytes were treated with insulin, the levels of peroxisome proliferator-activated receptor-coactivator-1 (PGC-1) and uncoupling protein-1 (UCP-1) mRNA were increased, and the induction was inhibited by overexpression of SIK2 (S587A) mutant or dominant-negative CREB. Insulin enhanced SIK2 phosphorylation at Ser⁵⁸⁷, which was accompanied by decrease in phospho-TORC2. Similarly, the decrease in the level of SIK2 phosphorylation at Ser⁵⁸⁷ was observed in the BAT of mice with diet-induced obesity, which was negatively correlated with TORC2 phosphorylation. To confirm the negative correlation between SIK2 phosphorylation at Ser⁵⁸⁷ and TORC2 phosphorylation in BAT, SIK2 mutant (S587A) was overexpressed in adipose tissues by using the adipocyte fatty acid-binding protein 2 promoter. The expression of recombinant SIK2 (S587A) was restricted to BAT, and the levels of phospho-TORC2 were elevated in BAT of transgenic mice. Male transgenic mice developed high-fat diet-induced obesity, and their BAT expressed low levels of PGC-1 and UCP-1 mRNA, suggesting that SIK2-TORC2 cascade may be important for the regulation of PGC-1 and UCP-1 gene expression in insulin signaling in BAT.

salt-inducible kinase 2; peroxisome proliferator-activated receptor-coactivator-1; uncoupling protein-1; brown adipocyte; adenosine 5',3'-cyclic monophosphate-response element-binding protein

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