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

Abstract

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 Ser 587 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 Ser 587 , which was accompanied by decrease in phospho-TORC2. Similarly, the decrease in the level of SIK2 phosphorylation at Ser 587 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 Ser 587 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␣

SIK2 Is Critical in the Regulation of Lipid Homeostasis and Adipogenesis In Vivo

“…On the other hand, depletion of SIK2 led to the increased expression of lipogenic genes both in mouse liver and in primary hepatocytes from SIK2 KO mice, showing the critical role of SIK2 in regulating hepatic lipogenesis, presumably by regulating SREBP-1c or ChREBP activity (23,35). The role of SIK2 in brown adipocytes was also suggested by a study using mice stably expressing aP2-driven transgene for dominant-negative SIK2, suggesting that SIK2 might block the thermogenic potential for the brown adipocytes (52). On the other hand, chronic depletion of SIK2 in brown adipocytes did not perturb expression of thermogenic genes, suggesting that the effect of a dominant negative transgene might not be SIK2 specific but could broadly affect functions of other SIK kinases or AMPK-related kinases.…”

Interaction between Salt-inducible Kinase 2 and Protein Phosphatase 2A Regulates the Activity of Calcium/Calmodulin-dependent Protein Kinase I and Protein Phosphatase Methylesterase-1

“…In mice, SIK2 was shown to regulate the melanogenesis by modulating the nuclear translocation of TORC1 (4). In adipocytes, SIK2 down-regulates the expression of lipogenic genes, PGC-1␣ and UCP-1 suggesting an involvement in metabolic regulation of adipose tissue (5). Moreover, SIK2 was shown to down-regulate the carbohydrate-responsive element-binding protein (ChREBP)-mediated lipogenesis in hepatocytes through the inhibitory phosphorylation of p300/Ser 89 and to prevent steatosis in mice (6).…”

LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues

“…We next determined how the reduced LKB1 expression affected the phosphorylation and/or activity status of AMPK, SIK2 and SIK3 -potential substrates downstream of LKB1 reported to directly regulate CRTC2 and class II HDACs (Screaton et al 2004, Muraoka et al 2009, Mihaylova et al 2011. In the absence of LKB1, the activity and specific phosphorylation of AMPK on the activity controlling T172 site were reduced (z50%), as was the total kinase activity of SIK2 and SIK3 in the basal state and after 1 h of induction of differentiation (Fig.…”

“…The tumour-suppressor kinase LKB1 and its substrates in the AMP-activated protein kinase (AMPK) family inhibit CREB-mediated gene expression via phosphorylation of CRTCs (Screaton et al 2004, Koo et al 2005, Muraoka et al 2009). Another recently identified group of substrates for AMPK family members is the class IIa histone deacetylases (HDAC4, HDAC5 and HDAC7).…”