Cyclic AMP promotes chronic expression of target genes mainly by protein kinase A-dependent activation of CREB transcription factor machineries in the metabolic tissues. Here we wanted to elaborate whether CREB regulated transcription factor (CRTC) 2 and its negative regulator salt inducible kinase (SIK) 2 are involved in the transcriptional control of the metabolic pathway in adipocytes. SIK2 knockout mice exhibited higher blood glucose levels that were associated with impaired glucose and insulin tolerance. Hypertriglyceridemia was apparent in SIK2 knockout mice, mainly due to the increased lipolysis from white adipocytes and the decreased fatty acid uptake in the peripheral tissues. Investigation of white adipocytes revealed the increases in fat cell size and macrophage infiltration, which could be linked to the metabolic anomaly that is associated in these mice. Interestingly, SIK2 knockout promoted the enhancement in CRTC2-CREB transcriptional pathway in white adipocytes. Increased expression of ATF3 and subsequent downregulation of GLUT4 expression and reduction in high molecular weight adiponectin levels in the plasma, leading to the reduced glucose uptake in the muscle and white adipocytes. The effect of SIK2-dependent regulation of adipocyte metabolism was further confirmed by in vitro cell cultures of 3T3 L1 adipocytes and the differentiated preadipocytes from the SIK2 or CRTC2 knockout mice. Collectively, these data suggest that SIK2 is critical in regulating whole body glucose metabolism primarily by controlling the CRTC2-CREB function of the white adipocytes.
† These authors contribute equally to this work.
- Received September 14, 2013.
- Accepted May 30, 2014.
- © 2014 by the American Diabetes Association.
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