title: SIK2 is critical in the regulation of lipid homeostasis and adipogenesis in vivo.
abstract: 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 (SIK2 KO) mice exhibited higher blood glucose levels that were associated with impaired glucose and insulin tolerance. Hypertriglyceridemia was apparent in SIK2 KO 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 KO promoted the enhancement in the CRTC2-CREB transcriptional pathway in white adipocytes. SIK2 KO mice displayed increased expression of activating transcription factor (ATF)3 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 KO 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.
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Han
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do, Korea.
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea koohoi@korea.ac.kr.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C504923:Crtc2 protein, mouse; D014157:Transcription Factors; D003847:Deoxyglucose; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases