title: The Ca2+/calmodulin-dependent protein kinase kinase, CaMKK2, inhibits preadipocyte differentiation.
abstract: When fed a standard chow diet, CaMKK2 null mice have increased adiposity and larger adipocytes than do wild-type mice, whereas energy balance is unchanged. Here, we show that Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is expressed in preadipocytes, where it functions as an AMP-activated protein kinase (AMPK)α kinase. Acute inhibition or deletion of CaMKK2 in preadipocytes enhances their differentiation into mature adipocytes, which can be reversed by 5-aminoimidazole-4-carboxamide ribonucleotide-mediated activation of AMPK. During adipogenesis, CaMKK2 expression is markedly decreased and temporally accompanied by increases in mRNA encoding the early adipogenic genes CCAAT/enhancer binding protein (C/EBP) β and C/EBP δ. Preadipocyte factor 1 has been reported to inhibit adipogenesis by up-regulating sex determining region Y-box 9 (Sox9) expression in preadipocytes and Sox9 suppresses C/EBPβ and C/EBPδ transcription. We show that inhibition of the CaMKK2/AMPK signaling cascade in preadipocytes reduces preadipocyte factor 1 and Sox9 mRNA resulting in accelerated adipogenesis. We conclude that CaMKK2 and AMPK function in a signaling pathway that participates in the regulation of adiposity.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical School, Durham, North Carolina 27710, USA.
authors.forename: Fumin
authors.initials: F
authors.lastname: Lin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ribar
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D002135:Calcium-Binding Proteins; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; D055372:AMP-Activated Protein Kinases