Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling
Authors
Danai, Laura V.Guilherme, Adilson L.
Guntur, Kalyani V. P.
Straubhaar, Juerg R.
Nicoloro, Sarah M.
Czech, Michael P.
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2013-10-01Keywords
3T3-L1 CellsAMP-Activated Protein Kinases
Adipocytes
Animals
Enzyme Activation
Gene Expression
Gene Knockdown Techniques
*Lipogenesis
*MAP Kinase Signaling System
Mice
Obesity
Protein-Serine-Threonine Kinases
Sterol Regulatory Element Binding Protein 1
TOR Serine-Threonine Kinases
Transcriptional Activation
Triglycerides
Biochemistry
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor alpha. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.Source
J Lipid Res. 2013 Oct;54(10):2697-707. doi: 10.1194/jlr.M038802. Epub 2013 Aug 7. Link to article on publisher's siteDOI
10.1194/jlr.M038802Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30267PubMed ID
23924694Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1194/jlr.M038802