Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling.
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 α. 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.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
Laura V
LV
Danai
Adilson
A
Guilherme
Kalyani V
KV
Guntur
Juerg
J
Straubhaar
Sarah M
SM
Nicoloro
Michael P
MP
Czech
D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D050155:Lipogenesis; D020935:MAP Kinase Signaling System; D051379:Mice; D009765:Obesity / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation; D014280:Triglycerides / Q000096:biosynthesis; D000097782:NF-kappaB-Inducing Kinase
D055372:AMP-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051780:Sterol Regulatory Element Binding Protein 1; D058570:TOR Serine-Threonine Kinases; D014280:Triglycerides; D000097782:NF-kappaB-Inducing Kinase; C497388:Srebf1 protein, mouse; C546843:mTOR protein, mouse
AMP-protein kinase; c-Jun NH2-terminal kinase; insulin; lipid synthesis; mechanistic target of rapamycin; mitogen-activated protein kinase kinase kinase kinase 4; sterol-regulated element binding protein-1