Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

Abstract

Extreme human obesity triggers adipose dysfunction, paradoxically resulting in decreased capacity for lipid synthesis and contributing to ectopic lipid deposition, lipotoxicity, and whole-body insulin resistance ( 1 ). Lipo dy strophic human subjects and mouse models demonstrate that deficits in adipose lipogenesis correlate with excess lipid deposition in liver and muscle as well as whole-body insulin resistance, highlighting the importance of adipose lipogenesis in metabolic dysfunction ( 1-4 ). Adipose tissue expression and activity of the lipogenic transcription factors peroxisome proliferator-activated receptor ␥ ( PPAR ␥ ), sterol-regulated element binding protein-1 (Srebp-1), and carbohydrate-responsive element binding protein (Chrebp, also known as Mlxipl) are suppressed in obese humans, leading to decreased expression of lipogenic enzymes and decreased adipose fatty acid (FA) and triglyceride (TG) synthesis; however, the mechanisms that lead to this inhibition are unclear ( 2, 3, 5-10 ). Therefore, understanding this deregulation is fundamental in developing strategies that promote adipose lipogenesis, to increase lipid sequestration in adipocytes and prevent ectopic fat deposition during obesity.Srebp-1 and Srebp-2 are transcription factors important for regulating the expression of genes involved in synthesis and uptake of cholesterol, FAs, TGs, and phospholipids ( 11 ). These factors reside in the endoplasmic reticulum and upon demand for lipid synthesis are transported to the Golgi apparatus where they are cleaved, allowing the functional N-terminal fragment to translocate into the Abbreviations: Acaca, acetyl-CoA carboxylase ␣ ; Ad, adenovirus; Acly, ATP citrate lyase; AMPK, AMP-protein kinase; AP-1, activator protein-1; Chrebp, carbohydrate-responsive element binding protein; CMV, cytomegalovirus; JNK, c-Jun NH 2 -terminal kinase; HA, hemagglutinin; Map4k4, mitogen-activated protein kinase kinase kinase kinase 4; mTOR, mechanistic target of rapamycin; mTORC1; mechanistic target of rapamycin complex 1; MBP, myelin basic protein; PPAR ␥ , peroxisome proliferator-activated receptor ␥ ; RNAi, RNA interference; Scd-1, stearoyl-CoA desaturase 1; siRNA, small interfering RNA; TG, triglyceride; TNF ␣ , tumor necrosis factor ␣ ; Srebp-1, sterol-regulated element binding protein-1 .

The Conserved Misshapen-Warts-Yorkie Pathway Acts in Enteroblasts to Regulate Intestinal Stem Cells in Drosophila

“…We also could not detect a change of JNK phosphorylation after loss of Msn. Mammalian MAP4K4 has also been shown to function independently of JNK in some biological contexts (Danai et al, 2013; Wang et al, 2012). Therefore, Msn and JNK probably have independent functions in the midgut.…”

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

“…The functions of Map4k4 in insulin signaling and energy metabolism were subsequently studied in various cell culture models. In adipocytes, Map4k4 repressed glucose transport and lipid synthesis (5,8), while in human myotubes, Map4k4 depletion protected cells from tumor necrosis factor alpha (TNF-␣)-induced insulin resistance (9). These studies suggested that systemic Map4k4 depletion might improve whole-body glucose metabolism in obesity.…”

“…Obesity-induced adipose tissue dysfunction-including adipose tissue inflammation, altered adipokine secretion, and reduced lipid-buffering capacity-contributes to the development of whole-body insulin resistance (15)(16)(17)(18)(19). Since Map4k4 expression is elevated in obese human adipose tissue (20) and studies performed in vitro suggest Map4k4 is a negative regulator of insulin action (5,8), we aimed to specifically ablate Map4k4 expression in adipocytes by crossing…”

Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

“…In cultured 3T3-L1 adipocytes, mTORC1 promotes lipogenesis and lipid homeostasis by activating sterol regulatory element-binding protein (SREBP) [59, 60], a key transcription factor that activates more than 30 genes dedicated to the synthesis and uptake of fatty acids, sterols, triglycerides and phospholipids [61]. However, the mechanism by which mTORC1 activates SREBP-1 is still under debate.…”