trichostatin-a and Obesity

Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism.. TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Fatty Acid-Binding Proteins; Glycerol; Histone Deacetylase Inhibitors; Hydroxamic Acids; Leptin; Lipolysis; Male; Mice; Mice, Obese; Obesity; Triglycerides

Sodium valporate (VPA), a broad-spectrum inhibitor of histone deacetylases (HDACs), increased ghrelin whereas decreased nesfatin-1 in mice fed normal chow diet or high-fat diet. Alterations in ghrelin and nucleobindin 2/nesfatin-1 were mediated by HDAC5 but not HDAC4. Activation of mTORC1 significantly attenuated the effect of VPA on ghrelin and nesfatin-1 levels. HDAC5 coimmunoprecipitated with raptor. Inhibition of HDAC5 by VPA, trichostatin A, or siHDAC5 markedly increased acetylation of raptor Lys840 and subsequent phosphorylation of raptor Ser792, resulting in suppression of mTORC1 signaling. A raptor mutant lacking the Lys840 acetylation site showed a decrement in phosphorylation of raptor Ser792 and subsequent increase in mTORC1 signaling. These alterations were associated with reciprocal changes in ghrelin and nucleobindin 2/nesfatin-1 expression. These findings reveal HDAC5-mTORC1 signaling as a novel mechanism in the differential regulation of gastric ghrelin and nesfatin-1.

Topics: Acetylation; Adaptor Proteins, Signal Transducing; Animals; Calcium-Binding Proteins; Cell Line; DNA-Binding Proteins; Enzyme Activation; Gastric Mucosa; Ghrelin; Histone Deacetylases; Hydroxamic Acids; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes; Nerve Tissue Proteins; Nucleobindins; Obesity; Phosphorylation; Regulatory-Associated Protein of mTOR; RNA Interference; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases; Valproic Acid

Lipin 1 is a bifunctional protein that regulates gene transcription and, as a Mg(2+)-dependent phosphatidic acid phosphatase (PAP), is a key enzyme in the biosynthesis of phospholipids and triacylglycerol. We describe here the functional interaction between lipin 1 and the nuclear factor of activated T cells c4 (NFATc4). Lipin 1 represses NFATc4 transcriptional activity through protein-protein interaction, and lipin 1 is present at the promoters of NFATc4 transcriptional targets in vivo. Catalytically active and inactive lipin 1 can suppress NFATc4 transcriptional activity, and this suppression may involve recruitment of histone deacetylases to target promoters. In fat pads from mice deficient for lipin 1 (fld mice) and in 3T3-L1 adipocytes depleted of lipin 1 there is increased expression of several NFAT target genes including tumor necrosis factor alpha, resistin, FABP4, and PPARgamma. Finally, both lipin 1 protein and total PAP activity are decreased with increasing adiposity in the visceral, but not subcutaneous, fat pads of ob/ob mice. These observations place lipin 1 as a potentially important link between triacylglycerol synthesis and adipose tissue inflammation.

Topics: 3T3-L1 Cells; Adipocytes; Aging; Animals; Calcium Signaling; DNA; Gene Expression Regulation; Histone Deacetylases; Hydroxamic Acids; Inflammation Mediators; Mice; NFATC Transcription Factors; Nuclear Proteins; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphatidate Phosphatase; PPAR alpha; Promoter Regions, Genetic; Protein Binding; Repressor Proteins; RNA, Messenger; Trans-Activators; Transcription Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha