TNF-alpha inhibits insulin action in liver and adipose tissue: A model of metabolic syndrome.
Several studies suggest that TNF-alpha contributes to the development of insulin resistance (IR). We compared transcriptional profiles of rat H-411E liver cells exposed to insulin in the absence or presence of TNF-alpha. We identified 33 genes whose expression was altered by insulin, and then reversed by TNF-alpha. Twenty-six of these 33 genes created a single network centered around: insulin, TNF-alpha, p38-MAPK, TGFb1; SMAD and STAT1; and enzymes and cytokines involved in apoptosis (CASP3, GADD45B, IL2, TNF-alpha, etc.). We analyzed our data together with other data of gene expression in adipocytes and found a number of processes common to both, for example, cell death and inflammation; intercellular signaling and metabolism; G-Protein, IL-10 and PTEN signaling. Moreover, the two datasets combined generated a single molecular network that further identified PTEN (a phosphatase) as a unique new link between insulin signaling, IR, and apoptosis reflecting the pathophysiology of "metabolic syndrome".
Solomon
S S
SS
Department of Medicine, University of Tennessee Health Science Center, Veterans Affairs Medical Center, Memphis, USA. ssolomon@utmem.edu
Odunusi
O
O
Carrigan
D
D
Majumdar
G
G
Kakoola
D
D
Lenchik
N I
NI
Gerling
I C
IC
D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015415:Biomarkers; D007328:Insulin; D007329:Insulin Antagonists; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha