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Tumor Necrosis Factor- Induces Intestinal Insulin Resistance and Stimulates the Overproduction of Intestinal Apolipoprotein B48-Containing Lipoproteins

From the Department of Laboratory Medicine and Pathobiology, the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Khosrow Adeli, Division of Clinical Biochemistry DPLM, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: k.adeli{at}utoronto.ca

Abbreviations: apo, apolipoprotein; ERK, extracellular signal–related kinase; IRS, insulin receptor substrate; JNK, Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MTP, microsomal triglyceride transfer protein; TNF, tumor necrosis factor

There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48–containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor- (TNF-) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF- infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-–treated hamsters indicated impaired phosphorylation of insulin receptor-ß, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal–related kinase-1/2, and Jun NH₂-terminal kinase. TNF- infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF- on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-–induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF- increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF- receptor types (p55 and p75), and antibodies against either of the two TNF- receptors partially blocked the stimulatory effect of TNF- on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF- infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-–induced stimulation of intestinal lipoprotein production appears to be mediated via TNF- receptors and the p38 mitogen-activated protein kinase pathway.

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