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

Abstract

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-␤, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH 2 -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. Diabetes 56: 450 -461, 2007

Tumor necrosis factor-α directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling

“…The right jugular vein and the left carotid artery were exposed under isoflurane anesthesia, and hamsters were inserted with catheters encased in silastic tubing that were exteriorized to the back of the neck (48,49). Following an overnight recovery period and a 16-h fast, a 4-h infusion of 0.9% normal saline (vehicle) or TNF-␣ (0.5 g/kg per h) was administered by the venous catheter.…”

“…Hepatocytes were lysed, and the immunoprecipitation/immunoblotting protocols were performed as described (49,59,60).…”

An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

“…Although we did not rule out the effect of hyperinsulinemia on the intestinal MTP activity and mRNA levels, hyperinsulinemic mice have higher intestinal ( 70 ) and hepatic ( 71 ) MTP expression and plasma triglyceride. Similarly, diabetic men and rabbits have been shown to express signifi cantly higher intestinal MTP mRNA levels compared with nondiabetic subjects ( 72,73 ).…”

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

“…MTP activity and protein expression however, were not altered. In the enterocyte of fructose fed golden hamster MTP mRNA and protein mass were increased by tumour necrosis factor(TNF)α but apo B levels in the enterocyte were not effected suggesting that there is considerable inter species variation [91]. In human studies in type 2 diabetes we demonstrated an increase in MTP mRNA in intestinal biopsies [71,90].…”

“…In the rabbit increased MTP mRNA is associated with increase in chylomicron particle numbers [88] but in the rat it is associated with larger particles [89]. The fructose-fed insulin resistant hamster model, has an increase in MTP protein mass and this was associated with an increase in the triglyceride-rich intestinally derived lipoproteins [91]. Zolotowska et al [92] in 2003 examined the B48 containing lipoprotein assembly in the small intestine of psamnonys obesus, a model of nutritionally-induced diabetes and insulin resistance.…”