Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor.

Abstract

Tumor necrosis factor (TNF)-alpha is postulated to play a major role in the pathogenesis of obesity-linked insulin resistance, probably resulting from an interaction with insulin signaling pathways. This cross talk has now been investigated in human adipocytes at the level of phosphatidylinositol (PI) 3-kinase, and the TNF receptors (TNFRs) mediating these processes have been identified. Equilibrium binding studies using human adipocytes from mammary tissue indicated the presence of two populations of TNFR with apparent affinity constants of 13 pmol/l and 1.6 nmol/l, respectively. Interaction of TNF-alpha with insulin signaling was determined by quantification of insulin receptor substrate (IRS)-1-associated PI 3-kinase activity. Under control conditions, PI 3-kinase was activated about 10-fold in response to insulin (10[-7] mol/l, 5 min). Preincubation of adipocytes with 5 nmol/l TNF-alpha for 15 min resulted in a 60-70% reduction of insulin action, reaching a stable inhibition (40%) after longer incubation with the cytokine. The inhibitory action of TNF-alpha was dose-dependent, already detectable at 10 pmol/l, and was correlated to inhibition of tyrosine phosphorylation of IRS-1 with an unaltered autophosphorylation of the insulin receptor beta-subunit. The modulation of insulin signaling by TNF-alpha was found to be paralleled by a comparable inhibition of insulin-stimulated glucose transport. An agonistic TNFR1 antibody completely mimicked the inhibitory action of TNF-alpha on insulin signaling, whereas at 100 pmol/l TNF-alpha, a nonagonistic p80 TNFR antibody, was shown to ameliorate the inhibitory action of the cytokine. These findings indicate that in human adipocytes, low concentrations of TNF-alpha induce a rapid inhibition of insulin signaling at the level of PI 3-kinase. We suggest that under these conditions, the p80 TNFR is essential for initiating the intracellular cross talk that involves signaling by the p60 TNFR.

Skeletal muscle triglycerides lowering is associated with net improvement of insulin sensitivity, TNF-α reduction and GLUT4 expression enhancement

“…28 Furthermore, numerous animal models of obesity and insulin resistance based on spontaneous genetic mutations or experimentally created gene deletions have been investigated to clarify the molecular mechanisms and role of different signal pathways and molecules involved in the development of these diseases. 29 -31 Also in these models it has been shown that TNF-a negatively interferes with insulin receptor signaling, 32,33 while, on the other hand, obese mice with a targeted null mutation in the gene encoding TNFa and those encoding the two receptors for TNFa showed a significant improved insulin sensitivity. 34 These mice had lower levels of circulating FFA, and were protected from the obesity-related reduction in the insulin receptor signaling in muscle and fat tissues.…”

TNFα expression of subcutaneous adipose tissue in obese and morbid obese females: relationship to adipocyte LPL activity and leptin synthesis

“…Some authors have suggested that TNFa is an inductor of insulin resistance in experimental models. 12,13,32 However, the role of adipose tissue TNFa in human insulin resistance is controversial. …”

“…3 -5 Several authors have suggested that TNFa produced in the adipocyte acts as a true adipostat, 2,6,7 but no direct evidence has yet been provided to support this. Some of the peripheral effects of TNFa are the inhibition of LPL activity, 8 -10 the downregulation of the expression of the glucose transporter GLUT 4, 11 the inhibition of insulin receptor activity 12,13 and the induction of adipose leptin production. 14 All these effects have been described in humans, culture cells and animals.…”

True

“…12,13 A recent study showed that TNF-a acutely inhibits insulin signaling in human adipocytes at the level of phosphatidylinositol 3-kinase and provided evidence that the p80 TNF receptor is involved in the development of insulin resistance. 9 In addition, recent data suggest that at least the p80 TNF receptor subtype is overexpressed in obesity and type 2 diabetes, 14,15 probably contributing to the catabolic effects of TNF-a in these metabolic disorders. Extracellular TNF-a originates from a membrane-bound 26 kD precursor protein (mTNF) with full biological activity, which is proteolytically cleaved into its ®nal soluble form.…”