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Abstract

BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (TNF-a) in human obesity. It was hypothesized from this ®nding and other data, that TNF-a may be a mediator of obesity-linked insulin resistance. OBJECTIVE: The aim of this study was to measure plasma concentrations of the two soluble TNF-a receptors, together with those of TNF-a in subjects with severe obesity with and without type 2 diabetes mellitus, in comparison to a lean control group, to examine whether plasma concentrations re¯ect an up-regulation of the TNF system in adipose tissue. PATIENTS AND METHODS: Plasma concentrations of the two soluble TNF-a receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9 kgam 2 , 95% con®dence intervals (CI) 42.3 ± 47.5 kgam 2 , including 19 type 2 diabetic individuals) and 28 lean controls, by using a highly sensitive enzyme-linked immunoassay (ELISA) technique. TNF-a concentrations were determined in 28 obese (10 with diabetes) and 23 lean subjects. RESULTS: The obese subjects showed signi®cantly higher plasma concentrations of the soluble p60 and p80 TNF receptor, respectively, compared to the lean control group, independent of the presence of diabetes. Multiple regression analysis, with the p80 TNF receptor as dependent variable, revealed that BMI and log insulin signi®cantly affected the plasma concentration of this soluble receptor subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only BMI turned out to in¯uence plasma concentrations. TNF-a plasma concentrations were not different between the three groups (Kruskal-Wallis test: P 0.34), but due to the low power of the test, an effect of obesity on TNF-a is not excluded. CONCLUSION: These data indicate that plasma concentrations of both soluble TNF receptors are elevated in obesity and insulin resistance, possibly as a function of excess body fat. The reported adipose overexpression of TNF-a does not seem to be re¯ected by elevated plasma concentrations, suggesting a primarily local role of the cytokine.

The Serum Concentration of Tumor Necrosis Factor Alpha Is Not an Index of Growth-Hormone- or Obesity-Induced Insulin Resistance

“…The high TNF-α concentrations reported by Serri et al [19]in plasma and cell supernatants of cultured human monocytes and monocyte-derived macrophages in GHDA patients might reflect elevated sTNF-R rather than true TNF-α concentrations. The higher BMI of the GHDA patients in that study as compared with our own makes this possibility even more likely, since plasma concentrations of sTNF-R have been shown to parallel BMI values [4]. At variance with Serri et al [19], we found no changes in TNF-α serum levels in GHDA patients after 6 months of treatment with rhGH.…”

“…1). The results of several studies on this issue have been variable: high [3], normal [4], low, and even undetectable [7, 31]circulating TNF-α concentrations having been reported. In man, no arteriovenous difference in TNF-α concentrations was found over a subcutaneous adipose tissue bed which argues against a substantial release of tissue TNF-α into the bloodstream [32].…”

“…It is mainly produced by monocytes/macrophages and activated lymphocytes, but also fat tissue is a significant source. While conflicting observations have been reported on circulating TNF-α concentrations in obese (OB) individuals [3, 4], the expression of this cytokine has been shown to be elevated in the adipose tissue of OB insulin-resistant rodents [5, 6]and humans [7], suggesting a critical role of TNF-α as a mediator of peripheral insulin resistance. Indeed, complete absence of the TNF-α gene or of its receptors results in a significant improvement in insulin sensitivity in mice with dietary, hypothalamic, or genetic obesity [8, 9], and in vivo neutralization of TNF-α in fa/fa rats causes a significant increase in the peripheral glucose uptake in response to insulin [5].…”