Influence of membrane-bound tumor necrosis factor (TNF)-alpha on obesity and glucose metabolism.

OBJECTIVES: To investigate the influence of transmembrane tumor necrosis factor (TNF)-alpha on adipose tissue development and insulin-mediated glucose metabolism. METHODS AND RESULTS: TNF-alpha and lymphotoxin-alpha-deficient mice expressing non-cleavable transmembrane TNF-alpha (Tg-tmTNF-alpha) and TNF-alpha/lymphotoxin-alpha double knockout (control) mice were kept on high-fat diet for 15 weeks. The food intake and feeding efficiency of Tg-tmTNF-alpha mice were significantly higher compared with control mice. At the end of the study, Tg-tmTNF-alpha mice had a significantly higher total body weight, as well as subcutaneous and gonadal adipose tissue mass. Histological analysis revealed that the expression of Tg-tmTNF-alpha resulted in a significantly increased adipocyte area and blood vessel density. Plasma leptin levels correlated positively with adipose tissue mass. The plasma levels of total cholesterol and HDL-cholesterol were significantly increased and LDL-cholesterol levels significantly decreased in Tg-tmTNF-alpha mice. Fasting blood glucose and plasma insulin levels were not different between the two genotypes and intraperitoneal glucose and insulin tolerance tests did not show significant differences. CONCLUSIONS: Transmembrane TNF-alpha enhances adipose tissue formation without altering insulin-mediated glucose metabolism in mice with nutritionally induced obesity.