High-fat diet induces increased tissue expression of TNF-α

In several strains of genetically obese and insulin resistant rodents, adipose tissue over expresses mRNA for tumor necrosis factor α (TNF-α). Our purpose was to determine whether tissue expression of TNF-α protein is elevated in rats that are made obese and insulin resistant by administration of a high-fat diet. Young Wistar rats weighing ∼50 g were fed for 39 days with either normal rat chow (12.4% fat) or a high-fat diet (50% fat). After 33 days, glucose tolerance was assessed and after 39 days, insulin-stimulated transport of [3H]-2-deoxyglucose was assessed in isolated strips of soleus muscle. Rats on the high-fat diet consumed slightly fewer calories but became obese, displaying significant ∼2-fold increases in the mass of both visceral and subcutaneous fat depots. High-fat feeding also caused a moderate degree of insulin resistance. Fasting serum insulin was significantly increased, as were insulin and glucose concentrations following glucose loading. In isolated strips of soleus muscle, the high-fat diet produced a trend toward a 33% decrease in the insulin-stimulated component of glucose transport (p = 0.064). Western analysis of muscle, liver and fat revealed two forms of TNF-α, a soluble 17 Kd form (sTNF-α) and a 26 Kd membrane form (mTNF-α). Both sTNF-α and mTNF-α were relatively abundant in fat; whereas sTNF-α was the predominant form present in muscle and liver. High-fat feeding caused a significant 2-fold increase in muscle sTNF-α, along with a trend toward a 54% increase in visceral fat sTNF-α (p = 0.055). TNF-α was undetectable in serum. We conclude that muscle over expression of TNF-α occurs during the development of diet-induced obesity and may, in part cause insulin resistance by an autocrine mechanism.