DEHYDROEPIANDROSTERONE DECREASES SERUM TUMOR-NECROSIS-FACTOR-ALPHA AND RESTORES INSULIN SENSITIVITY - INDEPENDENT EFFECT FROM SECONDARY WEIGHT-REDUCTION IN GENETICALLY-OBESE ZUCKER FATTY RATS

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abund ant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects o n insulin resistance have not been fully elucidated. In this study, th e effects of DHEA treatment on insulin sensitivity were investigated i n genetically obese Zucker rats, an animal model of insulin resistance , using the euglycemic clamp technique. After 0.4% DHEA was administer ed for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which wa s normally reduced in obese rats, rose significantly compared with age - and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats w as significantly greater than in pair-fed rats, suggesting a direct am eliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines c ausing insulin resistance, was also reduced significantly in DHEA-trea ted, but not in pair-fed obese rats. In conclusion, our results sugges t that DHEA treatment reduces body weight and serum TNF-alpha independ ently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.