Dehydroepiandrosterone Decreases Serum Tumor Necrosis Factor-  and Restores Insulin Sensitivity: Independent Effect from Secondary Weight Reduction in Genetically Obese Zucker Fatty Rats

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant 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 on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was 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 was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.

Dehydroepiandrosterone increases β‐cell mass and improves the glucose‐induced insulin secretion by pancreatic islets from aged rats

“…Administration of DHEA to rodents and humans reduces visceral fat accumulation and improves insulin sensitivity [14][15][16][17][18][19]. The endocrine pancreata plays a central role to cope sufficient insulin secretion with the metabolic demand.…”

Insulin-Mediated Hemodynamic Changes Are Impaired in Muscle of Zucker Obese Rats

“…Similarly, Cheung et al (37) showed that inhibition of TNF␣ activity through the adenovirus-5-mediated transfer of a TNF inhibitor gene improved peripheral and hepatic insulin sensitivity in obese Zucker rats. Raised plasma levels of TNF␣ have been reported in obese Zucker rats (38) and the blunted hemodynamic effects observed in these rats may be a consequence of this (18). However, elevated plasma free fatty acids may be more important (39) and responsible for the insulin resistance of the Zucker rat.…”

DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins

“…40 -42 Importantly, in obese Zucker rats, DHEA treatment reduced serum TNF-␣, 43 suggesting that the two pathways influence each other. The differential regulation of 11␤-HSD1 and 11␤-HSD2 is of physiologic relevance, because it modulates the intracellular availability of active glucocorticoids.…”