| Dehydroepiandrosterone (DHEA) and its conjugate DHEA sulfate (DHEAS), the most abundant steroids in human circulation, have been proposed as therapeutic drugs for obesity. Male Sprague-Dawley rats were administered drinking water supplemented with 0,10 or 100 μg/ml DHEAS for 14 days. DHEAS treatment reduced adipose tissue mass and cellularity, and serum triglycerides without altering food intake, body weight gain. Based on these observations, I hypothesized that rats with a propensity for diet-induced obesity may be more responsive to the antiobesity actions of DHEAS. Male Osborne-Mendel rats were administered either 0 or 10 μg/ml DHEAS or a low or high fat diet for 2 or 6 weeks. After 6 weeks of treatment, DHEAS-treated rats fed the high fat diet had lighter fat pads containing fewer adipocytes than their high fat fed cohorts. In contrast, DHEAS-treated rats fed the low fat diet had similar levels of adipose tissue mass and cellularity as control animals fed the low fat diet.; The effects of DHEA(S) on the proliferation and differentiation in cultures of 3T3-L1 preadipocytes were assessed. Cell number decreased as the level of DHEA in the cultures increased when proliferating cultures were incubated with 0–100 μM DHEA for 1–4 days. The antiproliferative effect was partially reversed by the addition of 1 μM mevalonic acid to DHEA treated cultures. When differentiating cultures of 3T3-L1 preadipocytes were incubated with 0–240 μM DHEA, preadipocyte differentiation decreased as the level of DHEA increased. Furthermore, comparison of the effects of DHEA and some of its metabolites demonstrated that DHEA and 17β-estradiol similarly inhibit 3T3-L1 differentiation. Pre-confluent and post-confluent (day 7) differentiated 3T3-L1 preadipocytes incubated with [3H] DHEA for 1–48 hours metabolized DHEA primarily to 7α-OHDHEA in proliferating cultures and to water soluble products, 7α-OHDHEA, androstenediol and testosterone in differentiated cultures.; To determine DHEA's estrogenic effects, proliferating and differentiating 3T3-L1 preadipocytes were transiently transfected with a luciferase reporter gene under the control of an estrogen response element (ERE). Significant luciferase activity was found with 100–1,000 nM DHEA in cultures of proliferating cultures and 1–1,000 nM in differentiating cultures. This stimulation was not inhibited by the addition of the aromatase inhibitor formestane, but was inhibited by the addition of the estrogen receptor antagonist ICI 182,780. These data imply that the stimulation of the ERE by DHEA is independent of estrogen production from DHEA and that DHEA acts via the estrogen receptor. However, the influence of this activation on preadipocyte growth and differentiation remains unanswered. |
