Concerning the mechanism of increased thermogenesis in rats treated with dehydroepiandrosterone

Abstract

Dehydroepiandrosterone (DHEA) treatment of rats decreases gain of body weight without affecting food intake; simultaneously, the activities of liver malic enzyme and cytosolic glycerol-3-P dehydrogenase are increased. In the present study experiments were conducted to test the possibility that DHEA enhances thermogenesis and decreases metabolic efficiency via transhydrogenation of cytosolic NADPH into mitochondrial FADH2 with a consequent loss of energy as heat. The following results provide evidence which supports the proposed hypothesis: (a) the activities of cytosolic enzymes involved in NADPH production (malic enzyme, cytosolic isocitrate dehydrogenase, and aconitase) are increased after DHEA treatment; (b) cytosolic glycerol-3-P dehydrogenase may use both NAD+ and NADP+ as coenzymes; (c) activities of both cytosolic and mitochondrial forms of glycerol-3-P dehydrogenase are increased by DHEA treatment; (d) cytosol obtained from DHEA-treated rats synthesizes more glycerol-3-P during incubation with fructose-1,6-P2 (used as source of dihydroxyacetone phosphate) and NADP+; the addition of citrate in vitro further increases this difference; (e) mitochondria prepared from DHEA-treated rats more rapidly consume glycerol-3-P added exogenously or formed endogenously in the cytosol in the presence of fructose-1,6-P2 and NADP+.

Citrate Oscillates in Liver and Pancreatic Beta Cell Mitochondria and in INS-1 Insulinoma Cells

“…The answer may involve citrate itself and other cycle intermediates. Communication among individual mitochondria is possible because in suspensions of isolated mitochondria, such as from organs as diverse as liver (16,17), pancreatic islets (11), and heart (18), almost all of the citrate and malate and several other metabolites formed from the metabolism of substrates can be found in the extramitochondrial space. After citrate reaches a high level, its rapid decrease must occur by the uptake of extramitochondrial citrate back into the mitochondria and metabolism in the citric acid cycle as well as by a decrease in its synthesis.…”

Dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone in male reproductive health: Implications of differential regulation of human Sertoli cells metabolic profile

“…However, the unawareness of the beneficial/harmful doses of DHEA and the uncertain long-term safety can cause potential health risks. For instance, the administration of DHEA for extended periods increases testosterone above normal levels, especially in women [18], a fact that may cause masculinization.…”

Transformations of DHEA and its metabolites by rat liver

“…In liver, malic enzyme converts malate to pyruvate, which can recirculate to the mitochondria. The NADPH generated is used to reduce dihydroxyacetone phosphate to glycerophosphate (42), the substrate for the dehydrogenase located on the mitochondrial membrane.…”