Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

Gender differences in insulin resistance, body composition, and energy balance.

Dehydroepiandrosterone (DHEA) is not a hormone but it is a very important prohormone secreted in large amounts by the adrenals in humans and other primates, but not in lower species. It is secreted in larger quantities than cortisol and is present in the blood at concentrations only second to cholesterol. All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues, thus permitting all androgen-sensitive and estrogen-sensitive tissues to make locally and control the intracellular levels of sex steroids according to local needs. This new field of endocrinology has been called intracrinology. In women, after menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA which indirectly exerts effects, among others, on bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido and well-being. In men, where the secretion of androgens by the testicles continues for life, the contribution of DHEA to androgens has been best evaluated in the prostate where about 50% of androgens are made locally from DHEA. Such knowledge has led to the development of combined androgen blockade (CAB), a treatment which adds a pure anti-androgen to medical (GnRH agonist) or surgical castration in order to block the access of the androgens made locally to the androgen receptor. In fact, CAB has been the first treatment demonstrated to prolong life in advanced prostate cancer while recent data indicate that it can permit long-term control and probably cure in at least 90% of cases of localized prostate cancer. The new field of intracrinology or local formation of sex steroids from DHEA in target tissues has permitted major advances in the treatment of the two most frequent cancers, namely breast and prostate cancer, while its potential use as a physiological HRT could well provide a physiological balance of androgens and estrogens, thus offering exciting possibilities for women's health at menopause.

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Is dehydroepiandrosterone a hormone

Dehydroepiandrosterone Activates Endothelial Cell Nitric-oxide Synthase by a Specific Plasma Membrane Receptor Coupled to Gαi2,3

The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism.

Previous studies showed that administration of dehydroepiandrosterone (DHEA) to lean and genetically obese Zucker rats reduced body weight. In the present experiments, the effect of DHEA treatment in rats with diet-induced obesity was evaluated. In experiment 1, male Sprague-Dawley rats (300 g) were fed a nonpurified diet (reference group) or a condensed milk-corn oil nonpurified diet [diet-induced obese (DIO) rats] for 7 wk. Then, 0.6% DHEA was included in the food of one-half of the DIO rats (DIO + DHEA rats). After 6 wk, DIO rats weighed 23% more and had greater fat pad weights, cell size and cell number than reference and DIO + DHEA rats. Brown fat mitochondrial respiration was similar in all groups. DIO rats had higher serum cholesterol and triacylglycerol concentrations than reference and DIO + DHEA rats. DIO + DHEA rats had lower serum insulin levels than DIO and reference rats. In experiment 2, male Sprague-Dawley rats (460 g) were fed either the nonpurified diet or the condensed milk diet for 8 wk. Condensed milk-fed rats were then divided into DIO and diet-resistant groups. One-half of the rats in each group were fed 0.6% DHEA for 2 wk. Body weights and serum glucose, insulin, triacylglycerol and triiodothyronine levels were lowered by DHEA treatment in all groups. Liver mitochondrial state 3 respiration rates per gram and per liver and peroxisomal beta-oxidation were higher in DHEA-treated than in control rats. In DIO rats, DHEA treatment appears to interfere with hyperplastic adipose tissue growth. In this strain of rats, DHEA appears to have hypolipidemic and hypoinsulinemic effects.

Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity.

Administration of dehydroepiandrosterone (DHEA) to rats results in alterations in liver and serum factors. This study was undertaken to determine the earliest metabolic change(s) associated with DHEA treatment. Serum cholesterol, triacylglycerol, glucose, insulin, glucagon, thyroid hormones and hepatic glucose-6-phosphate dehydrogenase activity were, in general, unaltered in obese Zucker rats after 7 d and 24, 12 and 3 h of DHEA treatment. Malic enzyme, long-chain fatty acyl-coenzyme A hydrolase and catalase activities and peroxisomal beta-oxidation rates were elevated after 7 d and 24 h in DHEA treatment, but not after 12 h. Mitochondrial beta-oxidation was not altered. Hepatic mitochondrial state 3 respiration per g liver with glutamate-malate was elevated after 7 d and 24, 12 and 3 h in DHEA-treated rats and was elevated per mg protein except after 7 d. Succinate-supported state 3 respiration per g liver was also elevated after 7 d and 24 and 12 h of DHEA treatment. Mitochondria from rats treated for 7 d had lower levels of cardiolipin and phosphatidylethanolamine and an increase in phosphatidylcholine. Changes in fatty acid composition of these phospholipids occurred after 7 d and 24 h of DHEA treatment. In an additional study, rats were treated with DHEA or DHEA plus ethidium bromide for 3 d. Ethidium bromide inhibited the increase in mitochondrial protein and respiration associated with DHEA treatment. These findings indicate that mitochondrial respiration is the earliest factor affected by DHEA and may be associated with protein synthesis.

Short-term effects of dehydroepiandrosterone treatment in rats on mitochondrial respiration.

Lean and obese Zucker rats, 7-8 wk of age, were treated with dehydroepiandrosterone (DHEA) for either 3 or 7 days to determine the initial cellular event(s) that might be responsible for the antiobesity activity of DHEA. Epididymal, retroperitoneal, and brown adipose tissue weights were unaltered by either 3 or 7 days of DHEA treatment. Liver weight was not affected by 3 days of treatment but was 13 and 18% higher in 7-day DHEA-treated lean and obese rats, respectively, compared with their corresponding control group. Mitochondrial state 3 respiration rates with glutamate-malate and succinate as substrates were elevated by an average of 35% in 3- and 7-day DHEA-treated obese rats and by 15-20% in 7-day DHEA-treated lean rats compared with rates obtained in the corresponding control groups. State 3 respiration was not affected in 3-day DHEA-treated lean rats compared with control lean rats. The specific activities of long-chain fatty acyl-coenzyme A synthase and hydrolase and the levels of free CoA were increased by severalfold in cellular fractions of both DHEA-treated lean and obese rats compared with their respective control group. Hepatic malic enzyme activity, which was shown earlier to be elevated with long-term DHEA treatment, was unaltered by either 3 or 7 days of DHEA administration. The above results suggest the involvement of mitochondrial respiration and fatty acid deacylation/reacylation in the antiobesity mechanism of action of DHEA.

Effect of short-term DHEA administration on liver metabolism of lean and obese rats.

The aim of the present investigation was to study the effects of fish oil feeding in obese Zucker rats to establish its suitability as an animal model of hyperlipidaemia, and to understand the possible mechanism of fish oil-induced perturbations in cell metabolism. Lean and obese Zucker rats were fed on diets containing 180 g coconut, safflower, or menhaden oil/kg for 10 weeks. Body-weights and food intakes of lean coconut (LC), safflower (LS), and menhaden (LM) groups were similar. Obese menhaden (OM) rats had lower food intakes and body-weights compared with obese coconut (OC) and obese safflower (OS) groups, but values for all obese rats were higher than those for lean rats. Liver weights were higher in obese compared with lean rats, but on a percentage body-weight basis menhaden oil rats had higher values within genotype. Serum cholesterol and triacylglycerol levels were lower in the OM group compared with the OC and OS groups, and in the LM group compared with the LC group. Glucose and insulin levels were highest in OS rats followed by OC and OM rats and then the lean rats. Serum triiodothyronine and thyroxine were lower in OM rats compared with OC and OS rats. Liver mitochondrial state 3 rates with glutamate-malate and succinate were lower; mitochondrial beta-oxidation was unaffected and peroxisomal beta-oxidation was higher in menhaden oil rats compared with both coconut and safflower oil rats. In general, consumption of menhaden oil lowered hepatic malic enzyme (EC 1.1.1.38, 1.1.1.40), glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and glutathione peroxidase (EC 1.11.1.9) activities and elevated long-chain fatty acyl-CoA hydrolase (EC 3.1.2.2) activity when compared with the two other diets. It is concluded that obese Zucker rats do respond like human subjects to fish oil feeding but not to vegetable oils. The hypolipidaemic effect of fish oil appears to be mediated through a lowering of lipogenic enzymes, glucose-6-phosphate dehydrogenase and malic enzyme.

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Pamarthi F. Mohan

Papers

Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity.

Short-term effects of dehydroepiandrosterone treatment in rats on mitochondrial respiration.

Effect of short-term DHEA administration on liver metabolism of lean and obese rats.

Metabolic effects of coconut, safflower, or menhaden oil feeding in lean and obese zucker rats

Dehydroepiandrosterone and related steroids inhibit mitochondrial respiration in vitro.