Combined effects of oleoyl-estrone and a β3-adrenergic agonist (CL316,243) on lipid stores of diet-induced overweight male Wistar rats

Abstract

Oleoyl-estrone (OE) decreases appetite, induces adipose tissue wasting and resets the ponderostat setting, sparing glucose and protein. The beta3-adrenergic agonists increase energy expenditure and lipolysis. We studied the combination of both treatments to enhance fat mobilization. Overweight male rats received oral OE for 10 days; they were compared with controls and rats receiving a beta3-adrenergic agonist, CL316,243 (B3A); another group received both OE and B3A. Serum 3-hydroxybutyrate, NEFA, triacylglycerols and glucose showed only slight changes in all groups vs. controls; OE-treated rats showed lower cholesterol. OE decreased food intake and B3A increased energy expenditure. OE rats lost about 15%, B3A 24%, and those receiving both compounds lost 39% of their initial total body energy. In all cases, most of this energy imbalance was accounted for by the loss of body lipid. The combined treatment of OE and B3A reduced food intake, nevertheless maintaining a high energy expenditure. The combination of a beta3-adrenergic agonist with OE may help compensate the short-lived effects of the agonist and enhance the lipid mobilization action of OE. The eventual combination of both compounds should be explored as a way to obtain faster and more effective ways to treat obesity.

Effects of Combined Oleoyl-Estrone and Rimonabant on Overweight Rats

“…OE effects on weight, energy, lipid, and protein were similar to the previously reported ones (4,9,21,22). Rimonabant effects and its rapid effect on appetite agree with previous studies (11).…”

“…Rats were maintained under standard housing conditions in two-rat cages, and they were fed for five weeks a reduced cafeteria diet (21,22) ad libitum. At the end of this phase, the animals were already overweight, that is, weighed 26% more than the same-age controls.…”

“…The combination of drugs for the treatment of obesity has been a widely extended practice in the past, in part because of the slow pace of weight loss and the usually limited overall effect, in spite of insufficient prior testing, with dramatically deleterious effects in some cases (18 -20). OE has been found to produce in rats a synergic boosting of body fat loss both with a β 3 -adrenergic agent (21) and a serotoninergic drug, sibutramine (22), indicating that its mechanism of action was complementary of both thermogenesis and inhibition of appetite by enhancement of postsynaptic serotonin activity. Combination of OE and dietary restriction, however, showed no improvement over the administration of OE alone in the handling of body fat, but OE markedly improved the body metabolic and hormonal environment when compared with restricted diet alone (9).…”

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

“…A peculiarity of OE treatment is the permanent loss of fat, suggesting a role as ponderostat signal for the estrone ester [12]. When OE is given in combination with a ␤ 3 -adrenergic agonist, the WAT wasting effects are markedly increased [13], with additive effects [14]. Similar, but less marked, additive effects were also observed with dexfenfluramine, sibutramine [15] and a thiazolidinedione [16], with opposing effects on WAT lipid integrity, but coincident in maintaining glycemia.…”

Cell physiology: The changing colour of fat

“…In mice, administering a compound that activates it (an agonist) prevents obesity and lowers the incidence of diabetes 5 . Unfortunately, says Seale, no equivalent agonist has been found in humans and the search has largely been abandoned by pharmaceutical companies.…”