Comparative effects of oleoyl-estrone and a specific β3-adrenergic agonist (CL316, 243) on the expression of genes involved in energy metabolism of rat white adipose tissue

Abstract

BackgroundThe combination of oleoyl-estrone (OE) and a selective β3-adrenergic agonist (B3A; CL316,243) treatment in rats results in a profound and rapid wasting of body reserves (lipid).MethodsIn the present study we investigated the effect of OE (oral gavage) and/or B3A (subcutaneous constant infusion) administration for 10 days to overweight male rats, compared with controls, on three distinct white adipose tissue (WAT) sites: subcutaneous inguinal, retroperitoneal and epididymal. Tissue weight, DNA (and, from these values cellularity), cAMP content and the expression of several key energy handling metabolism and control genes were analyzed and computed in relation to the whole site mass.ResultsBoth OE and B3A significantly decreased WAT mass, with no loss of DNA (cell numbers). OE decreased and B3A increased cAMP. Gene expression patterns were markedly different for OE and B3A. OE tended to decrease expression of most genes studied, with no changes (versus controls) of lipolytic but decrease of lipogenic enzyme genes. The effects of B3A were widely different, with a generalized increase in the expression of most genes, including the adrenergic receptors, and, especially the uncoupling protein UCP1.DiscussionOE and B3A, elicit widely different responses in WAT gene expression, end producing similar effects, such as shrinking of WAT, loss of fat, maintenance of cell numbers. OE acted essentially on the balance of lipolysis-lipogenesis and the blocking of the uptake of substrates; its decrease of synthesis favouring lipolysis. B3A induced a shotgun increase in the expression of most regulatory systems in the adipocyte, an effect that in the end favoured again the loss of lipid; this barely selective increase probably produces inefficiency, which coupled with the increase in UCP1 expression may help WAT to waste energy through thermogenesis.ConclusionsThere were considerable differences in the responses of the three WAT sites. OE in general lowered gene expression and stealthily induced a substrate imbalance. B3A increasing the expression of most genes enhanced energy waste through inefficiency rather than through specific pathway activation. There was not a synergistic effect between OE and B3A in WAT, but their combined action increased WAT energy waste.

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.…”

“…This increase is largely due to adrenal hypertrophia and increased expression of the entire corticosteroid synthetic pathway [23] but is also due to increased liver corticosteroid disposal via 5␣-reductase [22]. Treatment with OE reduces the WAT expression of most cytokines [5,14], especially leptin [5]. The expression of adiponectin is also decreased by OE [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. In fact, OE slightly decreased UCP1 expression in brown adipose tissue [17], but also increased the expression of this uncoupling protein in some WAT sites [14].…”

Effect of neonatal β3-adrenoceptor agonist CL 316,243 treatment on body fat accumulation and intestinal alkaline phosphatase activity in rats from reduced nests

“…It was previously suggested that b 3 -adrenoceptor, the predominant subtype of adrenoceptor expressed mainly in white and brown adipose tissue play an important role in the regulation of lipolysis, thermogenesis and energy homeostasis. Earlier studies reported that b 3 -adrenergic receptor stimulation in rats and mice fed high-fat diets is very effective in normalization of obesity [20,21]. Moreover, 4 weeks treatment of obese Zucker rats with CL 316,243 resulted in an increase metabolic rate by 96% per rat as well as in decrease and remodeling of retroperitoneal white fat depots [33].…”

“…It was shown that long--term administration of CL 316,243 (CL), a highly selective b 3 -adrenoceptor agonist, largely reduced fat stores and retarded the development of obesity in young rats fed a high-fat diet [18], as well as reversed established diet-induced obesity in older animals [19][20][21]. Similar fat-reducing effect of CL was also described in adult non-obese rats [22,23].…”