Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 1) fat store depletion and desensitization of β-adrenergic responses

Abstract

Beta3-adrenergic agonists have been considered as potent antiobesity and antidiabetic agents mainly on the basis of their beneficial actions discovered twenty years ago in obese and diabetic rodents. The aim of this work was to verify whether prolonged treatment with a beta3-adrenergic agonist known to stimulate lipid mobilisation, could promote desensitization of beta-adrenergic responses. Wistar rats and guinea pigs were treated during one week with CL 316243 (CL, 1 mg/kg/d) by implanted osmotic minipumps. In control animals, beta3-adrenergic agonists were lipolytic in rat but not in guinea pig adipocytes. CL-treatment did not alter body weight gain in both species, but reduced fat stores in rats. Lipolysis stimulation by forskolin was unmodified but responses to beta1-, beta2- and beta3-agonists were reduced in visceral or subcutaneous white adipose tissues of CL-treated rats. Similarly, the beta3-adrenergic-dependent impairment of insulin action on glucose transport and lipogenesis in rat adipocytes was diminished after CL-treatment. In rat adipocytes, [125I]ICYP binding and beta3-adrenoceptor mRNA levels were reduced after sustained CL administration. These findings show that CL 316243 exerts (beta3-adrenergic lipolytic and antilipogenic effects in rat adipocytes. These actions, which are likely involved in the fat depletion observed in rat, also lead to the desensitization of all beta-adrenergic responses. Therefore this desensitization, together with the lack of slimming action in guinea pig, seriously attenuates the usefulness of beta3-agonists as antiobesity agents, and may explain why such agonists have not been conducted to a widespread clinical use.

Influence of prolonged fasting on monoamine oxidase and semicarbazide-sensitive amine oxidase activities in rat white adipose tissue

“…Lipid content was gravimetrically determined after extraction in organic solvant as previously reported (16) Lipolytic activity of isolated adipocytes and glucose uptake into fat tissue pieces.-Freshly isolated white adipocytes were used for the determination of lipolytic activity, by assessing the glycerol release in incubation medium containing 3.5 % bovine albumin, as previously described (4). The results were expressed as percentage of responses to 10 nM isoprenaline, which is independent of fat cell size and basal triglyceride breakdown (9). The previously described technique used for the determination of 2-deoxyglucose uptake into adipocytes (8) was adapted to small pieces of adipose tissues, incubated without previous collagenase digestion, and separation between internalized hexose from extracellular was performed by successive washings as for muscle (19) instead of the centrifugation through dynonylphtalate layer used for buoyant fat cells (8).…”

Prolonged treatment with the β3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 2) modulation of glucose uptake and monoamine oxidase activity

“…Animals and protocols.-Male Wistar rats or guinea pigs were housed and handled as already described (14). The oneweek continuous sc-administration of CL mg/kg body weight/day was performed with osmotic minipumps (Alzet 2001) implanted in the dorsal region.…”

“…This led us to quantify insulin responsiveness as increase over basal values of glucose metabolism. Lipogenesis.-Lipogenesis from [3-3 H]-glucose was determined by measuring the radioactivity incorporated into lipids after extraction in an organic phase, as previously described (14). Briefly, adipocytes were incubated 90 min in 400 μl KRBH containing 0.5 mM labeled glucose (0.15 μCi).…”

“…The three β-AR subtypes, including the β 3 -receptor are present on rat adipocytes (16) while only β 1 -, and β 2 -ARs are functional in guinea pig adipocytes (4,8,10). Since we have reported that the β 3 -AR agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig (14) we aimed to compare in rat and guinea pig adipocytes the influence of chronic CLtreatment on glucose transport activity and insulin responsiveness.…”

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 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].…”