Mechanisms of the antidiabetic effects of the β₃-adrenergic agonist CL-316243 in obese Zucker-ZDF rats

Abstract

Previous studies have demonstrated that chronic cold exposure activates the sympathetic nervous system, increases energy expenditure, improves glucose tolerance, enhances insulin sensitivity, and stimulates glucose uptake in peripheral tissues [brown and white adipose tissues (BAT and WAT) and muscles] of normal rats. The goal of the present studies was to test whether the selective β3-adrenergic agonist CL-316243 (CL) would mimic the beneficial effects of cold exposure in lean and obese ZDF/Gmi- fa male (ZDF) rats, a new model of type II diabetes. In obese ZDF rats, chronic infusion of CL (1 mg ⋅ kg−1 ⋅ day−1for 14 days) significantly decreased body weight gain, food intake, and WAT weight. It also increased total tissue cytochrome oxidase activity, not only in BAT (15 times), but also in WAT (2–4 times), suggesting that it progressively enhanced mitochondriogenesis in adipose tissues. CL treatment normalized hyperglycemia and reduced hyperinsulinemia and circulating free fatty acid (FFA) levels. It also improved glucose tolerance and reduced insulin response during an intravenous glucose tolerance test. In general, the beneficial effects of CL were more pronounced in obese than in lean rats. Hyperinsulinemic-euglycemic glucose clamps combined with the [2-3H]deoxyglucose method revealed that CL markedly improved insulin responsiveness in obese rats (3–4 times) and increased glucose uptake in BAT (21 times), WAT (3 times), skeletal muscles (2–3 times), and in the diaphragm (2.8 times), but not in the heart. It is concluded that chronic CL treatment improves glucose tolerance and insulin responsiveness in obese ZDF rats by a mechanism similar to that induced by chronic cold exposure, i.e., by stimulating facultative thermogenesis, mitochondriogenesis, and glucose utilization in BAT and WAT. In addition to this mechanism, the reduction in plasma FFA levels induced by chronic CL treatment may further contribute to enhance glucose uptake in skeletal muscles (a tissue that does not express typical β3-adrenoceptors) via the “glucose-fatty acid” cycle. The antiobesity and antidiabetic properties of CL suggest that selective β3-adrenergic agonists may represent useful agents for the treatment of type II diabetes.

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

“…Chronic ␤ 3 -agonist treatment causes increased insulin sensitivity in various models (9,(32)(33)(34). However, chronic CL316243 administration had no effect on the diabetes phenotype of A-ZIP/F-1 mice, which suggests that the antidiabetic effects of this ␤ 3 agonist require adipose tissue.…”

Cold-induced PGC-1α expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway

“…The high adrenergic tonus generated by exposure of homeothermic animals to cold is thought to play a central role in the control of glucose uptake driven by insulin-independent mechanisms (20,21). This fact is reinforced by the demonstration of the antidiabetic effect of ␤ 3 -adrenergic compounds such as CL-316243 (17,21) and BRL-26830A (34).…”

“…This fact is reinforced by the demonstration of the antidiabetic effect of ␤ 3 -adrenergic compounds such as CL-316243 (17,21) and BRL-26830A (34). However, the molecular mechanisms by which the adrenergic stimulus improves glucose uptake independently of insulin action through the IR-IRSs-Akt pathway are not known.…”

β-Adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1

“…Brown adipose tissue has been shown to play an important role in the regulation of glucose homeostasis and insulin secretion [2]. Glucose uptake is significantly increased in brown adipose tissue in vivo by activation of the sympathetic nervous system independently of insulin [3,4] and by adrenergic agonists in brown adipocytes in vitro [5][6][7][8].…”