Effect of a beta-3 agonist on food intake in two strains of rats that differ in susceptibility to obesity

CONTEXT: Beta-3 agonists acutely reduce food intake, but the mechanism is not well understood. OBJECTIVE: To evaluate the effect of a beta3 agonist on food intake in two strains of rats that differ in their sensitivity to becoming obese while eating a high-fat (HF) diet. METHODS: Male Osborne-Mendel (OM) and S5B/Pl (S5B) rats were treated with a beta3-adrenergic agonist (CL 316,243) at 8 weeks of age, after an adaptation to either an HF (56% fat energy) or a low-fat (LF; 10% fat energy) diet that was equicaloric for protein (24% energy). Ad-lib-fed rats were injected intraperitoneally with CL 316,243, at doses of 0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg, or with vehicle at the beginning of the dark cycle. Food intake was measured at 1, 3, 6 and 24 h after injections. RESULTS: The beta3 agonist CL 316,243 significantly decreased food intake at all timepoints in both strains of rats eating both diets. However, this inhibition of food intake was significantly greater in the S5B rat. CL 316,243 significantly decreased serum leptin and serum glucose in both the OM and the S5B rats, and again, the inhibition was greater in the S5B rat. Whereas CL 316,243 increased serum insulin levels in the OM rat, it decreased them in the S5B rat on an LF diet. In a second experiment, chow-fed rats were implanted with vascular ports into the jugular vein and allowed to recover. When CL 316,243 was injected into the animals that were fasted overnight, rats of both strains significantly increased their serum insulin at 30 min, but the increase was much more pronounced in the S5B rat. Serum glucose was decreased significantly at both the 30- and 60-min timepoints in the OM rat and at 30 min in the S5B rat. CONCLUSION: These experiments demonstrate that a beta3 agonist (CL 316,243) has a much greater effect in a strain of rats that resist fat-induced obesity.