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APPETITE, OBESITY AND METABOLISM

Acute and chronic effects of FR-149175, a ₃-adrenergic receptor agonist, on energy expenditure in Zucker fatty rats

Department of Diabetes Research, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka 532-8514, Japan

Submitted 2 March 2004 ; accepted in final form 14 April 2004

Clinical therapies for both obesity and obese non-insulin-dependent diabetes mellitus require maintenance of reduced body weight after the initial successful reduction resulting from calorie control, exercise, or medication. Although ₃-adrenergic receptor (₃-AR) agonists have been shown to stimulate whole body energy expenditure and lipid mobilization, whether stimulatory effects on oxygen consumption and lipolysis are influenced by chronic exposure to agonists has not been fully characterized. We therefore examined the acute and chronic effects of FR-149175, a selective ₃-AR agonist, on whole body oxygen consumption in genetically obese Zucker fatty rats. Chronic treatment with FR-149175 caused a decrease in both body weight gain and white fat pad weight at doses that induced lipolysis in acute treatment (1 and 3.2 mg/kg po). Single administration of FR-149175 (0.1, 1, and 3.2 mg/kg po) dose dependently increased whole body oxygen consumption. Repetitive administration did not cause attenuation of the thermogenic response at lower doses (0.1 and 1 mg/kg 2 times daily), whereas the highest dose (3.2 mg/kg 2 times daily) induced a progressive increase in oxygen consumption. PCR analyses of retroperitoneal white adipose tissue indicated little or no change in ₃-AR mRNA levels. Uncoupling protein 1 gene expression increased at 1 mg/kg, and drastic upregulation was detected at 3.2 mg/kg. FR-149175 also increased HSL mRNA levels in a dose-related manner, whereas there was no effect on genes involved in -oxidation. These results support that the thermogenic effect of ₃-AR agonists is not attenuated by chronic exposure to agonists.

oxygen consumption; uncoupling protein 1; hormone-sensitive lipase; desensitization

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