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Am J Physiol Regul Integr Comp Physiol 284: R1399-R1408, 2003; doi:10.1152/ajpregu.00632.2002
0363-6119/03 $5.00
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Vol. 284, Issue 6, R1399-R1408, June 2003

SPECIAL TOPICS
Peptides that Regulate Food Intake
Antagonism of opioid receptors reduces body fat in obese rats by decreasing food intake and stimulating lipid utilization

Michael A. Statnick, Frank C. Tinsley, Brian J. Eastwood, Todd M. Suter, Charles H. Mitch, and Mark L. Heiman

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0545

Agonists to opioid receptors induce a positive energy balance, whereas antagonists at these receptors reduce food intake and body weight in rodent models of obesity. An analog of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, LY255582, is a potent non-morphinan antagonist for µ-, kappa -, and delta -receptors (Ki of 0.4, 2.0, and 5.2 nM, respectively). In the present study, we examined the effects of oral LY255582 treatment on caloric intake, calorie expenditure, and body composition in dietary-induced obese rats. Acute oral treatment of LY255582 produced a dose-dependent decrease in energy intake and respiratory quotient (RQ), which correlated with the occupancy of central opioid receptors. Animals receiving chronic oral treatment with LY255582 for 14 days maintained a negative energy balance that was sustained by increased lipid use. Analysis of body composition revealed a reduction in fat mass accretion, with no change in lean body mass, in animals treated with LY255582. Therefore, chronic treatment with LY255582 reduces adipose tissue mass by reducing energy intake and stimulating lipid use.

respiratory quotient; body composition; dual-energy X-ray absorptiometry; indirect calorimetry; ex vivo receptor binding


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