Peptides that regulate food intake: antagonism of opioid receptors reduces body fat in obese rats by decreasing food intake and stimulating lipid utilization.
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 mu-, kappa-, and delta-receptors (K(i) 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.
Statnick
Michael A
MA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0545, USA. m.statnick@lilly.com
Tinsley
Frank C
FC
Eastwood
Brian J
BJ
Suter
Todd M
TM
Mitch
Charles H
CH
Heiman
Mark L
ML
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D003510:Cyclohexanes / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D050356:Lipid Metabolism; D008297:Male; D009292:Narcotic Antagonists; D009765:Obesity / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D011957:Receptors, Opioid / Q000378:metabolism
D003510:Cyclohexanes; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C070736:LY 243670