Antagonism of opioid receptors reduces body fat in obese rats  by decreasing food intake and stimulating lipid utilization

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

doi:10.1152/ajpregu.00632.2002

Cited by 45 publications

(46 citation statements)

References 41 publications

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“…However, in those trials, these agents were nonselective and were given to already obese people. It should be emphasized that more consistent weight-reducing effects in rats were obtained with administration of opioid-receptor antagonists before or during the dynamic phase of obesity development than in animals with preexisting dietary obesity (6,8,24). Also, individual differences in the etiology of obesity (28) may play a role in the efficacy of an opioid receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…Two studies have reported that nonselective opioid antagonists induce a decrease in RQ, thereby indicating an opioid modulation of lipid oxidation, in rats fed regular and high-fat diets (7,8). However, RQ decreases with reductions in caloric intake (8), and it has not been possible thus far to separate the feeding and metabolic effects of opioids by pharmacological manipulation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the present study has provided evidence that the MOR plays a crucial role in the development of obesity and glucose intolerance in a Western diet environment. Previous human trials conducted in obese patients with opioid receptor antagonists have given inconsistent results (8,45). However, in those trials, these agents were nonselective and were given to already obese people.…”

Section: Discussionmentioning

confidence: 99%

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Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the -opioid receptor (MOR) gene (MOR ؊/؊ ), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR ؊/؊ mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR ؊/؊ mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets. Diabetes 54: 3510 -3516, 2005 T he endogenous opioid system encompasses cloned receptor populations (, ␦, and ) and ligands (␤-endorphin, the enkephalins, and the dynorphins). Extensive work indicates that the opioid system plays a role in the regulation of appetite. Opioid receptors and peptides are expressed in sites of the central nervous system that play a role in regulating feeding behavior, and pharmacological experiments using opioid receptor ligands show that agonists promote eating and antagonists decrease food intake, at least in the short term (1-3). Numerous pharmacological studies indicate that opioids also play a role in modulating the rewarding effects of food (3-5). In contrast, little information suggests that opioids have a role in energy metabolism (6 -8).The need to establish the specific role of the opioid receptors in energy homeostasis has led to studies using putative specific opioid receptor ligands or, more recently, antisense probes directed against specific exons of opioid receptor genes (3,9). Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).Recent studies conducted in mutant mice null for the opioid receptors have complemented pharmacological approaches and clarified the role of each receptor in nociception, anxiety, and drug abuse (14). To further define the role of the -opioid receptor (MOR) pathway in energy homeostasis, we characterized mice lacking the MOR gene ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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“…This compound has been carefully studied for its ability to regulate palatable food consumption and body weight in rats (Mitch et al, 1993;Shaw, 1993;Statnick et al, 2003). LY255582 has subnanomolar potency for rat MOR and is 5-and 13-fold selective over KOR and DOR, respectively; thus, it is considered to be relatively nonselective.…”

Section: Discussionmentioning

confidence: 99%

“…Because the cumulative reduction in food consumption was equivalent to the loss of weight, we conclude that GSK1521498 induced fat mass loss through the suppression of food consumption. It is not possible to compare the magnitude of weight loss efficacy for GSK1521498 with that of LY255582 because the models used were inherently different (Shaw, 1993;Statnick et al, 2003). Obese Zucker rats continue to gain weight and treatment of the DIO Long Evans rats started early in the weight gain curve; thus, LY255582 inhibited the progressive weight gain compared with that in the vehicle group.…”

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confidence: 99%

Regulation of Ingestive Behaviors in the Rat by GSK1521498, a Novel μ-Opioid Receptor-Selective Inverse Agonist

Ignar

Goetz

Noble

et al. 2011

J Pharmacol Exp Ther

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ABSTRACT-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{ [3,5-difluoro-3Ј-(1H-1,2,4-triazol-3-ylis a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10-or 50-fold selective for human or rat MOR, respectively, compared with -opioid receptors (KOR) and ␦-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and dietinduced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

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