l-152804 and Obesity

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cyclohexanes; Diet; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Organ Size; Rats; Rats, Zucker; Receptors, Neuropeptide Y; Weight Gain; Xanthenes

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucrose--loaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period.

Topics: Aging; Animals; Arginine; Brain; Cyclohexanes; Dietary Sucrose; Energy Intake; Homozygote; Humans; Mice; Mice, Knockout; Mice, Transgenic; Neuropeptide Y; Obesity; Phenotype; Promoter Regions, Genetic; Receptors, Neuropeptide Y; Reference Values; Thy-1 Antigens; Xanthenes