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Published on: June 8, 2021
A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced
Akane Ishihara1, Akio Kanatani, Satoshi Mashiko
1Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba 300-2611, Japan. akane_ishihara@merck.com
Abstract:
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.
Insights
A Neuropeptide Y Y5 receptor (Y5R) antagonist reduced diet-induced obesity in rodents by suppressing weight gain and improving insulin levels. This suggests Y5R antagonists may treat obesity.
Area of Science:
- Endocrinology
- Neuroscience
- Metabolic Research
Background:
- Neuropeptide Y (NPY) plays a role in energy homeostasis.
- The NPY Y5 receptor (Y5R) is a potential mediator of NPY's effects on energy balance.
- The specific role of Y5R in rodent obesity models is not well-defined.
Purpose of the Study:
- To investigate the effect of a selective Y5R antagonist on rodent obesity models.
- To determine if Y5R antagonism can ameliorate diet-induced obesity (DIO).
Main Methods:
- Administered a potent and selective Y5R antagonist to rodents.
- Utilized diet-induced obesity (DIO) models, lean mice, and genetically obese leptin receptor-deficient rodents.
- Assessed body weight, adiposity, and insulin levels.
- Conducted experiments with Y5R-deficient mice to confirm mechanism.
Main Results:
- The Y5R antagonist selectively reduced body weight gain and adiposity in DIO rodents.
- Hyperinsulinemia associated with DIO was improved by the Y5R antagonist.
- The compound did not affect body weight in lean or genetically obese rodents.
- Y5R deficiency prevented the amelioration of DIO by the antagonist, confirming a mechanism-based effect.
Conclusions:
- Y5R is implicated in the regulation and development of diet-induced obesity.
- Y5R antagonists show potential therapeutic utility for treating obesity.
