A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice

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.

Fig. 1.

Oral treatment with the Y5R antagonist inhibited the body weight gain in mice fed an MHF diet. (A) Body weight change. (B) Mean caloric intake. Veh., vehicle. Data are expressed as means ± SE (n = 8–9). ∗, P < 0.05 (compared with vehicle).

Fig. 2.

Effect of the Y5R antagonist on fat weight and plasma glucose and insulin levels. (A) Mesenteric fat weight. (B) Plasma glucose levels. (C) Plasma insulin levels. Data are expressed as means ± SE (n = 8–9). ∗, P < 0.05 (compared with vehicle).

Fig. 3.

Effect of the Y5R antagonist in wild-type (A) and Y5R KO (B) mice. Open symbols represent vehicle, Y5R antagonist (100 mg/kg), and vehicle during the first, second, and third phases, respectively. Filled symbols represent Y5R antagonist, vehicle, and Y5R antagonist, respectively. Data are expressed as means ± SE (n = 4–6).

Fig. 4.

Effect of the Y5R antagonist in lean mice and genetic obesity models. (A) Lean mice. (B) Lepr^db/db mice. (C) Lepr^db/db mice on MHF diet. (D) Zucker fatty rats. Data are expressed as means ± SE (n = 7–9).

Fig. 5.

Brain Y5R occupancy and drug exposure levels after oral administration of the Y5R antagonist. (A and B) Brain Y5R occupancy in lean C57BL/6J mice (A) and other obesity models (B). (C and D) Plasma concentration of the Y5R antagonist. In A, filled diamonds, asterisks, and open circles represent 10, 30, and 100 mg/kg, respectively, in lean mice. In B and C, filled circles represent mice with DIO, open circles represent lean mice, open triangles represent Lepr^db/db mice, filled triangles represent Lepr^db/db mice on an MHF diet, and open diamonds represent Zucker fatty rats. In D, open squares represent wild-type mice, and filled squares represent Y5R KO mice. Data are expressed as means ± SD (n = 3).