Effects of a Novel Y5 Antagonist in Obese Mice: Combination With Food Restriction or Sibutramine

Abstract

Objective:To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice. Methods and Procedures: Male C57BL/6 or Npy5r −/− mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r −/− mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. Results: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r −/− DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. Discussion: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.

Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome

“…In order to validate the HE-fed DIO rat as a useful animal model of obesity, we examined the body weight lowering effect of the well-known anti-obesity agent sibutramine and the once-daily human GLP-1 analog liraglutide. The findings of a transient (7 day) effect on food intake and a approximate 10% weight loss following 28 days of treatment with sibutramine is in agreement with data reported previously from other rodent DIO models (Boozer et al 2001, Bush et al 2006, Mashiko et al 2008 as well as in a previous study in the DIO rat (Levin & Dunn-Meynell 2000). The body weight loss of w10% seen in rodent models of obesity translates into an approximate 5% sustained weight loss in humans (Bray et al 1999, James et al 2000.…”

Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DIO-rats

“…Six-week-old Sprague-Dawley rats were offered a two-choice diet consisting of standard rodent chow diet or the gubra diet, a highly palatable high-fat, high-sugar diet. After a six-month feeding period, body weight changes, ingestive responses and feeding behaviors were examined following daily administration of sibutramine and liraglutide for 23 d. Compared to the vehicle control, chronic administration of either sibutramine or liraglutide to high-fat/sugar-fed DIO-rats caused significant reductions in body weight gain, which is in agreement with previously reported data using other rodent DIO models [14,15,[31][32][33][34] . The body weight loss observed in both groups was mainly caused by decreasing levels of total fat mass as revealed by the weekly measurements of whole body composition.…”

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

“…Specifically, data on EI and BW in the mouse are reported for rimonabant 10 mg/kg/day,35 sibutramine 10 mg/kg/day,36 and topiramate 66 mg/kg/day (only BW; Figure 3 a,c ). Data on EI and BW in the rat are reported for rimonabant 10 mg/kg/day,37 taranabant 3 mg/kg/day,37 sibutramine 5 mg/kg/day,38 and lorcaserin 4 mg/kg/day39 ( Figure 3 b,d ).…”