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AIM:: These studies were performed to test the hypothesis that endogenous neuropeptide Y (NPY) acting on the NPY Y5 receptor subtype contributes to the control of food intake. The hypothesis was tested using S 25585-a newly synthesized NPY Y5 receptor antagonist. METHODS AND RESULTS:: S 25585 was shown to be a high-affinity antagonist of the NPY Y5 receptor subtype (IC50 5?nM) with no significant affinity toward other NPY receptor subtypes and over 40 other receptors, channels or uptake systems. S 25585 (7.5?mg/kg, i.p.) did not induce a conditioned taste aversion, significantly alter need-induced sodium appetite or induce pica, suggesting that at this dose the compound did not induce illness or malaise. In satiated rats, S 25585 (5.0 and 7.5?mg/kg, i.p.) significantly decreased the overfeeding induced by i.c.v. injection of NPY (1?µg) and the highly selective NPY Y5 receptor agonist [hPP1-17, Ala31, Aib32]NPY (0.7?µg). In rats fasted for 4?h immediately before the dark phase, analysis of the microstructure of feeding behavior revealed that S 25585 significantly increased latency to eat and significantly decreased the duration and size of the meals without altering the meal number or eating rate. Analysis of the behavioral satiety sequence at this time revealed that the animals passed through the normal pattern of feeding, grooming and resting. Although S 25585 appeared to be influencing a physiological system controlling appetite, this does not involve the NPY Y5 receptor since the antagonist also markedly reduced food intake in the NPY Y5 knockout mouse. CONCLUSIONS:: The results presented do not support a role for the NPY Y5 receptor in the control of food intake. The results further illustrate that it is imperative that the activity of any new NPY Y5 antagonist be assessed in the NPY Y5 knockout mouse before assuming that its effect on food intake is due to blockade of this receptor.International Journal of Obesity (2004) 28, 628-639. doi:10.1038/sj.ijo.0802435 Published online 3 February 2004 [ABSTRACT FROM AUTHOR]

The respective roles of predisposing genetic factors and environmental factors in the development of type 2 diabetes (T2D) in obese subjects is poorly documented. Rodent models have been set up in an attempt to better understand of the differential effect of a prolonged metabolic stress induced by a high fat diet on glycaemic control according to the genetic background. In utero growth retardation resulting from a hypocaloric diet in pregnant rats induces a dramatic alteration of the development of islet cells leading to diabetes and insulin secretory defects in adult age. Experimentally induced diabetes in rodents results in hyperglycaemia and hyperinsulinemia in the fetus related to accelerated endocrine pancreas maturation responsible for the onset of diabetes in the adult. Deranged metabolic environment during fetal life may therefore further contribute to the onset of diabetes in the adult. Normal mouse strains with different genetic backgrounds show a wide range of responses to a high fat diet, with strains resistant to the diet and other more or less sensitive to the diet, the most sensitive exhibiting obesity diabetes and, insulin deficiency. The inability of the β cell to respond to the increased insulin demand related to insulin resistance seems to be pivotal in the pathophysiologic process and a new notion is emerging: "nutritional genetics" which studies the influence of nutrients on gene expression., (© 2013 médecine/sciences – Inserm.)

The compound S38151 is a nanomolar antagonist that acts at the melanin-concentrating hormone receptor 1 (MCH(1)). S38151 is more stable than its purely peptide counterpart, essentially because of the blockade of its N-terminus. Therefore, its action on various models of obesity was studied. Acute intra-cerebroventricular (i.c.v.) administration of S38151 in wild-type rats counteracted the effect of the stable precursor of melanin-concentrating hormone (MCH), NEI-MCH, in a dose-dependent manner (from 0.5 to 50 nmol/kg). In genetically obese Zucker fa/fa rats, daily i.c.v. administration of S38151 induced dose-dependent (5, 10, and 20 nmol/kg) inhibition of food intake, water intake, and body weight gain, as well as increased motility (maximal effect observed at 20 nmol/kg). In Zucker fa/fa rats, intraperitoneal injection of S38151 (30 mg/kg) induced complete inhibition of food consumption within 1 h. Daily intraperitoneal injection of S38151 (10 and 30 mg/kg) into genetically obese ob/ob mice or diet-induced obese mice is able to limit body weight gain. Furthermore, S38151 administration (10 and 30 mg/kg) does not affect food intake, water intake, or body weight gain in MCHR1-deleted mice, demonstrating that its effects are linked to its interaction with MCH(1). These results validate MCH(1) as a target of interest in obesity. S38151 cannot progress to the clinical phase because it is still too poorly stable in vivo.