Maud Weiss1, Lyne Fellmann2, Pierrick Regnard2, Pascal Bousquet1, Laurent Monassier1, Nathalie Niederhoffer3. 1. Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire - UR7296, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. 2. SILABE, Université de Strasbourg, Fort Foch, Niederhausbergen, Strasbourg, France. 3. Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire - UR7296, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. nathalie.niederhoffer@unistra.fr.
Abstract
BACKGROUND/ OBJECTIVES: Overweight and obesity are undoubtable risk factors for type 2 diabetes and cardiovascular diseases and significantly contribute to the global morbi-mortality. We previoulsy reported that LNP599, a pharmacological imidazoline-like activator of hepatic AMPK/adiponectin signaling, protects against the development of adiposity and obesity and the associated cardio-metabolic disorders, suggesting that it may be a suitable drug candidate for a therapeutic approach targeting the development of obesity at very early stages. The objective of the present study was to evaluate the metabolic effects of LNP599 in a model of diet-induced overweight and metabolic disorders in a nonhuman primate, the common marmoset (Callithrix jacchus), and more particularly to establish the impact of the compound on cholesterol homeostasis, i.e., HDL and LDL/VLDL lipoproteins. METHODS: Marmosets were fed normal (NC) or hypercaloric (HC) chow during 16 weeks. Diet-induced changes in body weight and metabolism were assessed. Effects of LNP599 were evaluated in a subset of HC animals (HC-LNP) receiving the compound at a daily dose of 10 mg/kg over the 16 weeks. RESULTS: HC-feeding induced significant overweight associated with a marked dyslipidemia (hypertriglyceridemia, hypercholesterolemia, and reduced HDL over LDL/VLDL cholesterol ratio). LNP599 blunted the diet-induced body weight gain and largely protected against the development of hypertriglyceridemia. Total cholesterol was unchanged but the ratio of HDL over LDL/VLDL cholesterol was more than doubled. CONCLUSIONS: The profile of metabolic troubles obtained upon enriched diet mimicked the disorders associated with spontaneous obesity in marmosets. HC marmosets represent an experimental model of high clinical relevance to study the pathophysiology of obesity and related dyslipidemia and to evaluate the effects of emerging therapies targeting these disorders. Our data confirm the preventing effects of LNP599 in a nonhuman primate model and demonstrate for the first time the high potency of this drug in promoting HDL-cholesterol.
BACKGROUND/ OBJECTIVES: Overweight and obesity are undoubtable risk factors for type 2 diabetes and cardiovascular diseases and significantly contribute to the global morbi-mortality. We previoulsy reported that LNP599, a pharmacological imidazoline-like activator of hepatic AMPK/adiponectin signaling, protects against the development of adiposity and obesity and the associated cardio-metabolic disorders, suggesting that it may be a suitable drug candidate for a therapeutic approach targeting the development of obesity at very early stages. The objective of the present study was to evaluate the metabolic effects of LNP599 in a model of diet-induced overweight and metabolic disorders in a nonhuman primate, the common marmoset (Callithrix jacchus), and more particularly to establish the impact of the compound on cholesterol homeostasis, i.e., HDL and LDL/VLDL lipoproteins. METHODS: Marmosets were fed normal (NC) or hypercaloric (HC) chow during 16 weeks. Diet-induced changes in body weight and metabolism were assessed. Effects of LNP599 were evaluated in a subset of HC animals (HC-LNP) receiving the compound at a daily dose of 10 mg/kg over the 16 weeks. RESULTS: HC-feeding induced significant overweight associated with a marked dyslipidemia (hypertriglyceridemia, hypercholesterolemia, and reduced HDL over LDL/VLDL cholesterol ratio). LNP599 blunted the diet-induced body weight gain and largely protected against the development of hypertriglyceridemia. Total cholesterol was unchanged but the ratio of HDL over LDL/VLDL cholesterol was more than doubled. CONCLUSIONS: The profile of metabolic troubles obtained upon enriched diet mimicked the disorders associated with spontaneous obesity in marmosets. HC marmosets represent an experimental model of high clinical relevance to study the pathophysiology of obesity and related dyslipidemia and to evaluate the effects of emerging therapies targeting these disorders. Our data confirm the preventing effects of LNP599 in a nonhuman primate model and demonstrate for the first time the high potency of this drug in promoting HDL-cholesterol.
Authors: Jean Ferrières; Dominik Lautsch; Anselm K Gitt; Gaetano De Ferrari; Hermann Toplak; Moses Elisaf; Heinz Drexel; Martin Horack; Carl Baxter; Baishali Ambegaonkar; Philippe Brudi; Peter P Toth Journal: Diabetes Obes Metab Date: 2018-07-10 Impact factor: 6.577
Authors: Daphne P Guh; Wei Zhang; Nick Bansback; Zubin Amarsi; C Laird Birmingham; Aslam H Anis Journal: BMC Public Health Date: 2009-03-25 Impact factor: 3.295