Obesity is an undoubtable risk factor for metabolic and cardiovascular diseases and significantly contributes to the global morbi-mortality. We previously reported that LNP599, an imidazoline-like activator of hepatic AMPK/adiponectin signaling, protects against the development of obesity and associated cardio-metabolic disorders in rats. LNP599 may therefore be a suitable drug candidate for a therapeutic approach targeting the development of obesity at very early stages.

The objective was to evaluate the effects of LNP599 in a model of diet-induced overweight and metabolic disorders in a nonhuman primate, the common marmoset (Callithrix jacchus), and particularly to establish the impact of the compound on cholesterol homeostasis, i.e., HDL and LDL/VLDL lipoproteins.

Marmosets were fed normal or hypercaloric chow during 16 weeks. Diet-induced changes in body weight and metabolism were assessed. Effects of LNP599 were evaluated in a subset of animals receiving the compound at a daily dose of 10mg/kg over the 16 weeks.

Hypercaloric chow induced significant overweight associated with a marked dyslipidemia: hypertriglyceridemia (+63%), hypercholesterolemia (+56%) and reduced HDL over LDL/VLDL cholesterol ratio (−24%). LNP599 blunted the diet-induced body weight gain and largely protected against the development of hypertriglyceridemia (+33%). Total cholesterol was unchanged but the ratio of HDL over LDL/VLDL cholesterol was more than doubled (≈2 in LNP599-treated animals vs. ≈0.9 in untreated marmosets).

Marmosets receiving the enriched diet represent a highly clinically relevant experimental model 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 this nonhuman primate model and demonstrate for the first time the high potency of this drug in promoting HDL-cholesterol.