Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire - UR7296, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
SILABE, Université de Strasbourg, Fort Foch, Niederhausbergen, Strasbourg, France.
Int J Obes (Lond). 2021 Jun;45(6):1229-1239. doi: 10.1038/s41366-021-00786-6. Epub 2021 Mar 2.
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.
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.
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.
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.
背景/目的：超重和肥胖无疑是 2 型糖尿病和心血管疾病的危险因素，并显著导致全球的发病率和死亡率。我们之前报道过，LNP599 是一种药理学咪唑啉样肝 AMPK/脂联素信号激活剂，可预防肥胖和肥胖的发展以及相关的心脏代谢紊乱，这表明它可能是一种适用于治疗肥胖的候选药物在非常早期的阶段。本研究的目的是评估 LNP599 在非人类灵长类动物（普通狨猴，Callithrix jacchus）中饮食诱导的超重和代谢紊乱模型中的代谢作用，特别是评估该化合物对胆固醇稳态的影响，即 HDL 和 LDL/VLDL 脂蛋白。
狨猴在 16 周内分别喂食正常（NC）或高热量（HC）饲料。评估体重和代谢的变化。在一组接受每日 10mg/kg LNP599 治疗 16 周的 HC 动物（HC-LNP）中评估 LNP599 的作用。
HC 喂养引起明显的超重，伴有明显的血脂异常（高甘油三酯血症、高胆固醇血症和 HDL 与 LDL/VLDL 胆固醇比值降低）。LNP599 抑制了饮食诱导的体重增加，并在很大程度上防止了高甘油三酯血症的发生。总胆固醇不变，但 HDL 与 LDL/VLDL 胆固醇的比值增加了一倍多。
富含饮食引起的代谢紊乱与狨猴自发肥胖相关的紊乱相似。HC 狨猴代表了一种具有高临床相关性的实验模型，可用于研究肥胖和相关血脂异常的病理生理学，并评估针对这些疾病的新兴疗法的效果。我们的数据证实了 LNP599 在非人类灵长类动物模型中的预防作用，并首次证明了该药物在促进 HDL 胆固醇方面的高效性。
