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  3. Pharmacological inhibition of acyl-coenzyme A:cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake

Pharmacological inhibition of acyl-coenzyme A:cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake

  • Metabolism. 2021 Oct;123:154861. doi: 10.1016/j.metabol.2021.154861.
Yuyan Zhu 1,  Sora Q Kim 2,  Yuan Zhang 3,  Qing Liu 4,  Kee-Hong Kim 5
Affiliations

Affiliations

  • 1 Department of Food Science, Purdue University, West Lafayette, IN 47907, USA; Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. Electronic address: [email protected].
  • 2 Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
  • 3 College of Food Science, Southwest University, Chongqing 400715, China.
  • 4 Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
  • 5 Department of Food Science, Purdue University, West Lafayette, IN 47907, USA; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA. Electronic address: [email protected].
PMID: 34371065 DOI: 10.1016/j.metabol.2021.154861
Abstract

Background/objectives: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyze the formation of cholesteryl ester (CE) from free Cholesterol to regulate intracellular Cholesterol homeostasis. Despite the well-documented role of ACATs in hypercholesterolemia and their emerging role in Cancer and Alzheimer's disease, the role of ACATs in adipose lipid metabolism and obesity is poorly understood. Herein, we investigated the therapeutic potential of pharmacological inhibition of ACATs in obesity.

Methods: We administrated avasimibe, an ACAT Inhibitor, or vehicle to high-fat diet-induced obese (DIO) mice via intraperitoneal injection and evaluated adiposity, food intake, energy expenditure, and glucose homeostasis. Moreover, we examined the effect of avasimibe on the expressions of the genes in adipogenesis, lipogenesis, inflammation and adipose pathology in adipose tissue by Real-Time PCR. We also performed a pair feeding study to determine the mechanism for body weight lowering effect of avasimibe.

Results: Avasimibe treatment markedly decreased body weight, body fat content and food intake with increased energy expenditure in DIO mice. Avasimibe treatment significantly lowered blood levels of glucose and Insulin, and improved glucose tolerance in obese mice. The beneficial effects of avasimibe were associated with lower levels of adipocyte-specific genes in adipose tissue and the suppression of food intake. Using a pair-feeding study, we further demonstrated that avasimibe-promoted weight loss is attributed mainly to the reduction of food intake.

Conclusions: These results indicate that avasimibe ameliorates obesity and its-related Insulin resistance in DIO mice through, at least in part, suppression of food intake.

Keywords

Acyl-coenzyme A:cholesterol acyltransferase; Avasimibe; Cholesterol ester; Food intake; Insulin resistance; Obesity.

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