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

Yuyan Zhu (Corresponding Author), Sora Q. Kim, Yuan Zhang, Qing Liu, Kee Hong Kim

Research output: Journal article publicationJournal articleAcademic researchpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Article number154861
JournalMetabolism: Clinical and Experimental
Volume123
DOIs
Publication statusPublished - Oct 2021

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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