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.
Abbreviations:
ACATs (Acyl-coenzyme A:cholesterol acyltransferases), CE (cholesterol ester), DIO (diet-induced obese), TG (triglyceride), LD (lipid droplet), FC (free cholesterol), epiWAT (epididymal white adipose tissue), VLDL (very low-density lipoprotein), AVA (avasimibe), CTRL (control), ALT (alanine transaminase), IPGTT (intraperitoneal glucose tolerance test), HOMA-IR (homeostatic model assessment of insulin resistance), HF (high fat), RER (respiratory exchange ratio)Keywords
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Article info
Publication history
Published online: August 06, 2021
Accepted:
July 27,
2021
Received:
October 23,
2020
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
