TY - JOUR
T1 - Pharmacological inhibition of acyl-coenzyme A:cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake
AU - Zhu, Yuyan
AU - Kim, Sora Q.
AU - Zhang, Yuan
AU - Liu, Qing
AU - Kim, Kee Hong
N1 - Funding Information:
This work was supported, in part, by Purdue Research Foundation , Ralph W. and Grace M. Showalter Research Trust , the USDA National Institute of Food and Agriculture Hatch project (No. 1013613 ) for K.-H.K., and by the Hong Kong Polytechnic University (No: P0030234 and No: P0036229 ) and the Hong Kong Research Grants Council (No. 25100420 ) for Y.Z.
Funding Information:
We thank Kimberly K. Buhman, Scott A. Crist and Lihao Huang for their insightful comments; Kolapo Ajuwon, Jonathan C Kershaw, Jordan Oshiro, Siyuan Sheng and Zhihong Song, Patricia Jaynes and Sydney E. Moser for their technical assistance. We thank Benjamin Yee for assistance in behavior experiment design. We also acknowledge Ko Chi-bun Ben and Pan Xiaohan for their assistance with the use of a high-content imaging system supported by Collaborative Research Fund, Hong Kong Research Grants Council # C5012-15E , and animal experiment.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - Acyl-coenzyme A:cholesterol acyltransferase
KW - Avasimibe
KW - Cholesterol ester
KW - Food intake
KW - Insulin resistance
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85112297619&partnerID=8YFLogxK
U2 - 10.1016/j.metabol.2021.154861
DO - 10.1016/j.metabol.2021.154861
M3 - Journal article
AN - SCOPUS:85112297619
SN - 0026-0495
VL - 123
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
M1 - 154861
ER -