title: Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet.
abstract: Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Zhiye
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Xueyao
authors.initials: X
authors.lastname: Yin
authors.affiliation: Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang ProvinceSir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Xihua
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of EndocrinologySir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, People's Republic of China zhengfenpingjindi@hotmail.com.
authors.forename: Fenping
authors.initials: F
authors.lastname: Zheng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D006529:Hepatomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015228:Hypertriglyceridemia / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008066:Lipolysis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000071518:Liver X Receptors; D047495:PPAR gamma; D005947:Glucose
keywords: adipose expansion; insulin resistance; liver X receptor (LXR); peroxisome proliferator-activated receptor gamma (PPARγ)