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.

Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues

“…Activation of LXRs in mice by oral administration of a synthetic LXR agonist T0901317 led to a marked increase in SREBP-1 and lipogenic enzyme expression, as well as TG content in the liver [ 46 ]. In agreement with this study, another study reported that mice developed fatty liver in three weeks after the treatment with T0901317 by intraperitoneal injection under high-fat diet conditions [ 87 ]. Furthermore, global loss of LXRs in ob / ob mice impairs hepatic lipogenesis and reduces hepatic steatosis compared with control because of the decreased expression of SREBP-1 and lipogenic enzymes [ 88 ].…”

“…The underlying mechanism is probably that LXRα deficiency in fat impairs adipocyte lipolysis and fatty acid availability and oxidation [ 90 ]. Conversely, administration of LXRα agonist T0901317 in mice fed with a high-fat diet reduced fat mass, which was accompanied with increased adipocyte lipolysis and apoptosis, and decreased PPARγ transcriptional activity [ 87 ]. Although different mouse models and diets may contribute to the different effects of LXRs in ATs, these studies suggest that LXRs play a different role in adipocytes and hepatocytes.…”

The Antagonist Effect of Arachidonic Acid on GLUT4 Gene Expression by Nuclear Receptor Type II Regulation

“…It has also been demonstrated that the activation of LXR-α impairs adipose expansion by increasing adipocyte apoptosis, lipolysis, and antagonizing the transcriptional activity mediated by PPAR-γ. This could contribute to a decrease in insulin sensitivity throughout the whole body [42]. These findings might explain what our study observed: that the LIR-MO individuals showed less expression of LXR-α in VAT in comparison with the HIR-MO individuals.…”

Colocalization of GWAS and eQTL signals at loci with multiple signals identifies additional candidate genes for body fat distribution

“…The allele associated with higher WHRadjBMI was associated with lower PRRX1, corresponding to more adipogenesis, and higher FMO1, corresponding to more storage of triglyceride in adipose 28,29 . The fourth gene detected using a secondary eQTL signal, SSR3, contributes to the formation of a vascular network in murine placenta 30 , and may reflect the blood component of adipose tissue; this GWAS signal colocalized with a primary eQTL for TIPARP, which positively regulates liver X receptor, which can impair adipose expansion 31 . While colocalized GWAS and eQTL signals do not provide causal mechanisms, they can suggest candidate genes for further investigation.…”