Abstract
Liver X receptors (LXRs) have been recognized as a promising therapeutic target for atherosclerosis; however, their role in insulin sensitivity is controversial. Adiponectin plays a unique role in maintaining insulin sensitivity. Currently, no systematic experiments elucidating the role of LXR activation in insulin function based on adiponectin signaling have been reported. Here, we investigated the role of LXR activation in insulin resistance based on adiponectin signaling, and possible mechanisms. C57BL/6 mice maintained on a regular chow received the LXR agonist, T0901317 (30 mg/kg.d) for 3 weeks by intraperitoneal injection, and differentiated 3T3-L1 adipocytes were treated with T0901317 or GW3965. T0901317 treatment induced significant insulin resistance in C57BL/6 mice. It decreased adiponectin gene transcription in epididymal fat, as well as serum adiponectin levels. Activity of AMPK, a key mediator of adiponectin signaling, was also decreased, resulting in decreased Glut-4 membrane translocation in epididymal fat. In contrast, adiponectin activity was not changed in the liver of T0901317 treated mice. In vitro, both T0901317 and GW3965 decreased adiponectin expression in adipocytes in a dose-dependent manner, an effect which was diminished by LXRα silencing. ChIP-qPCR studies demonstrated that T0901317 decreased the binding of PPARγ to the PPAR-responsive element (PPRE) of the adiponectin promoter in a dose-dependent manner. Furthermore, T0901317 exerted an antagonistic effect on the expression of adiponectin in adipocytes co-treated with 3 µM Pioglitazone. In luciferase reporter gene assays, T0901317 dose-dependently inhibited PPRE-Luc activity in HEK293 cells co-transfected with LXRα and PPARγ. These results suggest that LXR activation induces insulin resistance with decreased adiponectin signaling in epididymal fat, probably due to negative regulation of PPARγ signaling. These findings indicate that the potential of LXR activation as a therapeutic target for atherosclerosis may be limited by the possibility of exacerbating insulin resistance-related disease.
Highlights
Liver X receptors (LXRs), including a and b isoforms, are transcription factors belonging to the nuclear receptor superfamily
Both LXRa and b are expressed in fat tissue and the former is increased during adipogenesis and adipocyte differentiation, indicating that LXRa might play a more important role in adipose function [14,15]; the role of LXR activation in insulin function in fat tissue remains to be clarified
Treatment with the LXR agonist T0901317 (30 mg/kg. d i.p.) for 3 weeks had no effect on body weight at the end of treatment (P.0.05, Fig. 1A). Both fasting and 120 min glucose levels of intraperitoneal glucose tolerance tests (IPGTT) were higher in T0901317-treated mice, similar area under the curve (AUC) values of the glucose levels during IPGTT were observed in the two groups (AUC Glu, t = 20.773, P.0.05, Fig. 1B)
Summary
Liver X receptors (LXRs), including a and b isoforms, are transcription factors belonging to the nuclear receptor superfamily. Previous studies by Cao et al [6] and Laffitte et al [7] show that LXR activation improves glucose tolerance in insulin-resistant Zucker (fa/fa) rats and in a murine model of diet-induced obesity and insulin resistance. In these studies, positive outcomes are primarily mediated by inhibition of gluconeogenesis and limitation of glucose output from the liver; recent studies using LXR-knockout mice have demonstrated opposing results [8,9]. Both LXRa and b are expressed in fat tissue and the former is increased during adipogenesis and adipocyte differentiation, indicating that LXRa might play a more important role in adipose function [14,15]; the role of LXR activation in insulin function in fat tissue remains to be clarified
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