Regulation of Insulin Resistance and Adiponectin Signaling in Adipose Tissue by Liver X Receptor Activation Highlights a Cross-Talk with PPARγ

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.

Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet

“…They have shown that loss of LXR impairs hepatic lipogenesis, accompanied by a reciprocal increase in adipose lipid storage, by promoting adipose PPARγ pathway activity, indicating possible cross-talk between LXR and PPARγ in adipose tissue. Cross-talk between LXR and PPARγ in adipose tissue is also supported by our previous study that showed an antagonising effect of LXR on PPARγ in the regulation of adiponectin expression (Zheng et al 2014).…”

The potential disruption of estrogen and androgen homeostasis and adipocyte differentiation by metabolites of common airborne polychlorinated biphenyls

“…The differentiated adipocytes experienced increases in mRNA expression levels of SULT1E1, AdipoQ, and PPARγ (Figure 4-14) in comparison to the immortalized human preadipocytes in Figure 4-12. Differentiated adipocytes exhibited overall higher expression of AdipoQ and PPARγ genes and this was consistent with recent literature [250,345,346]. This also holds true for SULT1E1 expression, which was confirmed by the determination of estradiol sulfation in cytosol studies, where SULT1E1 activity was higher in differentiated adipocyte cytosol.…”

Liver X receptors as regulators of metabolism

“…Recently, studies on animal models and cell lines clearly show a cross talk between PPARγ and LXR in the regulation of adipocyte metabolism (8,72,73). This new finding could explain some discrepancies observed in the literature between LXR knockout studies and LXR activation studies in mouse models.…”