title: 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.
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Fenping
authors: F
authors: Zheng
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Saifei
authors: S
authors: Zhang
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Weina
authors: W
authors: Lu
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Fang
authors: F
authors: Wu
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Xueyao
authors: X
authors: Yin
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Dan
authors: D
authors: Yu
authors: Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P.R. China.
authors: Qianqian
authors: Q
authors: Pan
authors: Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China.
authors: Hong
authors: H
authors: Li
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007333:Insulin Resistance; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D020218:Response Elements; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D055372:AMP-Activated Protein Kinases; D052242:Adiponectin; D051275:Glucose Transporter Type 4; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D000077205:Pioglitazone; D013449:Sulfonamides; D045162:Thiazolidinediones; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides