title: Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control.
abstract: RORα is a member of the nuclear receptor (NR) superfamily and analysis of the (global) RORα-deficient mouse model revealed this NR has a role in glycemic control and fat deposition. Therefore, we generated an adipose-specific RORα 'gain of function' mouse model under the control of the fatty acid binding protein 4 (FABP4) promoter to elucidate the function of RORα in adipose tissue. The Tg-FABP4-RORα4 mice demonstrated a shift in fat distribution to non-adipose tissues when challenged with a high fat diet (HFD). Specifically, we observed a subcutaneous lipodystrophy, accompanied by hepatomegaly (fatty liver/mild portal fibrosis) and splenomegaly; in a background of decreased weight gain and total body fat after HFD. Moreover, we observed significantly higher fasting blood glucose and impaired clearance of glucose in Tg-FABP4-RORα4 mice. Genome wide expression and qPCR profiling analysis identified: (i) subcutaneous adipose specific decreases in the expression of genes involved in fatty acid biosynthesis, lipid droplet expansion and glycemic control, and (ii) the fibrosis pathway as the most significant pathway [including dysregulation of the collagen/extracellular matrix (ECM) pathways] in subcutaneous adipose and liver. The pathology presented in the Tg-FABP4-RORα4 mice is reminiscent of human metabolic disease (associated with aberrant ECM expression) highlighting the therapeutic potential of this NR.
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Zewen Kelvin
authors: ZK
authors: Tuong
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: r.fitzsimmons@imb.uq.edu.au.
authors: Rebecca
authors: R
authors: Fitzsimmons
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Shu-Ching Mary
authors: SM
authors: Wang
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Tae Gyu
authors: TG
authors: Oh
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Patrick
authors: P
authors: Lau
authors: University of Queensland Center for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; The Integrated Physiology Facility, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Frederik
authors: F
authors: Steyn
authors: Charles Sturt University, North Wagga, NSW 2678, Australia.
authors: Gethin
authors: G
authors: Thomas
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: g.muscat@imb.uq.edu.au.
authors: George E O
authors: GEO
authors: Muscat
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050154:Adiposity / Q000235:genetics* / Q000276:immunology; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose; D016000:Cluster Analysis; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D005951:Glucose Tolerance Test; D006529:Hepatomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D019076:Transgenes; D015430:Weight Gain
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008055:Lipids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1
keywords: Collagen; Fibrosis; Hepatomegaly; Obesity; RORα; Subcutaneous adipose