Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control

EBioMedicine. 2016 Sep:11:101-117. doi: 10.1016/j.ebiom.2016.08.027. Epub 2016 Aug 20.

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.

Keywords: Collagen; Fibrosis; Hepatomegaly; Obesity; RORα; Subcutaneous adipose.

MeSH terms

  • Adipose Tissue / immunology
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Adiposity / genetics*
  • Adiposity / immunology
  • Animals
  • Biomarkers
  • Blood Glucose*
  • Cluster Analysis
  • Extracellular Matrix / metabolism
  • Fibrosis
  • Gene Expression Profiling
  • Gene Expression*
  • Genotype
  • Glucose Tolerance Test
  • Hepatomegaly / genetics
  • Hepatomegaly / metabolism
  • Hepatomegaly / pathology
  • Humans
  • Insulin Resistance
  • Lipid Metabolism
  • Lipids / blood
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics*
  • Organ Specificity
  • Phenotype
  • Splenomegaly / genetics
  • Splenomegaly / metabolism
  • Splenomegaly / pathology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Transgenes
  • Weight Gain

Substances

  • Biomarkers
  • Blood Glucose
  • Lipids
  • Nuclear Receptor Subfamily 1, Group F, Member 1