Transgenic adipose-specific expression of the nuclear receptor RORα drives a striking shift in fat distribution and impairs glycemic control

Tuong, Zewen Kelvin, Fitzsimmons, Rebecca, Wang, Shu-Ching Mary, Oh, Tae Gyu, Lau, Patrick, Steyn, Frederik, Thomas, Gethin and Muscat, George E. O. (2016) Transgenic adipose-specific expression of the nuclear receptor RORα drives a striking shift in fat distribution and impairs glycemic control. EBioMedicine, 11 101-117. doi:10.1016/j.ebiom.2016.08.027


Author Tuong, Zewen Kelvin
Fitzsimmons, Rebecca
Wang, Shu-Ching Mary
Oh, Tae Gyu
Lau, Patrick
Steyn, Frederik
Thomas, Gethin
Muscat, George E. O.
Title Transgenic adipose-specific expression of the nuclear receptor RORα drives a striking shift in fat distribution and impairs glycemic control
Journal name EBioMedicine   Check publisher's open access policy
ISSN 2352-3964
Publication date 2016-09-20
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ebiom.2016.08.027
Open Access Status DOI
Volume 11
Start page 101
End page 117
Total pages 17
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Collection year 2017
Language eng
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.
Keyword RORα
Subcutaneous adipose
Obesity
Hepatomegaly
Fibrosis
Collagen
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Tue, 08 Nov 2016, 00:24:03 EST by Susan Allen on behalf of Institute for Molecular Bioscience