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
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