The biological significance of ROR

The biological significance of RORα in the regulation of important metabolic pathways is underscored by studies on the (global) Rorα-deficient staggerer (sg/sg) mouse model. For example, analysis of the global Rorα knockout model has revealed that Rorα regulates (i) adiposity (Lau et al., 2004, 2008), (ii) resistance to diet-induced obesity and hepatic steatosis (Lau et al., 2008), (iii) thermogenesis and browning/beiging of subcutaneous adipose tissue (SAT) (Lau et al., 2015), (iv) insulin sensitivity and signaling (Lau et al., 2011), (v) inflammation and phagocytosis (Tuong et al., 2013) and (vi) lipid droplet homeostasis (Tuong et al., 2016).
Specifically, the Rorα-deficient sg/sg mice display increased AKT signaling in skeletal muscle (Lau et al., 2011), improved glucose tolerance and insulin sensitivity. The lean phenotype in sg/sg mice is associated with reduced serum triglyceride and cholesterol levels (Lau et al., 2008, 2015; Kang et al., 2011; Mamontova et al., 1998). In addition, decreased adiposity is associated with an increased metabolic rate and cold tolerance in Rorα-deficient sg/sg mice. This phenotype involves browning/beiging of SAT, increased uncoupling protein 1 (Ucp1) smo inhibitor (mRNA and protein) and thermogenic gene expression (Lau et al., 2015), and significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. However, the significance of RORα in the regulation of adipose physiology remains unclear as it is difficult to dissect the contribution of this widely expressed receptor from the complex interactions that give rise to the lean phenotype. Several in vitro studies have suggested that RORα transcriptional activity acts to suppress adipocyte differentiation. Embryonic fibroblasts from Rorα-deficient sg/sg mice displayed enhanced differentiation into functional adipocytes (Duez et al., 2009) and in 3T3-L1 cells RORα constrained differentiation via increased expression during late adipogenesis (Okada et al., 2009). However, these authors also report a similar differentiation potentiality in pre-adipocytes sourced from homozygous sg/sg mice as their heterozygous sg/+ counterparts. It is evident that an in vivo investigation of RORα function – specifically in adipose tissue (i.e. an organ/tissue specific mouse model) that can account for the developmental, metabolic and compartmental context, is warranted. Therefore, we generated an adipose-specific RORα ‘gain of function’ transgenic mouse model in order to further understand the adipose-specific function of RORα in (i) lipid deposition, (ii) glucose tolerance and insulin sensitivity, (iii) obesity, and (iv) gene regulation. This is highly significant within the context of obesity as the capacity to expand the number of adipocyte cells to accommodate increased lipid storage requirements is a key determinant of the degree of metabolic dysfunction that accompanies increased adiposity.
Our studies indicate that (heterozygous, Tg-FABP4-RORα4 tg/+) mice with adipose-specific RORα4 expression have impaired glucose tolerance, decreased SAT, and hepatomegaly on a high fat diet, a phenotype often associated with obesity (Abdennour et al., 2014; Porter et al., 2009; Tam et al., 2012). RNA-seq, targeted qPCR and canonical pathway analysis suggests that adipose-specific RORα4 phenotype is associated with differential regulation of the fibrosis pathway in adipose and hepatic tissue. For example, genes that encode the extracellular matrix (ECM) collagen proteins are down-regulated in the SAT, but increased in tg/+ hepatic tissue. This is in accord with the role of collagen production in adipose development and physiology, as well as adipose plasticity to suit metabolic demands and changes (Mariman and Wang, 2010) and ectopic/aberrant fat deposition (Aikio et al., 2014).