Regulations of Adipocyte Phenotype and Obesity by IRX3. Positive or Negative?

Adipocyte is closely related to energy homeostasis. While white adipocyte stores energy as a form of lipids, brown adipocyte dissipates energy by producing heat. In mice and humans exposed to chronic cold temperature, white adipocyte transdifferentiates into brown adipocyte-like cell called beige (brite) cell. The regulation of brown adipocyte function and beigeing of white adipocyte is considered as a potential therapeutic target for obesity (reviewed in Inagaki et al., 2016). Genome-wide association studies (GWASs) have identified strong association of obesity and genetic variances within introns of FTO which encodes a demethylase for N-methyladenosine (m6A) residues in mRNA (reviewed in Tung et al., 2014). Recent studies revealed that this association is mediated by the mechanism independent of enzyme activity of FTO (Claussnitzer et al., 2015; Smemoet al., 2014). A region in the intron 1 of FTO physically interacts with the promoter sequence of IRX3 which locates ~500 kilo bases away from FTO locus by forming long range chromatin loop, acting as an enhancer to induce the expression of IRX3 which encodes a transcription factor involved in multiple developmental processes (Smemo et al., 2014 and reviewed in Gorkin and Ren, 2014). It is also reported that the binding of AT-rich interactive domain 5B (ARID5B) repressor protein to the region in the intron 1 of FTO negatively regulates IRX3 expression (Claussnitzer et al., 2015). In this issue of EBioMedicine, Zou et al. (2017) investigated the expression profile of IRX3 and function of IRX3 protein in adipocytes. They obtained tissues and stromal vascular fractions (SVFs) from different types of adipose tissues (i.e. brown adipose tissue (BAT), subcutaneous white adipose tissue (scWAT), and visceral WAT (vWAT)) of mouse and human to examine mRNA and protein expressions of IRX3. They revealed increased Irx3 expression in scWAT and BAT in response toβ-adrenergic stimulation and also during the time course of beige and brown adipogenesis of mouse SVFs. The profiles of mRNA expression and histological localization of UCP1 and IRX3 were positively correlated. These results indicated a potential role of IRX3 in the regulation of genes related to adipose cell fate. Cell autonomous study using mouse and human SVFs in which IRX3 expression was knocked down (KD) by infecting lentivirus expressing shRNA against IRX3 showed reduced mRNA expression of thermogenic