The role of the orphan nuclear receptor Rev-Erb alpha in adipocyte differentiation and function

Lipid and carbohydrate homeostasis in higher organisms is governed by an integrated system that has a capacity to rapidly respond to metabolic changes. Numerous signals reciprocally convey information about body fat status from the periphery to central nervous system in the attempt to maintain body weight nearly stable throughout life. The role of adipocyte in energy homeostasis extends its function as a simple energy storage cell. Indeed, adipose tissue not only secretes fatty acids, but is also an active endocrine and paracrine organ due to the production of secreted proteins and lipid indicators collectively called adipokines. These observations have spurred interest in the identification of the transcriptional and other regulatory pathways of adipocyte differentiation. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) (NR1C3) and members of the CCAAT enhancer-binding protein (C/EBP) family are central mediators controlling adipocyte differentiation and function. Rev-erb alpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene. Rev-erb alpha acts as a negative regulator of transcription binding to the same response element than another orphan nuclear receptor, ROR alpha. Rev-erb alpha is highly expressed in adipose tissue, skeletal muscle, heart, liver and brain. Rev-erb alpha expression increases during adipocyte differentiation of 3T3-L1 cells and is induced by PPAR gamma activation in both 3T3-L1 cells in vitro and in rat adipose tissue in vivo via a direct repeat (DR2) in the Rev-erb alpha promoter. Ectopic expression of Rev-erb alpha potentiates the adipocyte differentiation in 3T3-L1 cells. Recent results in vascular smooth muscle cells (VSMCs) indicate that Rev-erb alpha also controls inflammation by regulating NF-kappa B responsive genes, such as IL-6 and COX-2. Future studies on a potential role of Rev-erb alpha on glucose homeostasis and/or inflammation control are thus warranted.