An Adenosine Receptor-Kruppel-like Factor 4 Axis Inhibits Adipogenesis [Metabolism]

June 13th, 2014 by Eisenstein, A., Carroll, S. H., Johnston-Cox, H., Farb, M., Gokce, N., Ravid, K.

Adipogenesis represents a key process in adipose tissue development, and remodeling including during obesity. Exploring the regulation of adipogenesis by extracellular ligands is fundamental to our understanding of this process. Adenosine, an extracellular nucleotide signaling molecule, found in adipose tissue depots acts on adenosine receptors. Here, we report that among these receptors, the A2b adenosine receptor (A2bAR) is highly expressed in adipocyte progenitors. Activation of the A2bAR potently inhibits differentiation of mouse stromal-vascular cells into adipocytes, while A2bAR knockdown stimulates adipogenesis. The A2bAR inhibits differentiation through a novel signaling cascade involving sustained expression of Kruppel-like factor 4 (KLF4), a regulator of stem cell maintenance. Knockdown of KLF4 ablates the ability of A2bAR to inhibit differentiation. A2bAR activation also inhibits adipogenesis in a human primary preadipocyte culture system. We analyzed the A2bAR-KLF4 axis in adipose tissue of obese subjects, and intriguingly found a strong correlation between A2bAR and KLF4 expression in both subcutaneous and visceral human fat. Hence, our study implicates the A2bAR as a regulator of adipocyte differentiation and the A2bAR-KLF4 axis as a potentially significant modulator of adipose biology.