Cell Biology
An Adenosine Receptor-Krüppel-like Factor 4 Protein Axis Inhibits Adipogenesis*

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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 nucleoside 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, whereas A2bAR knockdown stimulates adipogenesis. The A2bAR inhibits differentiation through a novel signaling cascade involving sustained expression of Krüppel-like factor 4 (KLF4), a regulator of stem cell maintenance. Knockdown of KLF4 ablates the ability of the 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.

adenosine Receptor
Adipogenesis
Cell Differentiation
Kruppel-like Factor (KLF)
Obesity

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*

This work was supported, in whole or in part, by NHLBI, National Institutes of Health Grant HL93149 (to K. R.) and National Institutes of Health Grant R01HL114675-02) (to N. G.). This work was also supported by Boston Nutrition Obesity Research Center Pilot Grant DK046200 (to K. R.).

1

Supported by NIDDK, National Institutes of Health NRSA F30 award DK098834.

2

Supported by National Institutes of Health Cardiovascular Training Grant HL007969.

3

Supported by American Heart Association Postdoctoral Fellowship Grant 12POST11780028.