Increased cGMP promotes healthy expansion and browning of white adipose tissue

With more than half a billion individuals affected worldwide, obesity has reached pandemic proportions. Development of “brown‐like” or “brite” adipocytes within white adipose tissue (WAT) has potential antiobesity and insulin‐sensitizing effects. We investigated the role of cyclic GMP (cGMP) signaling, focusing on cGMP‐dependent protein kinase I (PKGI) in WAT. PKGI is expressed in murine WAT, primary adipocytes, and 3T3‐L1. Treatment of adipocytes with cGMP resulted in increased adipogenesis, with a 54% increase in expression of peroxisome proliferator‐activated receptor‐γ. Lentiviral overexpression of PKGI further increased adipogenesis, whereas loss of PKGI significantly reduced adipogenic differentiation. In addition to adipogenic effects, PKGI had an antihypertrophic and anti‐inflammatory effect via RhoA phosphorylation and reduction of proinflammatory adipokine expression. Moreover, PKGI induced a 4.3‐fold increase in abundance of UCP‐1 and the development of a brown‐like thermogenic program in primary adipocytes. Notably, treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6‐fold increase in uncoupling protein‐1 expression and promoted establishment of a brown fat cell‐like phenotype (“browning”) of WAT in vivo. Taken together, PKGI is a key regulator of cell size, adipokine secretion and browning of white fat depots and thus could be a valuable target in developing novel treatments for obesity.—Mitschke, M. M., Hoffmann, L. S., Gnad, T., Scholz, D., Kruithoff, K., Mayer, P., Haas, B., Sassmann, A., Alexander Pfeifer, A, Kilić, A. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27, 1621–1630 (2013). www.fasebj.org