Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue

Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. Wefind that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor alpha (TNF-alpha)-treated primary white adipocytes. TNF-alpha-mediated suppression of sGCb1 is mediated via NF-kB, whereas PKG is repressed by JNK signaling. Additionally, TNF alpha-activated JNK signaling suppresses PPAR gamma and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.