Nitric Oxide Mobilizes Intracellular Zn(2+) via the GC/cGMP/PKG Signaling Pathway and Stimulates Adipocyte Differentiation

Plasma and tissue zinc ion levels are associated with the development of obesity. Previous studies have suggested that zinc ions may regulate adipocyte metabolism and that nitric oxide (NO) plays a pivotal role in the regulation of adipocyte physiology. Our previous study showed that chronic NO deficiency causes a significant decrease in adipose tissue mass in rats. Studies also suggested that zinc ions play an important modulatory role in regulating NO function. This study aims to explore the role of zinc ions in NO-regulated adipocyte differentiation. We hypothesized that NO could increase intracellular Zn(2+) level and then stimulate adipocyte differentiation. ZnCl(2) and the NO donor, NONOate, were used to explore the effects of Zn(2+) and NO on adipocyte differentiation. Regulatory mechanisms of NO on intracellular Zn(2+) mobilization were determined by detection. Then, Zn(2+)-selective chelator TPEN was used to clarify the role of intracellular Zn(2+) on NO-regulated adipocyte differentiation. Furthermore, the relationship between adipocyte size, Zn(2+) level, and NOS expression in human subcutaneous fat tissue was elucidated. Results showed that both ZnCl(2) and NO stimulated adipocyte differentiation in a dose-dependent manner. NO stimulated intracellular Zn(2+) mobilization in adipocytes through the guanylate cyclase (GC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, and NO-stimulated adipocyte differentiation was Zn(2+)-dependent. In human subcutaneous adipose tissue, adipocyte size was negatively correlated with expression of eNOS. In conclusion, NO treatment stimulates intracellular Zn(2+) mobilization through the GC/cGMP/PKG pathway, subsequently stimulating adipocyte differentiation.