Diet-dependent natriuretic peptide receptor C expression in adipose tissue is mediated by PPARγ via long-range distal enhancers

The cardiac natriuretic peptides (NPs) are well established as regulators of blood pressure and fluid volume, but they also stimulate adipocyte lipolysis and control the gene program of nonshivering thermogenesis in brown adipose tissue. The NP "clearance" receptor C (NPRC) functions to clear NPs from the circulation via peptide internalization and degradation and thus is an important regulator of NP signaling and adipocyte metabolism. It is well known that the Nprc gene is highly expressed in adipose tissue and dynamically regulated upon nutrition and environmental changes. However, the molecular basis for how Nprc gene expression is regulated is still poorly understood. Here, we identified the nuclear receptor transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) as a transcriptional regulator of Nprc expression in mouse adipocytes. During 3T3-L1 adipocyte differentiation, levels of Nprc expression increase in parallel with PPARγ induction. Rosiglitazone, a classic PPARγ agonist, increases, whereas siRNA knockdown of PPARγ reduces, Nprc expression in 3T3-L1 adipocytes. By using chromosome conformation capture and luciferase reporter assays, we demonstrate that PPARγ controls Nprc gene expression in adipocytes through its long-range distal enhancers. Furthermore, the induction of Nprc expression in adipose tissue during high-fat diet feeding is found to be associated with increased PPARγ enhancer activity. Our findings define PPARγ as a mediator of adipocyte Nprc gene expression and establish a new connection between PPARγ and the control of adipocyte NP signaling in obesity.