Diet-dependent Natriuretic Peptide Receptor C expression in adipose tissue is mediated by PPARγ via long-range distal enhancers

In addition to their established role to maintain blood pressure and fluid volume, the cardiac natriuretic peptides (NPs) can stimulate adipocyte lipolysis and control the brown fat gene program of nonshivering thermogenesis. 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 appreciated that the Nprc gene is highly expressed in adipose tissue and is dynamically regulated with nutrition and environmental changes. However, the molecular basis for how Nprc gene expression is regulated is still poorly understood. Here we identified Peroxisome Proliferator-Activated Receptor gamma (PPAR{gamma}) as a transcriptional regulator of Nprc expression in mouse adipocytes. During 3T3-L1 adipocyte differentiation, levels of Nprc expression increase in parallel with PPAR{gamma} induction. Rosiglitazone, a classic PPAR{gamma} agonist, increases, while siRNA knockdown of PPAR{gamma} reduces, Nprc expression in 3T3-L1 adipocytes. We demonstrate that PPAR{gamma} 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 associated with increased PPAR{gamma} enhancer activity. Our findings define PPAR{gamma} as a mediator of adipocyte Nprc gene expression and establish a new connection between PPAR{gamma} and the control of adipocyte NP signaling in obesity.