The goal of this project is to assess the metabolic effects of cardiac natriuretic peptides (NPs) on fat metabolism and energy expenditure. We described studies showing that mice lacking the NP 'clearance'receptor, NPRC, grow to be lean and hypermetabolic, with significant amounts of brown adipocytes within white adipose tissue depots. This phenotype is believed to be due to the lack of NP clearance from the circulation by NPRC and consequently unrestrained activation of the guanylyl cyclase-coupled 'signaling'receptor, NPRA. Humans with obesity and metabolic syndrome have reduced levels of circulating NPs and increased levels of NPRC in their adipose tissue;and it is suspected that this situation contributes to a further propensity to gain weight elevated blood pressure. In this project we will generate unique animal models in which the NPRC is selectively deleted from adipose tissue and skeletal muscle, to determine the relative contributions of these tissues to the energy expenditure of the NPRC-/- mouse. Since both receptors NPRA and NPRC are highly regulated in response to hormonal milieu, diet and activation of the sympathetic nervous system, this project will also isolate regulatory regions of the NPRA and NPRC genes in order to determine the regions of the gene that are responsible for their significant transcriptional changes that lead to altered ratios of NPRA to NPRC. NPs are inactivated relatively quickly after their secretion from the heart. They are not only 'cleared'from circulation by NPRC, but they are also degraded very quickly by neutral endopeptidase (NEP). Therefore, the third goal of our project will test a concept that modified forms of NPs containing an Fc moiety to increase circulating half-life, as well as a decreased affinity for NPRC, will be long-lived and sufficientl potent agents to both lower blood pressure and increase fat oxidation. As such, this aim is designed as an early stage, translational proof-of-concept project, from which we will gain important knowledge that may be useful in pharmaceutical development. By understanding the tissues that respond to NPs to stimulate metabolism, coupled with a better mechanistic understanding of how these receptors are regulated in these target tissues and results obtained from an early-stage 'therapeutic'effort, together this project will provide an important foundatio upon which to build future investigative work as well as clinical approaches to obesity and hypertension.
In this project we will study heart hormones called 'cardiac natriuretic peptides'(NPs). These hormones help to decrease blood pressure by acting on the kidney. The goal is to understand a different aspect of these hormones: the biological basis by which these NPs can raise metabolic rate and energy expenditure. We will study fat and muscle tissue to determine whether these tissues are the main location for this energy burning. We will also determine how the 'receptors'that respond to these hormones are regulated in fat and muscle. Finally, since these hormones break down quickly in the blood, any treatment that would use these hormones would be improved if one could find long-acting versions. We will test the idea that forms of the NPs that we create will have a long enough lifetime in the body to be able to produce a sustained and safe reduction in blood pressure as well as increased fat burning and weight loss.