The influence of cardiac natriuretic peptides on the browning of adipose tissue

Abstract

Brown adipose tissue (BAT) evolved as a molecular mechanism for generating heat from stored metabolic products, i. e. carbohydrates and lipids. Brown adipocytes are highly enriched in mitochondria and express a unique protein called uncoupling protein-1 (UCP1) The brown fat humans is significantly correlated with reduced percent body fat, lower incidence of Type II diabetes, and greater insulin sensitivity. It was recently described that the cardiac hormones ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) stimulate a similar 'browning' of human and mouse adipocytes. Increases in circulating NPs have also been associated with increased post-prandial fat oxidation in humans. The release of NPs due to increased cardiac output with exercise also suggests that the heart has a central role in regulating the supply of fatty acids for both cardiac and skeletal muscle under aerobic conditions. The ability of NPs to stimulate adipocyte metabolism critically depends on the ratio of NPRA to NPRC. In healthy humans, ANP has been shown to increase during and immediately following exercise. These data help to understand the mechanisms of enhancement of the adipose tissue lipolitical capacity and browning usually seen in individuals under physical training. The ability of NPs to stimulate adipocyte metabolism critically depends on the ratio of NPRA to NPRC, which is influenced by nutritional and hormonal status. Evidence from clinical studies show that obese individuals have lower circulating levels of BNPs, increased NPRC levels in adipose tissue, and blunted lipolytic responses to NPs compared to lean individuals. In contrast, fasting improves the NPRA:NPRC ratio. So, we propose three specific aims.(1) Nprc-/- mice grow to be lean and hypermetabolic with significant UCP1-expressing adipocytes in their fat depots, and possibly increased fatty acid oxidation in muscle. However, these mice also exhibit a severe skeletal overgrowth phenotype. We have generated mice with floxed Nprc alleles in order to create mice with tissue-specific deletions of NPRC in adipose and skeletal muscle. Studies in vivo and in vitro will determine the relative contributions of each tissue to the energy expenditure phenotype.(2) The ability of NPs to stimulate metabolism depends on the ratio of NPRA to NPRC. We will (i) determine the transcriptional regulation of the NPRA and NPRC genes using a combination of complementary approaches including reporter gene assays and ChIP Seq. We will also (ii) test the hypothesis that increases in NPRC interfere with NPRA signaling due to the formation of heterodimers between the highly similar NPRA and NPRC proteins, which will lack a functional GC domain for cGMP production.(3) ANP and BNP have a half-life of 5-20 minutes. This aim will test a preclinical concept that novel ANP-Fc fusion proteins, including an NPRA-selective form of ANP, will show sustained efficacy in vivo. Using our unique animal models from Aim 1, blood pressure, energy expenditure, and tissue analyses will be performed. (AU)