Obesity and obesity-related cardiovascular and metabolic (“cardiometabolic”) diseases, including diabetes, insulin resistance, hypertension, and dyslipidemia, are leading causes of morbidity and mortality in veterans. The fact that obesity and its complications persist as major public health problems despite current available therapies indicates that obesity is a multifactorial disease, and highlights the need for additional approaches to treat obesity and obesity-related illnesses. The cardiac natriuretic peptide (NP) hormonal system is well-known for its important role in the regulation of blood pressure and volume status. There is accumulating evidence that the NP hormonal system may protect against the development of cardiometabolic risk, and that the NP system exerts important effects on metabolism. Recent studies in animals demonstrate that the NPs promote increases in energy expenditure and in thermogenic gene expression in white adipose tissue (the “beiging” of white adipose tissue). Although recent studies in rodents suggest that NPs may have important metabolic effects, there are few prospective data on the metabolic effects of NPs in humans. The overall hypothesis of the proposed research is that the administration of NPs in humans will cause increases in energy expenditure and promote the changes in gene expression in adipose tissue suggestive of the “beiging” of white fat. This application proposes a physiologic study in humans with the use of a prospective, randomized, cross-over, placebo-controlled design in 50 adults (25 lean and 25 obese) without significant medical problems. Subjects will undergo 2 interventions (in random order, separated by a 7-day washout period): an intravenous infusion of (1) BNP1-32 and (2) normal saline (control). Aim 1 tests the hypothesis that the acute administration of human B-type natriuretic peptide 1-32 (BNP1-32) increases energy expenditure in humans. In Aim 2, the acute effects of BNP1-32 on gene expression in white adipose tissue in humans will be determined. This physiologic study will provide novel insight into the effects of the NP system on energy metabolism and the development of a “beige” fat phenotype in humans. The long-term research goal is to elucidate the possible role of the NP system as a therapeutic target for obesity and obesity-associated cardiometabolic risk. Strategies that safely increase energy expenditure and/or promote the “beiging” of white adipose tissue could represent an effective treatment of obesity and obesity-associated metabolic dysfunction. Characterizing the metabolic effects of the NPs in the present study has the potential to inform future studies aimed at assessing the NP system as a target for the treatment of obesity and obesity-associated metabolic dysfunction. Thus, the overall research goal has tremendous relevance to the veteran population. Importantly, the proposed project is an essential component of a comprehensive career development program for a ...