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 promising junior investigator whose overarching career goal is to improve the health of veterans by reducing morbidity and mortality caused by obesity-associated cardiometabolic dysfunction. Carrying out the study, under an expert mentoring team including 3 VA MERIT funded physician-scientists, will help the candidate develop valuable skills, including experience in conducting randomized clinical studies and a thorough understanding of the natriuretic peptide system and energy metabolism. These skills will enable this junior physician-scientist to become a VA MERIT funded clinical investigator with a robust research program focused on improving the understanding of the pathogenesis of obesity-associated cardiometabolic dysfunction and at identifying novel pathways to treat these diseases.
Obesity is a major risk factor for cardiovascular disease and metabolic disorders, including diabetes, insulin resistance, hypertension, and hyperlipidemia. Obesity and obesity-associated cardiometabolic complications are leading causes of morbidity and mortality in the veteran population and across the U.S. population. The cardiac natriuretic peptide (NP) hormonal system may protect against the development of cardiometabolic risk. In addition, recent studies demonstrate that the NP system has important effects on metabolism, including on energy homeostasis and adipose tissue metabolism, in animals. However, prospective studies determining the metabolic effects in humans are limited. The proposed innovative study will determine the effects of natriuretic peptides on energy expenditure and on adipose tissue in humans. Defining the metabolic effects of NPs may inform future trials aimed at determining the utility of the NP system as a potential therapeutic target for obesity and obesity-associated cardiometabolic dysfunction.