Metabolic Effects of Natriuretic Peptide Hormones (MENP)

Accumulating evidence suggests that the natriuretic peptide (NP) hormonal system has important effects on metabolism. However, more information is needed to better understand the effects of NPs on metabolism in humans. Therefore, the investigators propose a study to determine the effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in fat tissue suggestive of fat "beiging" in humans. Interventions that safely increase energy expenditure and promote fat "beiging" represent potential strategies for treating metabolic dysfunction due to obesity.

As of 10/23/2020: awaiting supply of study drug Objective: The natriuretic peptide (NP) hormonal system is well-known for its important role in blood pressure regulation. However, accumulating evidence suggests that the NPs have significant effects on metabolism as well. For instance, administration of B-type natriuretic peptide (BNP) to wild-type mice leads to increased energy expenditure, changes in gene expression in fat tissue suggestive of fat "beiging" (which may be associated with cardiovascular and metabolic benefits), and reduced fat accumulation. Although recent studies in rodents suggest that NPs have important metabolic effects, there are few prospective data on the metabolic effects of NPs in humans. Therefore, the investigators propose a physiologic, proof-of-concept study to determine the acute effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in adipose tissue suggestive of a "beige" fat phenotype in humans. Research Plan: The investigators propose the following research plan to address the investigators' specific aims: Primary Aim: To investigate the acute effects of administration of BNP on energy expenditure in humans. The investigators propose a randomized, placebo-controlled, cross-over study in 50 adults (25 lean and 25 obese) without significant medical problems. Subjects will be randomized to intravenous infusion of recombinant human BNP1-32 or normal saline (control), with assessment of energy expenditure and other physiologic measures. After a 7-day washout period, subjects will then undergo the other intervention. Secondary Aim: To determine the acute effects of BNP on gene expression in white adipose tissue in humans. The investigators will assess markers suggestive of fat beiging in subcutaneous white adipose tissue biopsies after BNP infusion vs. control. This secondary aim will allow us to explore potential mechanisms underlying the hypothesized changes in energy expenditure. Methods: In this cross-over study, each subject will receive BNP infusion at one visit and control at the other visit, in random order. The sequence of the treatments will be randomized. There will be a washout period (at least 14 days) between visits. Subjects will be stratified by BMI category (lean or obese). To address the Primary Aim, energy expenditure will be assessed via indirect calorimetry (metabolic cart). To address the Secondary Aim, subcutaneous fat biopsies will be performed, and tissue will be analyzed for gene expression of markers suggestive of fat beiging. Clinical Relevance: This study will generate novel human data regarding the effects of the NPs on energy metabolism and adipose tissue. Interventions that safely increase energy expenditure and promote a beige fat phenotype represent potential strategies for treating obesity-associated metabolic dysfunction. The overarching scientific goals of this line of investigation are (1) to elucidate the role of the natriuretic peptide system in cardiometabolic health in humans, and (2) to investigate the potential for NP directed therapies in obesity-associated cardiometabolic dysfunction.

In this cross-over study, each subject will receive BNP infusion at one visit and control at the other visit, in random order. The sequence of the treatments will be randomized. There will be a washout period (at least 14 days) between visits. Subjects will be stratified by BMI category (lean or obese).

The participant will be blinded as to which infusion they are receiving at which visit. Also, the individuals analyzing fat gene expression will be blinded.

Subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes.

Subjects will receive an IV infusion of normal saline for 240 minutes. The volume of saline delivered will be equivalent to the volume of saline that the subject receives during the BNP infusion visit.

Subjects will receive an IV infusion of recombinant human BNP1-32 (6 mcg BNP/ml saline) for 240 minutes.

At each visit (Study Visits 1 and 2), energy expenditure will be determined by indirect calorimetry, using a metabolic cart. Energy expenditure will be measured at baseline and during the 240-minute intravenous infusion at Study Visits 1 and 2. The primary endpoint will be change in energy expenditure, calculated as final resting energy expenditure (at end of 240-minute infusion) adjusted for baseline value.

Through study completion, an average of approximately 1 month. At each study visit, EE will be assessed at baseline and at end of 240-minute intravenous infusion.

After the conclusion of the study infusion (Minute 240) at study visits 1 and 2, subcutaneous adipose tissue biopsies will be obtained and analyzed for adipose tissue gene expression. The adipose tissue gene expression after the BNP infusion will be compared to expression after the placebo infusion. Subjects will be stratified by BMI category (lean or obese).

Inclusion Criteria: Men and women ages 18-40 years Body Mass Index (BMI): 18.5 BMI<25 kg/m2 (lean) or BMI > or = 30 kg/m2 (obese) Exclusion Criteria: Significant cardiovascular disease (including heart failure and atrial fibrillation) Significant pulmonary, liver, or renal disease Diabetes Mellitus Significant Hypertension Hypotension Thyroid dysfunction Active malignancy Current or recent use of glucocorticoids Current use of antihypertensive medications, including diuretics Current use of medications affecting glucose metabolism, including metformin Current use of amphetamines or other medications known to affect energy homeostasis Currently pregnant or breastfeeding, or unwilling to avoid becoming pregnant or breastfeeding during study duration Significant claustrophobia that would prevent the use of the metabolic cart as part of the study protocol Currently abnormal serum or plasma sodium or potassium level Known hypersensitivity to recombinant human b-type natriuretic peptide, BNP(1-32) (nesiritide), or phenylephrine Hemoglobin A1c (HbA1c) >= 6.5% Liver Function Tests (LFTs) elevated >2x upper limit of normal Estimated Glomerular Filtration Rate (eGFR) <60 ml/min Currently abnormal thyroid stimulating hormone (TSH)

Individual enrolled subjects will not receive any of their unique study data. IPD (in a de-identified, anonymized format) underlying publications from this research will be shared publicly.