Metabolic Effects of Natriuretic Peptide Hormones

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.

Inclusion Criteria:

- Men and women ages 18-40 years

- Body Mass Index (BMI): 18.5 BMI<25 kg/m2 (lean) or BMI 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)