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.

Study Overview

• Status: Terminated
• Conditions: Obesity; Metabolism; Cardiovascular Physiological Phenomena
• Intervention / Treatment: Drug: recombinant human BNP(1-32); Drug: placebo (control, normal saline)

Detailed Description

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 BNP(1-32) 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.

Update about Study Drug Supply Issues: The study started in 7/2018, and the last time participants were able to receive study drug was in May 2019, due to discontinuation of study drug by the drug manufacturer (nesiritide, Natrecor, Scios, LLC) after May 2019. Another potential source of drug supply was being sought out by the study team, and study recruitment was placed on hold during the search for new potential sources of study drug. A new viable source of study drug has not been identified, and funding is being closed. Thus, this study is being terminated. Results will be posted for the 5 participants who were able to complete the study procedures prior to the discontinuation of study drug.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37212-2637
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BNP, then placebo; At Study Visit 1, subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of placebo (control, normal saline) for 240 minutes.	Drug: recombinant human BNP(1-32); Subjects will receive an IV infusion of recombinant human BNP(1-32) for 240 minutes at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg.; Other Names: Natrecor; nesiritide; Drug: placebo (control, normal saline); Subjects will receive an IV infusion of placebo (normal saline) at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg.
Experimental: Placebo, then BNP; At Study Visit 1, subjects will receive an IV infusion of placebo (control, normal saline) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes.	Drug: recombinant human BNP(1-32); Subjects will receive an IV infusion of recombinant human BNP(1-32) for 240 minutes at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg.; Other Names: Natrecor; nesiritide; Drug: placebo (control, normal saline); Subjects will receive an IV infusion of placebo (normal saline) at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Resting Energy Expenditure (EE)	At each visit (Study Visits 1 and 2), resting energy expenditure (EE) will be determined by indirect calorimetry, using a metabolic cart. Energy expenditure will be measured at baseline (just prior to the infusion) and during the 240-minute intravenous infusion at Study Visits 1 and 2. The primary endpoint will be change in resting energy expenditure, calculated as final resting energy expenditure (at end of 240-minute infusion) adjusted for baseline value.	At baseline and at end of 240-minute IV infusion (at each study visit). (At Study Visit 1 and 2, EE will be assessed at baseline and at end of 240-minute intravenous infusion. Visits will be separated by at least 14 days.)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipose Tissue Gene Expression of Uncoupling Protein 1 (UCP1)	Subcutaneous adipose tissue biopsies will be obtained after the conclusion of the 240-minute IV infusion at Study Visits 1 and 2. These tissues will be analyzed for adipose tissue gene expression. The adipose tissue gene expression after the BNP infusion will be compared to expression after the placebo infusion. Units are relative UCP1 gene expression (quantified using quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR)), normalized to a housekeeping gene).	A subcutaneous biopsy will be collected after the end of 240-minute IV infusion, at both Study Visits 1 and 2 (Visits will be separated by at least 14 days.)

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Talat A Ikizler, MD, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: December 20, 2017
• First Submitted That Met QC Criteria: January 5, 2018
• First Posted (Actual): January 12, 2018

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: obesity; metabolism; Energy Metabolism; Cardiovascular Physiological Phenomena
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Physiological Effects of Drugs; Natriuretic Agents; Natriuretic Peptide, Brain
• Other Study ID Numbers: ENDA-025-17S; CX001678 (Other Grant/Funding Number: VA CSR&D)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Relevant IPA underlying a publication will be available within 6 months after publication date
• IPD Sharing Access Criteria: Data requests will be evaluated for appropriateness and relevance.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No