Metabolic Effects of Natriuretic Peptide Hormones
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Change in Resting Energy Expenditure (EE)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
The participant and study investigators will be blinded as to which infusion the participant is receiving at which visit. Also, the individuals analyzing the energy expenditure and fat gene expression will be blinded.
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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)
排除标准
- •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)
研究组 & 干预措施
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.
干预措施: recombinant human BNP(1-32) (Drug)
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.
干预措施: placebo (control, normal saline) (Drug)
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.
干预措施: recombinant human BNP(1-32) (Drug)
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.
干预措施: placebo (control, normal saline) (Drug)
结局指标
主要结局
Change in Resting Energy Expenditure (EE)
时间窗: 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.)
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.
次要结局
- Adipose Tissue Gene Expression of Uncoupling Protein 1 (UCP1)(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.))