Angiotensin-(1-7) and Energy Expenditure in Human Obesity

Study Overview
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Brief Summary
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The objective of this study is to better define the role of the hormone angiotensin-(1-7) in energy balance. We will test the overall hypothesis that angiotensin-(1-7) increases resting energy expenditure and promotes markers of heat production (thermogenesis) in white adipose tissue in human obesity.

Detailed Description
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Angiotensin-(1-7) is a beneficial hormone of the renin-angiotensin system known to produce positive cardiovascular and metabolic effects in animal models. In this study, the investigators will determine if angiotensin-(1-7) can increase resting energy expenditure and promote white adipose tissue heat production (thermogenesis) in obese human subjects. The investigators will perform a randomized, double-blind, two-arm parallel group study to determine effects of acute intravenous angiotensin-(1-7) versus saline infusion on resting energy expenditure measured by indirect calorimetry in obese human participants. In addition, blood pressure and heart rate will be measured and blood samples obtained to measure for changes in circulating renin-angiotensin system and metabolic hormones. Abdominal subcutaneous white adipose biopsies will also be obtained from obese human participants during acute angiotensin-(1-7) versus saline infusions to examine for changes in gene expression for markers of thermogenesis. The findings from these studies will advance understanding of hormonal mechanisms involved in the etiology of obesity, and provide new insight into the potential for targeting angiotensin-(1-7) to improve energy balance in human obesity.

Official Title
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Angiotensin-(1-7) and Energy Expenditure in Human Obesity

Conditions
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Obesity

Intervention / Treatment
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* Drug: Angiotensin-(1-7)
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women of all races Capable of giving informed consent Age 18-60 years Body mass index (BMI) between 30-40 kg/m2 Satisfactory history and physical exam Exclusion Criteria: Age ≤ 17 or ≥ 61 years Pregnant, nursing, or postmenopausal women Decisional impairment Prisoners Alcohol or drug abuse Current smokers Highly trained athletes Claustrophobia Subjects with >5% weight change in the past 3 months Evidence of type I or type II diabetes (fasting glucose > 126 mg/dL or use of anti-diabetic medications) History of serious cardiovascular disease other than hypertension (e.g. myocardial infarction within 6 months, symptomatic coronary artery disease, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke, transient Ischemic attack). History or presence of immunological or hematological disorders Impaired hepatic function (aspartate aminotransferase or alanine aminotransferase levels >2 times upper limit of normal range) Impaired renal function (serum creatinine >2.0 mg/dl) Anemia Treatment with anticoagulants (e.g. warfarin) Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month) Treatment with medications influencing energy expenditure (e.g. psychostimulants) Treatment with any investigational drug in the 1-month preceding the study Inability to give, or withdraw, informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Angiotensin-(1-7)<br>Subjects will receive intravenous infusion of three ascending doses of angiotensin-(1-7). The doses are: 2, 4, and 8 ng/kg/min. Each dose will be maintained for 10 minutes, with the highest dose maintained for an additional 90 minutes. The total infusion period is 120 minutes. | Drug: Angiotensin-(1-7)<br>* This is a biologically active beneficial hormone of the renin-angiotensin system.<br>* Other names: Angiotensin I/II (1-7) Acetate;|
| Placebo Comparator: Placebo<br>Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7). The total infusion period is 120 minutes. | Drug: Saline<br>* Saline will be used as the placebo comparator.<br>* Other names: normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting energy expenditure | Change in resting energy expenditure measured by indirect calorimetry at baseline and at end of angiotensin-(1-7) versus saline infusion. | 120 minutes | 
| Uncoupling protein 1 | White adipose tissue biopsies will be taken at end of angiotensin-(1-7) versus saline infusion to assess gene expression of the heat producing (thermogenic) marker uncoupling protein 1. | 120 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure | Change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion | 120 minutes | 
| Heart rate | Change in heart rate following angiotensin-(1-7) versus saline infusion | 120 minutes |