DNA Methylation and Vascular Function

Sponsor

University of Illinois at Chicago (Other)

Overall Status

Recruiting

CT.gov ID

NCT03527420

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Location

Arms

34.7

Anticipated Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main objective is to examine DNA hypomethylation as an underlying mechanism for the increased production of inflammatory cytokines and the impaired vascular function in obese individuals and as a potential target for nonpharmacological preventive/therapeutic interventions such as aerobic exercise.

Condition or Disease	Intervention/Treatment	Phase
Obesity Vascular Dysfunction	Other: Exercise training	N/A

Detailed Description

The long-term goal of this study is to identify valid targets and strategies for the prevention and treatment of obesity-related cardiovascular disease. Obesity is characterized by a large accumulation of fat tissues that secrete numerous inflammatory mediators (called adipocytokines), generating a systemic inflammatory state. These adipocytokines induce vascular dysfunction which is the initial step towards developing cardiovascular disease. Obesity is affected by environmental factors such as diet and physical activity. These factors induce epigenetic changes, which are changes that affect gene expression without altering the DNA sequence. One of these epigenetic modifications is the reduction in DNA methylation (referred to as hypomethylation) resulting in subsequent increases in gene expression. Preliminary data of the current study showed that the extracted DNA from fat tissues of obese subjects is hypomethylated compared to non-obese controls. DNA hypomethylation correlated significantly with higher expression of adipocytokines and impaired vasodilation in obese subjects. Therefore, the main hypothesis in this study is that the increase in adipocytokine expression in obese adults is mediated by DNA hypomethylation and that DNA hypomethylation is a promising target to prevent obesity-associated inflammation and vascular dysfunction. The flexible modifiable nature of DNA methylation makes it a perfect target for lifestyle interventions such as physical activity and weight loss. Thus, the investigators propose that aerobic exercise training and weight loss following Bariatric surgery will reverse DNA hypomethylation and improve vascular function in obese subjects. This hypothesis will be tested by (1) Investigating abnormal DNA methylation patterns of adipocytokines in fat tissues from obese adults between the age of 18 and 50 compared to non-obese subjects; (2) Test the effectiveness of 12-week aerobic exercise training on reversing DNA hypomethylation and improving vascular function in obese adults; and (3) Examine the effectiveness of weight loss surgery on DNA methylation and vascular function. The proposed studies will improve the understanding of the epigenetic underpinning of obesity-related vascular dysfunction, identify novel therapeutic targets for improving vascular function in obese adults, and provide an evidence for the positive effects of aerobic exercise training and weight loss on the prevention and treatment of obesity-associated cardiovascular disease. These studies will have a positive impact on improving the prevention and therapeutic management of obesity-related cardiovascular morbidities that affect millions of people worldwide.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

DNA Methylation and Vascular Function in Obesity: Role of Exercise and Weight Loss

Actual Study Start Date :

Oct 11, 2019

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Exercising 12 weeks of aerobic exercise training	Other: Exercise training Twelve weeks of aerobic exercise training
No Intervention: Non-exercising standard of care

Arm

Intervention/Treatment

Active Comparator: Exercising

12 weeks of aerobic exercise training

Other: Exercise training

Twelve weeks of aerobic exercise training

No Intervention: Non-exercising

standard of care

Outcome Measures

Primary Outcome Measures

DNA methylation status of adipocytokines in obese individuals [Month 24-30]
DNA methylation of 20 preselected adipocytokines using "Amplicon sequencing-based methylation profiling" will be measured in fat tissue collected from obese individuals who are scheduled for bariatric surgery before and after 12 weeks of aerobic exercise training.

Secondary Outcome Measures

Vascular health biomarkers in obese individuals before and after exercise training [Month 24-30]
Serum or plasma levels (pg/ml) of biomarkers of vascular function such as endothelin-1, cyclic guanosine monophosphate (cGMP), and endothelial cell adhesion molecules (soluble intracellular adhesion molecules, soluble vascular cell adhesion molecules, soluble platelet and endothelial cell adhesion molecules, soluble E-selectin, and soluble P-selectin).
Flow induced dilation [Month 1-20]
Measuring reactivity of brachial artery and isolated arterioles from adipose tissues

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

BMI ≥ 35 kg/m2
Between ages 18-50 years
Not pregnant
Approved for a bariatric surgery

Exclusion Criteria:

To avoid confounding from other inflammatory conditions individuals with current cancer, heart, kidney or liver disease, gallbladder disease or acute or chronic inflammatory diseases (including rheumatoid arthritis, lupus and other autoimmune diseases and genetic diseases) will be excluded
Pregnant women will be excluded, as they will not be eligible for bariatric surgery
Current smokers
Currently abusing alcohol or drugs