Effect of Moderate Weight Loss in Metabolically Abnormal Lean Subjects

Study Overview
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Brief Summary
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Obesity is associated with a constellation of cardiometabolic abnormalities (including insulin resistance, elevated blood pressure and dyslipidemia) that are risk factors for diabetes and cardiovascular disease. Weight loss can improve all of the cardiometabolic abnormalities associated with obesity. Up to  25% of lean people (Body Mass Index [BMI] 18.5-24.9 kg/m²) have many of the cardiometabolic abnormalities associated with obesity and are referred to as metabolically abnormal lean (MAL) people. However, the MAL phenotype is not well characterized, and it is unclear whether weight loss has beneficial metabolic effects in already lean people. Accordingly, the goal of this study is to: 1) carefully phenotype MAL people and 2) evaluate the effect of moderate (8-10%) diet-induced weight loss in MAL people. This will be investigated in 15 MAL (defined as having 2 or more of the following: intrahepatic triglyceride (IHTG) content ≥5.6%, glycated hemoglobin ≥5.7%, fasting plasma glucose concentration ≥100 mg/dl, 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≥140 mg/dl, homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 2.5) men and women. Only lean people who have a BMI ≥21.0 but <25.0 kg/m² will be asked to lose weight to avoid the risk that participants become underweight (BMI <18.5 kg/m²) during weight loss therapy.

Official Title
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Effect of Moderate Weight Loss in Metabolically Abnormal Lean Subjects

Conditions
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Weight Loss

Intervention / Treatment
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* Other: Moderate (8-10%) diet-induced weight loss


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI 21.0-24.9 kg/m² Weight stable (+/- 2% for at least 3 months before enrollment) Two or more of the following: IHTG content ≥5.6%, HOMA- IR index ≥ 2.5, HbA1C ≥ 5.7%, 2-hr OGTT plasma glucose concentration ≥ 140 mg/dl, fasting plasma glucose concentration ≥ 100 mg/dl. Exclusion Criteria: Women who are pregnant or breastfeeding Evidence of significant organ system dysfunction or disease (e.g., diabetes, chronic kidney disease, advanced heart disease, etc.) Men who consume >21 units (e.g., glass of wine or bottle of beer) of alcohol per week and women who consume >14 units of alcohol per week Use of dietary supplements or medications known to affect metabolism Eating disorder (assessed by using the Eating Disorder Examination Questionnaire [EDE-Q]) Participation in structured endurance or resistance exercise program >150 min/week Use of tobacco products Unable or unwilling to follow the study protocol or the research team believes that for any reason the volunteer is not an appropriate candidate for this study, including non-compliance with screening appointments or previous appointments/contact arrangements Individuals that take Coumadin or similar anticoagulants Use of antibiotics in last 60 days Previous bariatric surgery Cancer or cancer that has been in remission for <5 years Major psychiatric illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metabolically abnormal lean<br>Moderate (8-10%) diet-induced weight loss. | Other: Moderate (8-10%) diet-induced weight loss<br>* MAL participants will meet with the study dietitian to lose  8-10% of their body weight through diet-intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity as assessed by the hyperinsulinemic-euglycemic clamp technique | Evaluate insulin sensitivity through the hyperinsulinemic-euglycemic clamp procedure. | An average of 6-8 months from baseline testing to 8-10% weight loss | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Beta-Cell function | Administer 3 hour oral glucose tolerance test before and after weight loss to determine the effects of weight loss on beta cell function | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Change in fat mass and fat free mass as assessed by dual-energy x-ray absorptiometry (DXA) |  | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Change in intra-abdominal adipose tissue volume as assessed by magnetic resonance imagining. | Inta-abdominal adipose tissue volume will be assessed before and after weight loss to determine the effects of weight loss | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Change in plasma lipid profile as assessed by the complete metabolic panel and lipid panel. | Blood will be drawn for the complete metabolic panel and lipid panel before and after weight loss | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Change in markers of inflammation in plasma and adipose tissue as assessed from samples obtained during the hyperinsulinemic-euglycemic clamp procedure with adipose tissue biopsies | Plasma samples and adipose tissue biopsies will be obtained during the hyperinsulinemic-euglycemic clamp procedure before and after weight loss | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Change in cellular factors involved in mediating insulin action in muscle and adipose tissue as assessed by muscle and adipose tissue biopsies obtained during the hyperinsulinemic-euglycemic clamp procedure | Muscle and adipose tissue biopsy samples will be obtained during the hyperinsulinemic-euglycemic clamp procedure before and after weight loss | An average of 6-8 months from baseline testing to 8-10% weight loss | 
| Modification of gut microbiota | Monthly stool collection will be used to assess the composition of the gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota), and the meta-metabolome (metabolites made by the microbiota). | An average of 6-8 months from baseline testing to 8-10% weight loss |