Calorie Restriction, Protein Supplementation and Metabolic Health

Study Overview
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Brief Summary
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The purpose of this study is to determine whether consuming additional protein during calorie restriction induced weight loss has beneficial or harmful effects on multi-organ (liver, muscle, adipose tissue) insulin sensitivity, colonocyte proliferation rates, the gut microbiome, muscle mass and function, and bone mineral density in obese, postmenopausal women.

Official Title
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Calorie Restriction and Metabolic Health

Conditions
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Obesity, Menopause, Osteoporosis, Sarcopenia

Intervention / Treatment
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* Behavioral: Weight loss with normal protein intake
* Behavioral: Weight loss with protein supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obese with body mass index (BMI) between 30 and 50 kg/m2 Postmenopausal Sedentary (i.e., less than 1.5 hours of exercise per week) Exclusion Criteria: Individuals with diabetes and/or uncontrolled hypertension Individuals with hepatitis B and/or C Individuals who smoke Individuals with an allergy to whey protein

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Weight maintenance<br>Weight maintenance with normal protein intake | |
| Active Comparator: Weight loss with normal protein intake<br> | Behavioral: Weight loss with normal protein intake<br>* Goal of 8 to 10% weight loss while consuming the recommended daily allowance of protein (i.e, 0.8 grams of protein per kg body weight per day).<br>|
| Experimental: Weight loss with protein supplementation<br> | Behavioral: Weight loss with protein supplementation<br>* Goal of 8 to 10% weight loss while consuming 150% of the recommended daily allowance of protein (i.e., 1.2 grams of protein per kg body weight per day).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle volume | Thigh muscle volume will be measured by magnetic resonance imaging (MRI) | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 
| Change in muscle strength | Muscle strength will be evaluated by administering maximum one repetition strength and isokinetic strength tests. | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 
| Changes in bone mineral density and bone mineral content | Total bone mass and total body and regional bone mineral density will be evaluated by using dual X-ray energy absorptiometry (DXA). | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity | Insulin sensitivity (glucose rate of disappearance [Rd] during a hyperinsulinemic-euglycemic clamp procedure) will be evaluated in a subset of 10 participants per group because power analysis has determined that this number is sufficient to detect a 25% difference between groups assuming 80% power, an alpha value of 0.05 and an average baseline insulin-stimulated glucose Rd of 2,590 ± 492 µmol/min, the average ± SD insulin stimulated glucose Rd the investigators have measured during the past 20 y in obese subjects. In the investigators' experience (Kirk et al., 2009 and Magkos et al., 2016), the weight loss induced increase in insulin stimulated glucose Rd is  50%. | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 
| Change in muscle protein metabolism | Rates of muscle protein synthesis, breakdown and net protein balance will be assessed during postabsorptive conditions and when insulin and/or amino acid concentrations are elevated. | Baseline and at 5% weight loss in the calorie restriction groups and after  3 months in the weight maintenance group | 
| Change in bacterial populations found in the stool |  | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 
| Change in cell proliferation (growth) rates in the colon | Colon cell proliferation rates will be determined using stable isotope labelled tracer methods in conjunction with sigmoid colon biopsy samples | Baseline and at 10% weight loss in calorie restriction groups and  6 to 7 months in the weight maintenance group | 
| Determine the acute effect of whey protein ingestion on skeletal muscle insulin sensitivity | Insulin sensitivity will be evaluated using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope labeled tracer infusions | Prior to starting the weight loss or maintenance intervention | 
| Determine the acute effect of whey protein ingestion on muscle protein metabolism | Rates of muscle protein synthesis, breakdown and net protein balance will be assessed using stable isotope labeled tracer methods during postabsorptive conditions and during insulin infusion with or without whey protein ingestion | Prior to starting the weight loss or maintenance intervention |