Metabolic Fuels Study

Study Overview
=================
Brief Summary
-----------------
This study will evaluate a potential physiologic mechanism underlying the effects of dietary composition on control of body weight

Detailed Description
-----------------
The challenge in maintaining long-term weight loss is well known, however new research suggests diet quality may be the driving factor. A pilot study from our group demonstrated that a higher carbohydrate-containing diet was associated with lower total energy expenditure during weight loss maintenance (Ebbeling et al). These findings will be confirmed in the ongoing Framingham State Food Study (NCT02068885): Following weight loss on a standard diet, 150 overweight or obese adults (aged 18 to 65 years) will be randomized to one of three weight-loss maintenance diets varying in carbohydrate to fat ratios for 20 weeks. However, the specific mechanisms underlying the calorie-independent effects of diet remain unclear. Another study from our group demonstrated lower energy availability (calculated based on caloric content of circulating metabolic fuel concentrations) in the fasting and late post-prandial periods in 8 overweight or obese young adults who were maintained on a low-fat (high-carbohydrate) diet (Walsh et al). We hypothesize that this lower metabolic fuel availability on a high carbohydrate diet results in part from increased anabolic changes within the adipocyte, favoring fat storage in preference to oxidation. We will invite subjects already enrolled in the Framingham State Food Study to participate, aiming for a total of 30 subjects (with the goal of approximately equal numbers per diet group following randomization to assigned test diet in the parent study). Participants will be admitted to a research unit for a 24-hour period during weight maintenance on the test diet, during which they will undergo frequent blood sampling for the measurement of circulating metabolic fuels, hunger and satiety ratings, while consuming their assigned diet meals. Each participant will also undergo two abdominal subcutaneous fat aspiration biopsies under local anesthesia, the first immediately following weight loss (before initiating the test diet) and the second during weight maintenance, in order to perform gene expression analyses on the adipose tissue. Our main outcomes will be a comparison in energy availability (the sum of energy in the major metabolic fuels in the blood) between diet groups in the late postprandial period and changes in adipose tissue gene expression within-individuals and by diet group assignment. Other outcomes will include differences in hunger and satiety ratings, total 24-hour energy availability, and specific metabolic fuel concentrations.

Official Title
-----------------
A Mechanistic Examination of Dietary Composition on Metabolic Fuels Availability

Conditions
-----------------
Obesity

Intervention / Treatment
-----------------
* Behavioral: Low carbohydrate diet
* Behavioral: Moderate carbohydrate diet
* Behavioral: High carbohydrate diet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Inclusion Criteria (as detailed in Framingham State Food Study, NCT02068885) Aged 18 to 65 years BMI ≥ 25 kg/m2 BMI < 40 kg/m2 and weight ≤ 300 lbs (136 kg) Medical clearance from a primary care provider Student or employee at Framingham State University throughout enrollment in the study Willing and able to eat and drink only the foods and beverages on the study menus Willing to eat in the dining hall Willing to abstain from consuming alcohol during participation Additional Inclusion Criteria: • Willing to undergo additional procedures in this ancillary study Exclusion Criteria: Exclusion Criteria (as detailed in Framingham State Food Study, NCT02068885) Change in body weight exceeding ±10% during prior year Recent adherence to a special diet Recent adherence to a vigorous physical activity regimen (e.g., participation in a varsity sport) Chronic use of any medication or dietary supplement that could affect study outcomes Current smoking (1 cigarette in the last week) Heavy baseline alcohol consumption or history of binge drinking Physician diagnosis of a major medical/psychiatric illness or eating disorder Abnormal blood glucose, TSH, CBC, BUN, Creatinine ALT greater than 150% of the normal upper limit Plans for a vacation during the study that would preclude adherence to prescribed diet Additional exclusions for female participants: Irregular menstrual cycles; any change in birth control medication during the 3 months prior to enrollment; pregnancy or lactation during the 12 months prior to enrollment Additional Exclusion Criteria: Allergy or prior reaction to Lidocaine Medical condition or medication that would increase risk of bleeding, infection or skin reactions

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low carbohydrate diet<br> | Behavioral: Low carbohydrate diet<br>* Composition (by proportion of calories) : 15% carbohydrate, 65% fat, 20% protein<br>* Other names: Composition : 15% carbohydrate, 65% fat, 20% protein;|
| Active Comparator: Moderate carbohydrate diet<br> | Behavioral: Moderate carbohydrate diet<br>* Feeding study. Composition (by proportion of calories): 40% carbohydrate, 40% fat, 20% protein<br>|
| Active Comparator: High carbohydrate diet<br> | Behavioral: High carbohydrate diet<br>* Feeding study. Composition (by proportion of calories): 60% carbohydrate, 20% fat, 20% protein<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Late postprandial energy availability | Post-prandial energy availability calculated as the sum, in kcal/L, of energy from circulating metabolic fuels (glucose, non-esterified fatty acids, lactate and ketoacids), as measured during a 24 hr inpatient admission. Time of interest includes 2.5 - 5 hr in the postprandial period after breakfast, lunch and dinner. | 10 - 15 weeks after initiation of test diets | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Late postprandial energy availability, with lactate excluded | Post-prandial energy availability calculated as the sum, in kcal/L, of energy from circulating metabolic fuels (glucose, non-esterified fatty acids, and ketoacids), as measured during a 24 hr inpatient admission. Time of interest includes 2.5 - 5 hr in the postprandial period after breakfast, lunch and dinner. (Lactate is metabolized primarily by the liver, which uses this substrate to produce glucose. Thus, including lactate in the calculation of metabolic fuels may comprise double counting -- and not accurately reflect actual fuel availability to body tissues) | 10 - 15 weeks after initiation of test diets | 
| Fasting energy availability | Fasting energy availability calculated as the sum, in kcal/L, of energy from circulating metabolic fuels (glucose, non-esterified fatty acids, lactate and ketoacids), as measured during a 24 hr inpatient admission. | 10 - 15 weeks after initiation of test diet | 
| Total energy availability | Total energy availability calculated as the sum, in kcal/L, of energy from circulating metabolic fuels (glucose, non-esterified fatty acids, lactate and ketoacids), as measured during a 24 hr inpatient admission. | 10 - 15 weeks after initiation of test diets | 
| Hunger | Measured during a 24 hr inpatient admission. | 10 - 15 weeks after initiation of test diets | 
| Satiety | Measured during a 24 hr inpatient admission. | 10 - 15 weeks after initiation of test diets | 
| Glucose | Concentration during 24-hr inpatient admission | 10 - 15 weeks after initiation of test diets | 
| Non-esterified fatty acids | Concentration during 24-hr inpatient admission | 10 - 15 weeks after initiation after test diet | 
| Lactate | Concentration during 24-hr inpatient admission | 10 - 15 weeks after initiation of test diets | 
| Ketoacids | Concentration during 24-hr inpatient admission | 10 - 15 weeks after initiation of test diets | 
| Insulin | Concentration during 24-hr inpatient admission | 10 - 15 weeks after initiation of test diets |