Effects of Macronutrient Diet on Brain Activity

Study Overview
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Brief Summary
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This study will evaluate the effect of macronutrient diets on brain activity in homeostatic and mesolimbic reward regions.

Detailed Description
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A question critical to the field of obesity is what causes overweight and obese individuals to overeat? One common explanation holds that weight gain at the population-level is caused by increases in the widespread availability of highly palatable foods. An alternative explanation is that the biological effects of the modern diet produce effects in the central nervous system and periphery that augment homeostatic and hedonic hunger. Reducing glycemic load preferentially maintains total energy expenditure during weight-loss maintenance (Ebbeling et al., 2012), and this group of investigators previously showed that in the late postprandial period, a nutrient-controlled high glycemic load vs. low glycemic load meal increases resting regional cerebral blood flow in the nucleus accumbens (Lennerz et al., 2013), part of the mesoaccumbal reward circuitry implicated in craving and addiction. However, the effects of macronutrient composition on blood flow to and activity in homeostatic and reward-related brain regions cannot be fully ascertained from studies of acute ingestion of a single macronutrient, because these do not generalize to mixed-nutrient meals consumed as part of typical American diets. Further, retrospective designs that rely on participant report of frequency of recent macronutrient ingestion and prospective designs with limited duration of diet prescription cannot address the critical question of the long-term, cumulative effects of dietary composition on brain function. Therefore, the investigators propose an approach to identifying brain responses to randomized, mixed-meal diets of varying macronutrient composition during long-term weight-loss maintenance on these diets, using arterial spin labeling (ASL) for regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD)-based functional connectivity. To explore these outcomes, the investigators will partner with 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. Investigators will invite subjects already enrolled in the Framingham State Food Study to participate with a goal of enrolling 75 subjects (aiming to be equally divided per diet group following randomization to assigned test diet in the parent study). Participants will complete 1 morning visit to the MRI imaging center at Brigham and Women's Hospital approximately 14-20 weeks into the weight maintenance test diet phase. During the visit, they will undergo a fasting baseline brain imaging session, consume their assigned diet breakfast meal, and undergo a late postprandial brain imaging session. Participants will additionally provide frequent ratings of their food cravings, mood, and anxiety level throughout the visit. The main outcomes will be resting blood flow to the nucleus accumbens and connected striatal regions in the late postprandial period, with additional secondary and other outcomes including blood flow to the hypothalamus and connectivity between the hypothalamus during the late postprandial period.

Official Title
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Effects of Macronutrient Diet Composition on Brain Reward Activity

Conditions
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Obesity

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 55 years BMI ≥ 23 kg/m2 BMI < 45 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 Community-based participants from the greater Framingham and Assabet Valley communities 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: Body circumference of <64 in Willingness to undergo 2, 30-minute MRI scans 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: Previous bariatric surgery Other contraindications to MRI scanning (severe claustrophobia/extensive orthopedic hardware/pacemaker, cerebral aneurysm clip)

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: 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>* Feeding study. Composition (by proportion of calories): 20% carbohydrate, 60% fat, 20% protein<br>|
| 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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood flow to the nucleus accumbens and connected striatal regions | Regional cerebral blood flow (rCBF) measured using arterial spin labeling (ASL) at rest, in neuroanatomically-defined a priori regions (nucleus accumbens, caudate, putamen). | 14-20 weeks after initiation of test diet | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood flow to the hypothalamus | Regional cerebral blood flow (rCBF) measured using arterial spin labeling (ASL) at rest, in neuroanatomically-defined a priori regions (hypothalamus). | 14-20 weeks after initiation of test diet | 
| Functional connectivity between the hypothalamus and nucleus accumbens | Blood-oxygen-level-dependent (BOLD) fMRI connectivity between neuroanatomically-defined regions of interest (hypothalamus, nucleus accumbens), measured during rest. | 14-20 weeks after initiation of test diet |