Obesity
Conditions
Keywords
Obesity, Weight Loss, Carbohydrate, Fat, Macronutrient Balance, Healthy Volunteer
Brief summary
Popular weight loss strategies often involve reducing an individual's consumption of carbohydrates or fat. However, no controlled study has been carried out to evaluate the effects of reducing carbohydrate versus fat consumption while keeping the other nutrients at standard levels to maintain an individual's weight. Researchers are interested in investigating how different restrictions of carbohydrates or fats affect the many processes involved in weight loss, including brain activity and blood and brain chemical composition.
Detailed description
Popular weight loss strategies often prescribe a targeted reduction of dietary carbohydrate or fat. But surprisingly, no controlled human feeding study has ever investigated the effects of a selective reduction of dietary carbohydrate versus fat while keeping the other dietary macronutrients at their baseline weight-maintenance values. The present study was designed to address this knowledge gap and improve our understanding of how selective reduction of dietary fat versus carbohydrate may differentially impact the many feedback control processes that act to resist weight loss. Objectives: \- To determine the comparative effects of two controlled fat- or carbohydrate-restricted diets and an outpatient weight loss program on blood and brain chemical composition, weight loss (fat and lean body mass), and regional brain activity in lean and obese individuals. Eligibility: \- Healthy individuals between 18 and 45 years of age who are either lean (body mass index between 18.5 kg/m(2) and 25 kg/m(2)) or obese (body mass index above 30.0 kg/m(2), weight less than 350 pounds) and are right-handed. Design: * Lean participants: Participants will be screened with a medical history, physical examination, blood and urine tests, and weight maintenance observations (food diaries and physical activity monitors). For the scanning visit, participants will receive balanced meals from the National Institutes of Health to consume for 2 days before the visit. During the scanning visit, participants will continue to eat the weight maintenance diet, complete questionnaires, and have a series of imaging studies (including positron emission tomography and magnetic resonance imaging tests) to evaluate brain response to food and other stimuli. * Obese participants: Participants will be screened with a medical history, physical examination, blood and urine tests, and weight maintenance observations (food diaries and physical activity monitors). During the first inpatient visit, obese participants will eat a weight-maintenance diet for 5 days to establish baseline measurements. After several days of eating a weight-maintenance diet, 20 obese adult volunteers (BMI above 30 kg/m2) will be admitted to the metabolic clinical research unit (MCRU) and, after 5 additional days of the baseline diet, their diets will be modified to result in either 85% reduction of the baseline dietary fat or a 60% reduction of the baseline dietary carbohydrate for the next 6 days. These diet modifications produce an equivalent caloric reduction. The primary outcome measurements will be changes of metabolism, brain reward circuitry and regional brain activity in response to food stimuli measured during the baseline and reduced calorie diet phases. Immediately following each controlled diet, we will measure 3 days of ad-libitum food intake using a computerized vending machine system. The subjects will return to the MCRU after a 2-10 week washout period to receive the opposite reduced calorie diet. Twenty control subjects with normal body weight (BMI between 18.5 - 25 kg/m2) will have measurements of brain reward circuitry and regional brain activity in response to food stimuli while on a balanced, weight-maintenance diet. Immediately following the second in-patient visit, all of the obese subjects will be assigned to a 12 week out-patient weight loss program with the goal of achieving at least 5% weight loss. We will investigate the relationship between short-term fat imbalances measured during the in-patient phases, and the body weight and fat changes during the weight loss program. We will evaluate the effects of weight loss on metabolism, brain reward circuitry, and regional brain activity in response to food stimuli. Finally, if the subjects are available for long-term follow-up, then we will investigate their metabolic phenotype, brain reward circuitry, and regional brain activity in response to food stimuli yearly over the subsequent 5 years following the weight loss intervention. This study will result in an improved understanding of the physiological mechanisms that sense and respond to negative energy balance acutely, after several weeks, and after several years, and may eventually lead to increased long-term success of obesity treatment.
Interventions
OTHERReduced fat diet
RF (selective reduction of 85% of baseline fat calories per day)
RC (selective reduction of 60% of baseline carbohydrate calories per day)
DRUGDrug: f-18 fallypride
Dopamine D2 receptor availability is measured by positron emission tomography (PET) using the positron emitting compound \[18F\] fallypride which binds competitively with dopamine to the D2 receptor.
DEVICEfMRI
Functional MRI (fMRI) will be used to measure the effects of diet and weight loss on regional brain activity
DEVICEPET
Positron emission tomography (PET) will be used to assess whether To assess whether brain activity and reward pathways are altered
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: * Age 18-45 years, male or female * Body mass less than 350 lbs. (max. weight dictated by table limit for functional magnetic resonance imaging (fMRI) scanner) when acquisition of large bore fMRI is complete, max. wt. limit will increase to 400 lbs. * Weight stable (less than plus or minus 5 kg over past 6 months) * Body mass index greater than or equal to 30.0 kg/m(2) * Premenopausal (women only) * Healthy, as determined by medical history and laboratory tests * Able to complete daily bouts of walking at a moderate rate * Written informed consent
Exclusion criteria
* Body mass greater than 350 lbs. (max. weight dictated by table limit for fMRI scanner) when acquisition of large bore fMRI is complete, max. wt. limit will increase to 400 lbs. * BMI less than 30.0 kg/m(2) * Evidence of metabolic or cardiovascular disease, or disease that may influence metabolism (e.g. cancer, diabetes, thyroid disease) * Taking any prescription medication (except birth control) or other drug that may influence metabolism (e.g. diet/weight-loss medication) * Hematocrit less than 34% (women only) * Hematocrit less than 40% (men only) * Pregnancy, lactation (women only) * Allergy to lidocaine or ethanol * Participating in a regular exercise program (greater than 2h/week of vigorous activity) * Caffeine consumption greater than 150 mg/day (will be clamped at baseline intake during study) * Regular use of alcohol (greater than 2 drinks per day), tobacco (smoking or chewing), amphetamines, cocaine, heroin, or marijuana over past 6 months * Past or present history of eating disorder (including binge eating) or psychiatric disease * Volunteers with strict dietary concerns (e.g. vegetarian or kosher diet, multiple food allergies) * Are claustrophobic to a degree that they would feel uncomfortable in the MRI machine. * Having any metal in their body (for example, pacemakers, metallic prostheses such as cochlear implants or heart valves, shrapnel fragments, etc.). * Left-handedness * Non-native English speakers * Volunteers unwilling or unable to give informed consent Control Subjects INCLUSION CRITERIA: * Age 18-45 years, male or female * 18.5 kg/m(2) less than BMI less than 25.0 kg/m(2) * Weight stable (less than plus or minus 5 kg over past 6 months) * Premenopausal (women only) * Healthy, as determined by medical history and laboratory tests * Written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Respiratory Quotient (RQ) | Baseline and day 14 | Respiratory quotient was calculated as the ratio of carbon dioxide production to oxygen consumption as measured in a metabolic chamber for at least 23 continuous hours on days 2 and 5 of the baseline diet and days 1, 4, and 6 of the reduced-energy diets. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 24 Hour Energy Expenditure | Baseline and 14 days | 24 hour energy expenditure was measured in a respiratory chamber. |
| Change in Cumulative Fat Imbalance | Baseline and 14 days | Measured as the difference between dietary fat intake and fat oxidation by the body as measured in the respiratory chamber |
| Caudate Dopamine D2-like Receptor Binding Potential (D2BP) | Day 2 of in-patient admission | The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest. |
| Putamen Dopamine D2-like Receptor Binding Potential (D2BP) | Day 2 of in-patient admission | The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest. |
| Accumbens Dopamine D2-like Receptor Binding Potential (D2BP) | Day 2 of in-patient admission | The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest. |
Countries
United States
Participant flow
Recruitment details
71 participants were screened and 43 were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Obese RF Then RC Obese adult volunteers (BMI above 30 kg/m2) randomized to receive an 85% reduction of baseline dietary fat for 2 weeks, then a 60% reduction of baseline dietary carbohydrate for 2 weeks | 10 |
| Obese RC Then RF Obese adult volunteers (BMI above 30 kg/m2) randomized to receive a 60% reduction of baseline dietary carbohydrate for 2 weeks, then an 85% reduction of baseline dietary fat for 2 weeks. | 10 |
| Lean Control Lean adult volunteers (BMI below 30kg/m2) placed on a weight-maintenance diet using a standard diet composition of 50% carbohydrate, 35% fat, and 15% protein on an out-patient basis | 23 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Baseline: Days 1-5 | Withdrawal by Subject | 1 | 0 | 0 |
| Washout: 2 Weeks to 10 Weeks | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Obese RF Then RC | Obese RC Then RF | Lean Control | Total |
|---|---|---|---|---|
| Age, Continuous | 34.1 years STANDARD_DEVIATION 6.9 | 35.6 years STANDARD_DEVIATION 8.1 | 28 years STANDARD_DEVIATION 6.2 | 31.2 years STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 23 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 12 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 12 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 17 | 0 / 23 |
| other Total, other adverse events | 0 / 19 | 0 / 17 | 0 / 23 |
| serious Total, serious adverse events | 0 / 19 | 0 / 17 | 0 / 23 |
Outcome results
Primary
Change in Respiratory Quotient (RQ)
Respiratory quotient was calculated as the ratio of carbon dioxide production to oxygen consumption as measured in a metabolic chamber for at least 23 continuous hours on days 2 and 5 of the baseline diet and days 1, 4, and 6 of the reduced-energy diets.
Time frame: Baseline and day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RC Diet | Change in Respiratory Quotient (RQ) | -0.0552 ratio | Standard Error 0.003 |
| RF Diet | Change in Respiratory Quotient (RQ) | 0.00453 ratio | Standard Error 0.003 |
Secondary
Accumbens Dopamine D2-like Receptor Binding Potential (D2BP)
The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest.
Time frame: Day 2 of in-patient admission
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RC Diet | Accumbens Dopamine D2-like Receptor Binding Potential (D2BP) | 18.3 ratio |
| RF Diet | Accumbens Dopamine D2-like Receptor Binding Potential (D2BP) | 16.7 ratio |
Secondary
Caudate Dopamine D2-like Receptor Binding Potential (D2BP)
The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest.
Time frame: Day 2 of in-patient admission
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RC Diet | Caudate Dopamine D2-like Receptor Binding Potential (D2BP) | 28.2 ratio |
| RF Diet | Caudate Dopamine D2-like Receptor Binding Potential (D2BP) | 24.9 ratio |
Secondary
Change in 24 Hour Energy Expenditure
24 hour energy expenditure was measured in a respiratory chamber.
Time frame: Baseline and 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RC Diet | Change in 24 Hour Energy Expenditure | -97.7 kcal/day | Standard Error 23 |
| RF Diet | Change in 24 Hour Energy Expenditure | -49.6 kcal/day | Standard Error 24 |
Secondary
Change in Cumulative Fat Imbalance
Measured as the difference between dietary fat intake and fat oxidation by the body as measured in the respiratory chamber
Time frame: Baseline and 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RC Diet | Change in Cumulative Fat Imbalance | -245 grams | Standard Error 21 |
| RF Diet | Change in Cumulative Fat Imbalance | -463 grams | Standard Error 37 |
Secondary
Putamen Dopamine D2-like Receptor Binding Potential (D2BP)
The time-activity curves for \[18F\]fallypride tracer concentration in the ROIs were measured by PET and kinetic parameters were fit to a four compartment mathematical model (with the cerebellum used as the reference tissue). D2BP was expressed as the dimensionless ratio of rate constants quantifying binding and unbinding of tracer in the regions of interest.
Time frame: Day 2 of in-patient admission
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RC Diet | Putamen Dopamine D2-like Receptor Binding Potential (D2BP) | 30.7 ratio |
| RF Diet | Putamen Dopamine D2-like Receptor Binding Potential (D2BP) | 27 ratio |