Overweight and Obesity
Conditions
Brief summary
Obesity remains a public health epidemic despite substantial advances in treatment strategies and therapies in the last decade. Effective strategies to support maintenance of improved metabolic health and reduced body weight are still needed. Signals from the gut to the brain are important in regulating metabolism and energy balance and have been linked with food reward and preference in metabolically healthy individuals with normal body mass index. In particular, post-ingestive signaling related to glucose metabolism has been linked with food reward and preference. However, not much is known about how these gut and brain signals interact to influence eating behaviors in states of obesity or altered metabolic health. In addition, evidence in rodent models and human studies indicates obesity is associated with a blunted brain response to foods compared with normal body weight. However, whether altered nutrient utilization, termed metabolic inflexibility, influences the relationship between obesity and food reward has yet to be studied. The overall objective of this proof-of-concept pilot study is to assess the feasibility of measuring reward response following a flavor-nutrient conditioning paradigm across the normal to obese body mass index (BMI) range and in states of altered metabolic health. The aims of this study are: 1) to determine whether differences in reinforcement learning/flavor-nutrient conditioning of carbohydrate can be measured across the body mass index range; and 2) to determine the feasibility of assessing metabolic flexibility and whether a relationship between metabolic flexibility and calorie-predictive reward can be detected.
Interventions
OTHERConditioned Stimulus + (CS+): Flavored beverage solution with 75 calories of sucrose
Participants will consume flavored beverage solutions containing 75 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws over a 2-hour period, and one exposure session will include indirect calorimetry measurement pre- and post-consumption. The other 4 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.
OTHERConditioned Stimulus - (CS-): Flavored beverage solution with sweetness-matched sucralose
Participants will consume flavored beverage solutions sweetened with sucralose to match the sweetness of 75 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws over a 2-hour period, and one exposure session will include indirect calorimetry measurement pre- and post-consumption. The other 4 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.
OTHERHigh-Fat Test Meal Inside a Metabolic Chamber
A high-fat test meal (60% fat, 20% carbohydrate) will be provided after a 1-hour baseline measurement of substrate oxidation during a 6-hour metabolic chamber stay. Postprandial substrate oxidation will be measured for 5 hours.
OTHERHigh-Carbohydrate Test Meal Inside a Metabolic Chamber
A high-carbohydrate test meal (60% carbohydrate, 20% fat) will be provided after a 1-hour baseline measurement of substrate oxidation during a 6-hour metabolic chamber stay. Postprandial substrate oxidation will be measured for 5 hours.
OTHERfMRI Scan
A subset of participants with BMI \> 25 will be invited to complete an functional magnetic resonance imaging (fMRI) scan as a feasibility measure. fMRI scans will be performed while beverages (without calories) used during the intervention are delivered through a custom manifold fitted to a head coil and connected to a pump system that allows precisely timed and measured delivery of liquids. Because this is feasibility-based measure, the outcome is a count of participants who completed this task.
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Virginia Polytechnic Institute and State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. BMI between 18.5-40 kg/m2 2. Not pregnant or planning to become pregnant during study participation 3. Residing in the Roanoke area and/or willing/able to attend sessions at the Fralin Biomedical Research Institute 4. Able to speak and write in English 5. Specific to fMRI scan only: BMI between 25-35 kg/m2
Exclusion criteria
1. Current inhaled nicotine use 2. History of alcohol dependence. 3. Current or past diagnosis of diabetes or thyroid problems. 4. Glycated hemoglobin (Hemoglobin A1C) \>5.7% 5. Taking medications known to influence study measures (including antiglycemic agents, thyroid medications, sleep medications) 6. Active medical or neurologic disorder. 7. Recent change in body weight (gain or loss of \> 5 lbs within the past 3 months) 8. Current shift work (typical pattern of work/activity overnight) 9. Previous weight loss surgery 10. Adherence to a special diet within the past 3 months (e.g., low-carb or ketogenic diet, exclusion of food groups/specific macronutrients, intermittent fasting, etc.) 11. Allergy to any food or ingredient included in the study diets, meals, or beverages 12. Currently pregnant or planning to become pregnant during study participation 13. Claustrophobia 14. Contraindications for MRI, including pacemaker, aneurysm clips, neurostimulators, cochlear or other implants, metal in eyes, regular work with steel, etc. (Note: This is an fMRI-specific exclusion criterion. Participants may be allowed to participate in all other study sessions and measures that do not involve fMRI.) 15. Contraindications for bioelectrical impedance analysis, specifically implanted devices
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Preference- Liking | Baseline and at 4 weeks | Subjective ratings of liking of flavors used in the intervention were assessed at baseline and after the intervention. The generalized Labeled Magnitude Scale will be used. The scale is anchored by descriptors of Most Disliked Sensation Imaginable and Most Liked Sensation Imaginable at the lower and upper ends, respectively. The score is determined by the place on the scale participants select (range of scale is 0-100). An increase in score from baseline to post-intervention indicates an increase in liking. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Preference- Wanting | 30-minute measurement | Ad libitum intake will be used as a measure of wanting in a post-test session. Participants will be provided each beverage used during the intervention and asked to drink as much or as little of them as they would like over a 30-minute period. Total beverage intake over 30 minutes is reported as the outcome. |
| Blood Oxygen Level-dependent (BOLD) Response to Beverages | 30-minute measurement that occurs during the post-test, approximately 4 weeks after the first study session | In a post-test session, functional magnetic resonance imaging (fMRI) scans were performed while beverages (without calories) used during the intervention and a tasteless solution are delivered through a custom manifold fitted to a head coil and connected to a pump system that allows precisely timed and measured delivery of liquids. Only participants with BMI \> 25 were invited to complete this portion of the study, per our protocol. In total, participants receive the CS+, CS-, and tasteless (control) solutions 24 times over the course of 2 runs. Contrasts of interest are the blood oxygen level-dependent (BOLD) response of CS+\>tasteless solution and CS-\>tasteless solution deliveries. Parameter estimates for these contrasts are extracted and reported. A positive outcome reflects greater whole-brain BOLD response for the CS condition compared with a tasteless solution. |
| Substrate Oxidation Response to Test Meals | 6-hour measurement | Indirect calorimetry in a metabolic chamber will be used to assess substrate oxidation response to high-fat and high-carbohydrate test meals. |
| Blood Glucose Response to Beverages | 2-hour measurement | Blood glucose will be assessed at baseline and at set time points for 1 hour after consumption of intervention beverages in one exposure session. |
| Post-test Preference - Wanting | Baseline and at 4 weeks | Subjective ratings of wanting of flavors used in the intervention will be assessed at baseline and after the intervention. A Visual Analog Scale will be used. Participants select a place on the line that corresponds with their subjective rating, and the score is determined by the place selected (range of scores is 0-100). The line is anchored by polar opposite descriptors (Do not want at all and Want very much). An increase in score from baseline to post-intervention indicates and increase in wanting. |
| Energy Expenditure in Response to Beverages | 1.5-hour measurement | Indirect calorimetry will be used to determine energy expenditure at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session. |
| Respiratory Exchange Ratio in Response to Beverages | 1.5-hour measurement | Indirect calorimetry will be used to determine respiratory exchange ratio (RER) at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session. Areas under the curve for change in RER were calculated for each condition and presented as outcomes. |
| Substrate Oxidation in Response to Beverages | 1.5-hour measurement | Indirect calorimetry will be used to determine substrate oxidation at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session. |
| Blood Insulin Response to Beverages | 2-hour measurement | Blood insulin will be assessed at baseline and at set time points for 2 hours after consumption of intervention beverages in an exposure session. |
Countries
United States
Participant flow
Recruitment details
20 individuals were screened for eligibility between February 1, 2022 and May 1, 2023 in Roanoke, VA.
Pre-assignment details
16 of 20 participants were randomized. Of those not randomized, 3 did not meet inclusion criteria and 1 declined to participate.
Participants by arm
| Arm | Count |
|---|---|
| Conditioned Stimulus+ (CS+) Then Conditioned Stimulus- (CS-), and High Fat Meal Then High Carb Meal Participants underwent exposure sessions with flavored beverage solutions containing sucrose first. Then, they underwent exposure sessions with flavored beverages containing sucralose. Participants underwent the high fat meal test session inside the metabolic chamber first. Then they underwent the high carbohydrate test meal session. | 3 |
| Conditioned Stimulus- (CS-) Then Conditioned Stimulus+ (CS+), and High Fat Meal Then High Carb Meal Participants underwent exposure sessions with flavored beverage solutions containing sucralose first. Then, they underwent exposure sessions with flavored beverages containing sucrose. Participants underwent the high fat meal test session inside the metabolic chamber first. Then they underwent the high carbohydrate test meal session. | 5 |
| Conditioned Stimulus- (CS-) Then Conditioned Stimulus+ (CS+), and High Carb Meal Then High Fat Meal Participants underwent exposure sessions with flavored beverage solutions containing sucralose first. Then, they underwent exposure sessions with flavored beverages containing sucrose. Participants underwent the high carbohydrate meal test session inside the metabolic chamber first. Then they underwent the high fat test meal session. | 5 |
| Conditioned Stimulus+ (CS+) Then Conditioned Stimulus- (CS-), and High Carb Meal Then High Fat Meal Participants underwent exposure sessions with flavored beverage solutions containing sucrose first. Then, they underwent exposure sessions with flavored beverages containing sucralose. Participants underwent the high carbohydrate meal test session inside the metabolic chamber first. Then they underwent the high fat test meal session. | 3 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | stopped collecting pilot data for metabolic chamber | 1 | 1 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Conditioned Stimulus+ (CS+) Then Conditioned Stimulus- (CS-), and High Fat Meal Then High Carb Meal | Total | Conditioned Stimulus+ (CS+) Then Conditioned Stimulus- (CS-), and High Carb Meal Then High Fat Meal | Conditioned Stimulus- (CS-) Then Conditioned Stimulus+ (CS+), and High Carb Meal Then High Fat Meal | Conditioned Stimulus- (CS-) Then Conditioned Stimulus+ (CS+), and High Fat Meal Then High Carb Meal |
|---|---|---|---|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 7 | 29.3 years STANDARD_DEVIATION 6.6 | 30.0 years STANDARD_DEVIATION 6.7 | 30.0 years STANDARD_DEVIATION 8.1 | 26.2 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 15 Participants | 3 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 13 Participants | 3 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United States | 3 participants | 16 participants | 5 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 1 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 7 Participants | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 | 0 / 12 | 0 / 10 |
| other Total, other adverse events | 0 / 15 | 0 / 16 | 0 / 12 | 0 / 10 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 | 0 / 12 | 0 / 10 |
Outcome results
Primary
Change in Preference- Liking
Subjective ratings of liking of flavors used in the intervention were assessed at baseline and after the intervention. The generalized Labeled Magnitude Scale will be used. The scale is anchored by descriptors of Most Disliked Sensation Imaginable and Most Liked Sensation Imaginable at the lower and upper ends, respectively. The score is determined by the place on the scale participants select (range of scale is 0-100). An increase in score from baseline to post-intervention indicates an increase in liking.
Time frame: Baseline and at 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Change in Preference- Liking | 6.5 units on a scale | Standard Deviation 10.7 |
| Conditioned Stimulus - (CS-) | Change in Preference- Liking | 4.5 units on a scale | Standard Deviation 13 |
Secondary
Blood Glucose Response to Beverages
Blood glucose will be assessed at baseline and at set time points for 1 hour after consumption of intervention beverages in one exposure session.
Time frame: 2-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Blood Glucose Response to Beverages | 882.4 mg/dl*min | Standard Deviation 404.5 |
| Conditioned Stimulus - (CS-) | Blood Glucose Response to Beverages | 37.9 mg/dl*min | Standard Deviation 315.6 |
Secondary
Blood Insulin Response to Beverages
Blood insulin will be assessed at baseline and at set time points for 2 hours after consumption of intervention beverages in an exposure session.
Time frame: 2-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Blood Insulin Response to Beverages | 694.4 uIU/ml*min | Standard Deviation 601 |
| Conditioned Stimulus - (CS-) | Blood Insulin Response to Beverages | 39.2 uIU/ml*min | Standard Deviation 132.9 |
Secondary
Blood Oxygen Level-dependent (BOLD) Response to Beverages
In a post-test session, functional magnetic resonance imaging (fMRI) scans were performed while beverages (without calories) used during the intervention and a tasteless solution are delivered through a custom manifold fitted to a head coil and connected to a pump system that allows precisely timed and measured delivery of liquids. Only participants with BMI \> 25 were invited to complete this portion of the study, per our protocol. In total, participants receive the CS+, CS-, and tasteless (control) solutions 24 times over the course of 2 runs. Contrasts of interest are the blood oxygen level-dependent (BOLD) response of CS+\>tasteless solution and CS-\>tasteless solution deliveries. Parameter estimates for these contrasts are extracted and reported. A positive outcome reflects greater whole-brain BOLD response for the CS condition compared with a tasteless solution.
Time frame: 30-minute measurement that occurs during the post-test, approximately 4 weeks after the first study session
Population: The sample size is smaller for this measure due to the feasibility assessment nature of the measure. Only a subset of our recruited participants were invited to complete this measure. Only individuals with BMI \> 25 were recruited for this portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Blood Oxygen Level-dependent (BOLD) Response to Beverages | 0.0615 arbitrary units | Standard Deviation 0.194 |
| Conditioned Stimulus - (CS-) | Blood Oxygen Level-dependent (BOLD) Response to Beverages | 0.0467 arbitrary units | Standard Deviation 0.1025 |
Secondary
Change in Preference- Wanting
Ad libitum intake will be used as a measure of wanting in a post-test session. Participants will be provided each beverage used during the intervention and asked to drink as much or as little of them as they would like over a 30-minute period. Total beverage intake over 30 minutes is reported as the outcome.
Time frame: 30-minute measurement
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Change in Preference- Wanting | 187.4 ml | Standard Deviation 152.2 |
| Conditioned Stimulus - (CS-) | Change in Preference- Wanting | 147.3 ml | Standard Deviation 140.6 |
Secondary
Change in Preference- Wanting
Forced choice will be used as a measure of wanting in a post-test session. Participants will be provided each of the beverages used during the intervention and asked to choose 1 to take home with them. The outcome variable is a count of number of participants who chose each beverage condition during the forced choice test.
Time frame: 5-minute measurement
Population: In the post-test session, participants are asked to choose between the CS+ and CS- beverage which they would like to take home in a forced choice test.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conditioned Stimulus + (CS+) | Change in Preference- Wanting | 9 Participants |
| Conditioned Stimulus - (CS-) | Change in Preference- Wanting | 6 Participants |
Secondary
Energy Expenditure in Response to Beverages
Indirect calorimetry will be used to determine energy expenditure at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session.
Time frame: 1.5-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Energy Expenditure in Response to Beverages | 3.11 kcal/min*min | Standard Deviation 2.97 |
| Conditioned Stimulus - (CS-) | Energy Expenditure in Response to Beverages | 0.76 kcal/min*min | Standard Deviation 3 |
Secondary
Post-test Preference - Wanting
Subjective ratings of wanting of flavors used in the intervention will be assessed at baseline and after the intervention. A Visual Analog Scale will be used. Participants select a place on the line that corresponds with their subjective rating, and the score is determined by the place selected (range of scores is 0-100). The line is anchored by polar opposite descriptors (Do not want at all and Want very much). An increase in score from baseline to post-intervention indicates and increase in wanting.
Time frame: Baseline and at 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Post-test Preference - Wanting | 50.6 units on a scale | — |
| Conditioned Stimulus - (CS-) | Post-test Preference - Wanting | 47.7 units on a scale | Standard Deviation 10.2 |
Secondary
Respiratory Exchange Ratio in Response to Beverages
Indirect calorimetry will be used to determine respiratory exchange ratio (RER) at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session. Areas under the curve for change in RER were calculated for each condition and presented as outcomes.
Time frame: 1.5-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Respiratory Exchange Ratio in Response to Beverages | 2.9 ratio*minutes | Standard Deviation 1.7 |
| Conditioned Stimulus - (CS-) | Respiratory Exchange Ratio in Response to Beverages | 0.8 ratio*minutes | Standard Deviation 1.3 |
Secondary
Substrate Oxidation in Response to Beverages
Indirect calorimetry will be used to determine substrate oxidation at baseline (for 30 minutes) and for 1 hour after consumption of intervention beverages in an exposure session.
Time frame: 1.5-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Substrate Oxidation in Response to Beverages | 3.5 carbohydrate oxidation grams/min*min | Standard Deviation 2 |
| Conditioned Stimulus - (CS-) | Substrate Oxidation in Response to Beverages | 0.9 carbohydrate oxidation grams/min*min | Standard Deviation 1.3 |
Secondary
Substrate Oxidation Response to Test Meals
Indirect calorimetry in a metabolic chamber will be used to assess substrate oxidation response to high-fat and high-carbohydrate test meals.
Time frame: 6-hour measurement
Population: Smaller sample size due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conditioned Stimulus + (CS+) | Substrate Oxidation Response to Test Meals | 4.6 fat oxidation grams/min*min | Standard Deviation 3.7 |
| Conditioned Stimulus - (CS-) | Substrate Oxidation Response to Test Meals | -3.5 fat oxidation grams/min*min | Standard Deviation 3.3 |