Exercise and Weight Control
Condition: Obesity; Exercise Reinforcement
Study type: Interventional

Summary: 
      The objective of this project is to determine the biological, neurobehavioral, and behavioral
      compensatory responses to exercise training-induced energy deficits in overweight to obese
      men and women. Participants will engage in exercise at either 2 days or 6 days per week for
      12 weeks and have body composition assessed via DXA before and after the exercise
      intervention. Accumulated energy balance (weight loss converted to kcal) will be compared to
      exercise energy expenditure to determine each individual's level of compensation, termed
      compensation index. Predictors of compensation index that will be assessed will include
      hunger/satiety hormone concentrations at rest and in response to a meal, reward driven
      feeding, changes in metabolic rate, and energy intake throughout the intervention. Exercise
      reinforcement and physical activity will also be assessed as a separate aim to determine if
      exercise reinforcement can be increased and if this can promote greater habitual physical
      activity after the intervention has ceased.
    

Detailed description: 
      Study Design: A factorial design will be employed with exercise frequency (6 days/week or 2
      days/week) treated as a between-subjects variable and time (baseline, end of training, end
      follow-up) treated as a within subjects variable. Subjects will be randomly assigned to
      exercise groups (6 days/week, 2 days/week) or sedentary control. The control group will be
      offered the intervention (personalized exercise plan, provided membership to YMCA) after
      follow-up measures.

      Study Population:

      This study will aim to complete all assessments on 60 participants

      Inclusion Criteria:

        -  Male or female between the ages of 18 and 40

        -  Participants must be overweight to obese (BMI 25-35 kg/m2) Not pregnant or lactating or
           planning to become pregnant in the next 6 months

        -  No limitations to safely participating in physical activity

      Exclusion Criteria:

        -  Currently dieting to lose weight and no weight loss or gain >2kg over the past 3 months,

        -  Taking any medications that affect energy expenditure or eating,

        -  Regularly exercising (planned and structured aerobic or resistance activity).

        -  Participants must have no major health problems, cannot have known cardiovascular
           (cardiac, peripheral vascular, cerebrovascular), pulmonary (COPD, interstitial lung
           disease, cystic fibrosis) or metabolic (diabetes, thyroid disorders, renal or liver
           disease) disease.

        -  Tobacco use

        -  Have a medical condition that prevents safe exercise.

      Appropriateness of exercise will be screened using a Health History and Physical Activity
      Readiness Questionnaire. Subjects will taste and rate their liking of the study foods.
      Subjects must have a liking of at least 5 out of 10 for 50% of the study foods. Subjects will
      provide informed consent before participation. There are no hypotheses on gender or race
      effects and we will strive to recruit a representative sample that includes all gender and
      ethnic groups.

      Specific hypotheses include:

      H1: (Primary) Accumulated negative energy balance will be greater when exercising 2 times per
      week than exercising 6 times per week at 3000 kcal/week for 12 weeks.

      H2: The RRVfood will increase more in response to 6 weekly exercise sessions than 2 sessions
      after 12 weeks of exercise.

      H3: Energy intake will increase more in response to 6 weekly exercise sessions than 2
      sessions after 12 weeks.

      H4: Changes in GLP-1 concentration and RRVfood will be positively associated. H5: GLP-1, PYY,
      CCK, leptin, and pancreatic polypeptide concentrations will decrease in response to a meal
      more with 6 weekly exercise sessions than 2 sessions.

      H6: Ghrelin concentrations will increase in response to a meal more with 6 weekly exercise
      sessions than 2 sessions.

      H7: RRVexercise will increase more in response to 2 weekly exercise sessions than 6 sessions
      after 12 weeks.

      H8: Tolerance to exercise discomfort will increase more in response to 2 weekly exercise
      sessions than 6 sessions after 12 weeks.

      H9: The RRVexercise and tolerance to exercise discomfort will be positively associated with
      maintenance of exercise behaviors 4 weeks after the intervention (week 16).

      H10: Changes in hunger hormones/peptides after 12 weeks of exercise will predict weight loss
      maintenance at week 17.

      Research Procedures:

      During the initial visit, participants will be informed about the study and have any
      questions answered. If deemed eligible and the participant desires to participate, they will
      be asked to provide written informed consent. After signing the consent, participants will
      fill out a demographic form, a medical history form and Physical Activity Readiness form, and
      be measured for anthropometrics (height and weight). These forms will be stored in a locked
      file cabinet in Dr. Flack's office separate from other study files. Subjects will also be
      provided an ActiGraph device to wear for the following week to monitor free-living physical
      activity and complete the Preference for and Tolerance of the Intensity of Exercise
      Questionnaire (PRETIE-Q), the Behavioral Regulation in Exercise Questionnaire (BREVQ-3), and
      the vendor form, so a payment can be processed) at this time.

      Outcome visits: Outcome measures will be completed during baseline and immediately following
      the 12 weeks of training (Post/ week 13). Outcome measures will be completed at the CCTS,
      laboratory space in Funkhouser (room 117), Joe Craft Football Training Facility, or the Human
      Performance Laboratory as needed. The sequential order of the visits to measure outcomes is
      flexible in order to meet the scheduling complexities of participants.

      Accelerometer administration: occurs at screening, after post-training assessments (week 14),
      and after follow-up assessments (week 19). Subjects will wear an accelerometer for seven
      consecutive days after receiving the accelerometer to measure usual physical activity. This
      will be scheduled so no exercise tests or sessions will fall on the 7 days wearing the
      monitor. This will be administered on participants' initial visit to Funkhouser 117 where
      they will also sign the consent form.

      Surveys, taste test, height, weight: Will occur at screening, post-training/week 13, and
      follow up/week 18. The taste test will be used to determine the foods to be used in the
      RRVfood test. This visit will occur in Funkhouser 117.

      RRVfood test: Will occur at weeks -1 or -2, 13, and 18. Subjects will report 2 to 3 hours
      postprandial to room 117 Funkhouser and complete a task where they will earn points towards
      their chosen foods.

      RRVexercise test: Will occur at weeks -2 or -3, 13, and 18 at the Human Performance
      Laboratory (MDS, B04). subjects will sample for 2 minutes each and rate their liking of the 3
      exercise options (treadmill, elliptical ergometer, or cycle ergometer) and sedentary
      alternatives (magazines, puzzles, card games). This testing can take place in the morning or
      afternoon, but will occur at the same time of day for a given subject.

      BodPod + RMR test: Will occur at weeks -1 or -2, and 13. Subjects will report at least 10
      hours postprandial and be assessed for their body composition (BodPod) and resting metabolic
      rate (RMR) at Funkhouser 117.

      CCTS Meal test visit Will occur at weeks -1 or -2, and 13. Subjects will arrive to the CCTS
      (Center for Clinical and Transnational Science) on the UK campus at least 10 hours
      postprandial and have an IV-catheter placed and fasted blood sample collected. Subjects will
      then be administered a standardized breakfast and have blood drawn immediately after
      breakfast (-2.75), and every 15 minutes during the first hour (-2.5, -2.25, -2 hr) and then
      every 30 minutes thereafter (-1.5, -1, -0.5, 0) for a total testing time of 3 hrs. Subjects
      will also complete VAS scales for hunger and satiety at each blood draw time point.

      CCTS Exercise test and DXA visit Will occur at weeks -1 or -2, week 6, week 13 Participants
      will report to the CCTS to perform a graded exercise test to determine kcal expended per
      minute at different heart rate intensities using indirect calorimetry. This information will
      be used to set the intensity and duration of their exercise training sessions during the
      intervention period of the study. This will be performed at baseline, on weeks 6 - 7, and
      after training. The mid-point measure will be used to adjust the duration and intensity of
      the exercise training sessions to account for any improvements in aerobic fitness. The
      post-time point measure will be used to determine aerobic fitness improvements. Prior to this
      test participants will also have a DXA scan preformed.

      Additional DEXA test: Will occur at weeks -1 or -2 and 13. Subjects will report to the Joe
      Craft Football Training Facility to have an additional DXA performed on the UK athletics'
      Norland model DXA, a different model than the "gold standard" iDXA used at the CCTS.

      Food Diary: for weeks -3, 4, 8, 12, 17 participants will record all foods they eat with
      details on quantity and cooking methods in a dietary intake record.

      Exercise session download meeting: Once per week during the exercise intervention (weeks
      1-12) participants will return to Funkhouser 117 to have their exercise sessions for the
      previous week downloaded to ensure compliance.

      Intervention: For the exercise treatments, participants will engage in aerobic exercise
      (treadmill, stationary bike, elliptical) to induce a 3000 kcal/week energy expenditure
      exercising either 6 sessions per week (500 kcal per session) or 2 sessions per week (1500
      kcal per session). The exercise intervention will last 12 weeks, followed by one week of
      post-testing and an unsupervised 4-week period where participants may exercise or not before
      final follow-up assessments at week 17. Exercise will occur at a moderate to difficult
      intensity and prescribed based on individual rates of energy expenditure (kcal/min) at
      different heart rate zones. Most exercise will occur at 65% of HRR, an intensity commonly
      prescribed for sedentary individuals beginning an exercise program [28]. The 6 session per
      week group should be able to complete the session in 20 to 60 min, while the 2 session per
      week group may take between 1.5 and 2.5 hours based on how many calories subjects burn
      exercising at 65% HHR. Subjects can take rest breaks as necessary during the exercise
      sessions. The first 2 to 5 exercise sessions will be supervised by research staff to
      introduce subjects to the use of the equipment and to ensure participants will be able to
      exercise for the prescribed time to meet their energy-expenditure goal. Then, exercise
      sessions will be supervised on an as needed basis in order to encourage compliance. To verify
      treatment implementation, subjects will wear a chest-strap heart rate monitor. Missed
      sessions (unless due to injury or illness) will be compensated for during the following
      sessions or made-up on another day. Heart rate and workout data will be reviewed by the
      research staff every week. Subjects will be able to use a 12-week pass to the Lexington-area
      YMCA(s) to assure access to exercise facilities if needed.

      Measurements

      Height and Weight. Body weight will be measured with a Tanita bioelectrical impedance scale
      after voiding. Subjects will wear scrubs or shorts and a t-shirt and no shoes when being
      weighed. Height will be with a stadiometer and standard anthropometric technique. These
      measurements will occur at screening to determine if subjects meets BMI inclusion criteria.

      Food reinforcement task. Subjects will report 2-4 hr post-prandial to Funkhouser 117. RRVfood
      is assessed by evaluating the number of responses (mouse button presses) a participant is
      willing to complete to gain access to food. The foods used in the task were chosen to allow
      subjects to choose foods that are often considered both "junk" foods and "healthy" snacks
      with similar nutrient densities. The experimental environment will include two personal
      computers on separate workstations. At one station is the computer on which the participant
      can earn points towards their most liked junk food, with the other station being set up for
      them to earn points for their most liked healthy food. The most liked foods of each category
      are determined at screening by tasting a small portion of each food and rating each using a
      Likert-type scale. Participants can freely go back and forth between stations. The program
      used for the reinforcement task presents a game that mimics a slot machine. A point is earned
      each time the 3 shapes that appear with each mouse button press match in shape and color.
      Access to the alternatives is dependent on earning points, which can be exchanged for access
      to the reinforcers. For every 5 points earned, the subject will receive a 70-100 kcal portion
      of the food they were working for. Points are delivered on independent progressive
      fixed-ratio schedules. The schedules of reinforcement for food and reading begin at a fixed
      ratio of 4 and then doubles (8, 16, 32, […] 2048) each time 5 points are earned. For
      instance, the participant initially has to click the mouse four times to earn each point, but
      after the first portion is earned, then 8 clicks are required to earn each of the 5 points,
      and so on. The reinforcer not earned does not increase to the next level until it is earned.
      The testing session will end when participants no longer wish to earn points for access to
      either food choice. Water will be provided ad libitum. Participants are instructed on how to
      complete the computer task and will complete a practice session to demonstrate their
      understanding of the task. The task is completed with the experimenter in an adjacent room.
      Outcomes include the total number of responses (mouse-presses) performed for each type of
      food and the Pmax [29] of each choice, which is the last schedule that a participant met the
      response requirements for access to each food choice.

      Physical activity reinforcement task. To assess the reinforcing value to be physically
      active, one computer station is set-up for the subject to earn access to physical activity
      (treadmill, elliptical ergometer, cycle ergometer) and the other computer station is set to
      earn access to sedentary alternatives (magazines, puzzles, card games). Access to the
      alternatives is dependent on earning points, which can be exchanged for the reinforcers using
      the schedules of reinforcement described above. For every 5 points earned, the subject will
      receive 5 min of access to exercise or 5 min of time to engage in the sedentary behavior,
      depending on the reinforcer that they were working for. Prior to the test participants will
      rate how much they like the exercise options and the sedentary alternative (APPENDIX 14) This
      sedentary alternative is provided to reduce the likelihood that participants would engage in
      responding for exercise out of boredom. This test will take place in the Human Performance
      Laboratory.

      Body Composition. Body composition will be measured using a GE Lunar iDXA machine at the
      CCTS. A total body scan will be conducted with participants lying supine on the table and
      arms positioned to the side and palms flat on the table. Scans will be completed using the
      standard mode, unless the thick scan mode is suggested by the software. All scans will be
      analyzed using GE Lunar enCORE Software (13.60.033). Automatic edge detection will be used
      for scan analyses. The machine will be calibrated before each scanning session, using the GE
      Lunar calibration phantom. Outcomes will include total body lean mass, fat mass, bone mineral
      content and bone mineral density.

      Each subject will undergo total body composition testing using a total body dual-energy x-ray
      absorptiometry (DXA) scan, and have their regional fat estimations performed using 3
      circumference measures. Total body and regional, absolute and relative measures of soft
      tissue (fat, fat-free and mineral-free lean) masses will be made and analyzed by DXA scanning
      using a Lunar iDXA (GE Lunar Inc., Madison, WI; software version 13.10) using standardized
      procedures. The Lunar iDXA is the machine that is used during standard clinical testing. The
      waist, abdominal, and hip circumference measurements will be performed in triplicate using a
      flexible steel anthropometric tape (Rosscraft Anthrotape; Rosscraft Innovations Inc.) using
      standardized procedures. The body composition assessments testing will take place in the
      University of Kentucky Clinical Services Core (CSC) Functional Assessment and Body
      Composition Core (FAABC; inpatient suit 5th floor Chandler Medical Center) (CCTS).

      Additional body composition tests will be performed on the Department of Dietetics and Human
      Nutrition's BodPod (air-displacement plethysmography) and the UK Athletics' DXA (Norland
      model) as a separate measure of internal reliability of these machines by comparing to the
      iDXA. The iDXA is the "gold standard" and will be used as the primary measure to test the
      current hypotheses.

      Aerobic Fitness. A graded exercise treadmill test will be used to test aerobic fitness in
      addition to calculating rate of energy expenditure. Oxygen consumed and expired CO2 will be
      analyzed by indirect calorimetry. The test begins with a 5 minute warm-up of walking at 0%
      grade, 3.0 mph. Upon completion of the warm-up, the grade increases to 2.5% for 3 minutes
      with the speed fixed at 3.0 mph. The treadmill grade will then increase every 3 minutes to
      produce an approximately 10 beat/minute increase in heart rate from the previous stage. The
      test will continue until a heart rate of 85% HRR was attained or the participant fells they
      can no longer continue. The treadmill test will be performed at baseline, during week 6, and
      post training. The week 6 measurements will be used to adjust the intensity and duration of
      the exercise training sessions to account for improvements in aerobic fitness. Performance
      work capacity (PWC) will be utilized as a measurement of sub-maximal aerobic fitness with the
      rates of oxygen consumed at heart rates of 150 and 170 beats/minute serving as aerobic
      fitness outcomes.

      Resting Metabolic Rate. Subjects will arrive to Funkhouser 117 fasted one morning prior to
      beginning the intervention (baseline) and 48 or more hours after their final exercise session
      of the intervention (week 13) to determine their RMR via indirect calorimetry (Cosmed USA,
      Chicago). This test lasts 45 minutes. Resting heart rate will be determined during the RMR
      test to be used to calculate HHR.

      Hormone measurement. Subjects will report fasted to the CCTS and have an IV catheter placed
      to provide a fasted blood sample to analyze hormone and peptide concentrations associated
      with hunger and body weight regulation and complete VAS to determine hunger and satiety
      immediately prior to a standardized breakfast. The standardized breakfast will provide 20% of
      estimated energy needs for each individual based on their RMR and a sedentary activity factor
      of 1.4. Breakfast will consist of 2% milk and cornflakes (with the option of substituting
      unsweetened soy milk for those with a lactose sensitivity). Breakfasts will be consumed
      within 15 minutes. VAS scales for hunger and satiety and blood draws for hunger hormone
      measurement will be completed immediately before breakfast (-3hr) immediately after (-2.75),
      and every 15 minutes during the first hour (-2.5, -2.25, -2 hr) and then every 30 minutes
      thereafter (-1.5, -1, -0.5, 0) [30, 31]. Blood samples will be collected in EDTA-coated and
      serum tubes. Serum GLP-1, leptin, glucagon, and active grehlin will be measured using ELISA
      (Millipore, Phoenix Pharmaceuticals, Alpco). Serum insulin will be measured with a
      chemiluminescent immunometric assay (Siemens). Samples will be batch-analyzed to reduce
      interassay variability and stored at the CCTS until the conclusion of the study.

      Habitual physical activity. For a 7 day period starting the day after subject's screening, 7
      days following post-testing outcome assessments, and for 7 days during week 17, an ActiGraph
      accelerometer (GT3XPB model; Pensacola, Florida) will be worn to provide information
      regarding changes in habitual, free-living physical activity. Subjects will be instructed to
      wear it at the hip using the provided belt during all hours awake except when bathing or
      swimming. Data will be cleaned of non-wear time, defined as consecutive strings of zeros
      greater than 20 minutes. An epoch of 10 seconds will used for data collection. This will be
      used to measure weekly minutes of moderate to vigorous physical activity (MVPA) as well as
      minutes of sedentary activity and light intensity activity using the Crouter et.al algorithm
      [32], and Freedson cut-points [33].

      Treatment Adherence. Subjects will be instructed to follow specific exercise plans that will
      elicit a 3,000 kcal energy expenditure per week. The length of the exercise session will
      depend on each individual's rate of energy expenditure. Each subject will be given a Polar
      heart rate monitor device to wear for each training session and meet with a research staff
      member weekly to download the previous week's exercise sessions to monitor compliance.

      Tolerance for the discomfort of exercise. Discomfort tolerance will be measured by
      questionnaires. Subjects will complete the validated Preference for and Tolerance of the
      Intensity of Exercise Questionnaire (PRETIE-Q) at baseline and after training.

      Energy and macronutrient intake. During weeks -3, 4, 8, 12, 17, participants will record
      their dietary intake for seven consecutive days.

      Calculations. The accumulated energy balance (AEB) will be calculated from changes in FM and
      FFM as body composition changes reflect long-term alterations in energy balance (Rosenkilde
      et al. 13). Gains of 1kg FM or 1kg FFM will reflect 12,000 and 1,780 kcal, respectively (Elia
      et al., 2003). Losses of 1kg FM or 1kg FFM will be assumed to equal 9,417 and 884 kcal,
      respectively.

      Exercise energy expenditure (ExEE) is calculated from the training-induced energy expenditure
      (TrEE) of 300 or 600 kcal/session with the addition of 15% excess post-exercise energy
      expenditure (Bahr, et al., 1997). The resting energy expenditure (REE) that would have
      occurred during the exercise sessions (REE x 1.2) will be subtracted. Thus, ExEE = (TrEE x
      0.15) + (TrEE - training duration x REE 1.2).

      The degree of compensation in response to the increase in ExEE is assessed through a
      compensation index calculated as (ExEE - AEB)/ExEE x 100%. When the compensation index equals
      zero AEB equals ExEE, or changes in body composition equal calories expended during exercise.
      Positive compensation suggests changes in body composition indicating a less negative energy
      balance than expected, whereas a larger than expected negative energy balance is referred to
      as negative compensation. Degree of compensation = (ExEE - AEB)/ExEE x 100%.

      Statistical Analysis Plan: Baseline demographic and physical characteristics will be reported
      as means and standard errors. Baseline group (6 days/week, 2 days per week exercise,
      sedentary control) differences will be tested with one-way ANOVA. Alterations in accumulated
      negative energy balance, body composition, RRVfood, RRVexercise, dietary intake, energy
      expenditure, exercise discomfort, hunger/satiety hormones, and fitness will be tested with
      two-way repeated measures analysis of variance (RMANOVA) with group treated as a
      between-subjects variable and time treated as a within subjects variable. Power Analysis: The
      primary outcome is accumulated negative energy balance. Based on previous research the mean
      accumulated negative energy balances for 300 kcal of exercise and 600 kcal of exercise
      conditions were -83% + 100% (mean + SD) and 20% + 50%, respectively.

      8. Resources:

      The proposed study will utilize CCTS staff and facilities for measurement of hunger/satiety
      hormone concentrations, body composition (DEXA), and aerobic fitness tests. Laboratory space
      at Funkhouser includes a Quark RMR measurement equipment (Cosmed), NDS-R software for
      nutrition analysis, BodPod for air displacement plethysmography, and computers and space
      necessary for the food reinforcement task. The reinforcing value of exercise measurement will
      take place in the Human Performance Laboratory, where treadmills and cycle ergometers are
      available for participant use. The Department of Dietetics and Human Nutrition recently
      purchased new Polar A-300 heart rate monitors and ActiGraph accelerometers for the proposed
      study. Dr. Flack (PI) has led similar studies and may be training up to three graduate
      students that will assist in conducting the study.

      9. Potential Risks:

      DXA Scan. All subjects will be informed of the small amount of radiation they will receive
      while going through this procedure. Female subjects of childbearing potential will receive a
      urine pregnancy test prior to undergoing the DXA Scan. Those women found to be pregnant will
      not undergo the scan and will be removed from the study.

      Blood Draw/ placement of IV catheter: Upon placement of the IV catheter, there may be some
      slight discomfort experienced from the insertion of the needle into the vein. Potential
      infection, soreness, pain, bleeding, bruising, and fainting may occur. This pain and soreness
      may last up to 24 hrs following the procedure. A trained nurse will place the IV catheter and
      standard precautions will be taken to guard against the following potential risks.

      10. Safety Precautions:

      Provisions to guard against the potential risks and discomforts discussed in section 9 are as
      follows: Every precaution to prevent a direct study injury will be taken by medical personnel
      and the investigators. Should an adverse or serious adverse event occur, the research
      participant will be followed by physicians, registered nurses and other research staff
      members for the duration of the participant's hospitalization. Routine care will be provided
      by the hospital staff. Emergency medical equipment, medications and supplies will be at the
      physician's disposal should the participants have an acute untoward reaction.
    

Intervention name(s): Exercise
Intervention type(s): Behavioral
Intervention description(s): The intervention groups will perform aerobic exercise for 12 weeks, expending 3,000 kcal of energy per week.
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: Baseline demographic and physical characteristics will be reported as means and standard errors. Baseline group (6 days/week, 2 days per week exercise, sedentary control) differences will be tested with one-way ANOVA. Alterations in accumulated negative energy balance, body composition, RRVfood, RRVexercise, dietary intake, energy expenditure, exercise discomfort, hunger/satiety hormones, and fitness will be tested with two-way repeated measures analysis of variance (RMANOVA) with group treated as a between-subjects variable and time treated as a within subjects variable.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: weight loss; exercise; reinforcement; compensation