<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03029364</url>
  </required_header>
  <id_info>
    <org_study_id>17/SW/0269</org_study_id>
    <nct_id>NCT03029364</nct_id>
  </id_info>
  <brief_title>Body Composition and Lipid Metabolism at Rest and During Exercise: A Cross-Sectional Analysis.</brief_title>
  <official_title>Body Composition and Lipid Metabolism at Rest and During Exercise: A Cross-Sectional Analysis.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Bath</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Bath</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The ability to upregulate fat oxidation at appropriate times such as during fasting, low to&#xD;
      moderate intensity exercise and after a high fat meal, is popularly advocated. This is&#xD;
      presumably due to the perception that a high capacity to utilise fat may improve (ultra)&#xD;
      endurance performance and help in the regulation of body fat and metabolic diseases. In&#xD;
      accordance, impaired fat use at rest has been associated with obesity and insulin resistance&#xD;
      (Kelley et al., 1999). However, there is inconclusive and / or a lack of systematic evidence,&#xD;
      especially in a large diverse range of adults, exploring:&#xD;
&#xD;
      1) Whether whole body fat use during exercise is altered in individuals with overweight or&#xD;
      obesity compared to lean individuals&#xD;
&#xD;
      3) The intra-individual variability in whole-body fat use at rest and during exercise&#xD;
&#xD;
      4) Physiological, metabolic, lifestyle and genetic characteristics that are associated with&#xD;
      whole-body fat use at rest and during exercise&#xD;
&#xD;
      Therefore, the objectives of this study are three-fold:&#xD;
&#xD;
        1. To explore whether whole body fat use is associated with body composition&#xD;
&#xD;
        2. To explore associations between whole-body fat use and physiological, metabolic,&#xD;
           lifestyle and genetic variables&#xD;
&#xD;
        3. To assess the intra-individual variability of whole-body fat use.&#xD;
&#xD;
      This study is an observational, exploratory cross-sectional study. A wide range of 'healthy'&#xD;
      and 'at-risk of metabolic disease' adults will be recruited.&#xD;
&#xD;
      Participants will be asked to visit a laboratory at the University of Bath four times. Visit&#xD;
      1 is a screening and study familiarisation visit. Visits 2 and 3 are to be completed within&#xD;
      7-14 days and involve lifestyle monitoring (dietary and physical activity), a one-off urine&#xD;
      and blood sample, assessment of fuel use at rest and during exercise (the latter through an&#xD;
      incremental graded cycling exercise test to exhaustion). Visit 4 is to assess body&#xD;
      composition via a dual-energy x-ray absorptiometry (DEXA) scan in addition to an optional&#xD;
      skeletal muscle and / or fat tissue biopsy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Metabolic flexibility broadly refers to the ability to utilize the right fuel source for&#xD;
      energy (primarily either carbohydrate or fat) at the right time (Kelley and Mandarino, 2000).&#xD;
      This was first conceptualised at the level of skeletal muscle (Kelley and Mandarino, 1990;&#xD;
      Andres et al., 1956). A main tenant originally captured by 'metabolic flexibility' is the&#xD;
      predominant utilization of fat as an energy source under rested post-absorptive conditions in&#xD;
      'healthy' individuals (Kelley et al., 1999; Kelley and Mandarino, 1990). Recently, there has&#xD;
      been a call to extend the concept of 'metabolic flexibility' to exercising conditions&#xD;
      (Goodpaster and Sparks, 2017; Rynders et al., 2017). Similarly to at rest, fat provides an&#xD;
      important source of energy during low-to-moderate intensity exercise (van Loon et al., 2001;&#xD;
      Romijn et al., 1993). Thus, in healthy individuals at the whole-body and skeletal muscle&#xD;
      level, it is robustly characterised and accepted that fat is an important and predominant&#xD;
      fuel source for energy under such conditions.&#xD;
&#xD;
      However, it is commonly proposed that a lower reliance upon fat as a fuel source is present&#xD;
      in individuals with obesity and type 2 diabetes and consequently, has been implicated in the&#xD;
      pathogenesis of such conditions (Rynders et al., 2017; Kelley and Mandarino, 2000).&#xD;
      Alternatively, a high capacity to utilize fat under the aforementioned two situations is&#xD;
      advocated to be a desirable trait for both athletes and non-athletes, presumably due to the&#xD;
      perception that high rates of fat utilization may improve endurance performance and/or assist&#xD;
      with the regulation of body fat and metabolic health. As such, much interest has been&#xD;
      generated into upregulating fat utilization at appropriate times e.g. during fasting and&#xD;
      low-to-moderate intensity exercise.&#xD;
&#xD;
      Correspondingly, lower resting and exercising fat use has been reported in individuals with&#xD;
      obesity vs lean (e.g. Lanzi et al., 2014; Perez-Martin et al., 2001; Kelley et al., 1999).&#xD;
      Furthermore, greater fat use at rest has been associated with lower future body weight and&#xD;
      fat gain / regain (e.g. Shook et al., 2016; Seidell et al., 1992), and during exercise with&#xD;
      reduced short term post-exercise energy intake / balance (e.g. Hopkins et al., 2012),&#xD;
      exercise-induced fat loss (Barwell et al., 2008) and weight loss / maintenance (Dandadell et&#xD;
      al., 2017). Importantly, however, this relationship is not always apparent with similar (e.g.&#xD;
      Blaize et a., 2014; Croci et al., 2014) or higher (e.g. Ara et al., 2011; Goodpaster et al.,&#xD;
      2002; Horowtiz et al., 2000) rates of fat use at rest and during exercise reported in&#xD;
      individuals with obesity compared to lean counterparts. Furthermore, cross-sectional and&#xD;
      prospective associations do not always exist between lower fat use and greater body weight /&#xD;
      fat mass gain or regain (e.g. Dandanell et al., 2017; Ellis et al., 2010). Thus, despite&#xD;
      being popularly advocated, it is currently unclear whether lower fat use at rest or during&#xD;
      exercise predisposes or is a characteristic of excess adiposity (i.e. obesity).&#xD;
&#xD;
      The inconsistent findings could partly be due to numerous methodological discrepancies&#xD;
      between studies such as participant characteristics, matching of comparative groups, the&#xD;
      exercise protocol utilised and / or the assessment of body composition, lipid oxidation and&#xD;
      cardio-respiratory fitness levels.&#xD;
&#xD;
      Therefore, through the use of well-established and respected techniques, we aim to&#xD;
      comprehensively and systematically explore whether whole-body fat use at rest and during&#xD;
      exercise is:&#xD;
&#xD;
        1. Altered in individuals with overweight or obesity compared to lean individuals&#xD;
&#xD;
        2. Further determinants / factors that may influence fat use&#xD;
&#xD;
        3. The intra-individual variation in fat use which will help to more confidently determine&#xD;
           the above objectives.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 8, 2018</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Actual">May 28, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal rate of whole-body fat oxidation (mg/kg FFM/min)</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>Fat free mass (FFM). Assessed during the incremental stage maximal cardio-respiratory fitness test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximal rate of whole-body fat oxidation (g/min)</measure>
    <time_frame>7-14 days</time_frame>
    <description>Non-adjusted rate. Assessed during the incremental stage maximal cardio-respiratory fitness test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FATmax (% of maximum oxygen consumption)</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>The exercise intensity that maximal rate of whole-body fat oxidation occurs at. Expressed as % of VO2peak). Assessed during the incremental stage maximal cardio-respiratory fitness test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FATmax (% of Watt max)</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>The exercise intensity that maximal rate of whole-body fat oxidation occurs at. Expressed as % of Watt max). Assessed during the incremental stage maximal cardio-respiratory fitness test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FATmax (% of Heart Rate max)</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>The exercise intensity that maximal rate of whole-body fat oxidation occurs at. expressed either as % of heart rate max). Assessed during the incremental stage maximal cardio-respiratory fitness test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Whole-body substrate oxidation rates (Carbohydrates and Lipid) during exercise</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>Assessed during the incremental stage maximal cardio-respiratory fitness test via indirect calorimetry of expired gas samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Whole-body substrate oxidation rates (Carbohydrates and Lipid) at rest</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>Assessed at rest through the participant lying in a semi-supine position via indirect calorimetry of expired gas samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resting metabolic rate</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>Assessed at rest through the participant lying in a semi-supine position via indirect calorimetry of expired gas samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiorespiratory fitness (VO2peak)</measure>
    <time_frame>7 - 14 days</time_frame>
    <description>Assessed during the incremental stage maximal cardio-respiratory fitness test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Habitual Energy Intake</measure>
    <time_frame>7 - 21 days</time_frame>
    <description>Participants will be asked to complete a self-weighed food and drink diary before each main trial day (Visit 2 and 3) so that average daily calorie and macronutrient intake can be calculated. The procedure will be explained by the CI. This diet monitoring period must include 3 week-days, at least one 1 weekend day and the immediate 48-hrs prior to the beginning of each main trial (Visit 2 and 3). Additionally, the prior 48-hrs before Visit 2 will be replicated before Visit 3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Habitual Energy Expenditure / Physical Activity</measure>
    <time_frame>7 - 21 days</time_frame>
    <description>Physical activity will be measured by accelerometry and heart-rate monitoring for 7 days before each main trial day (Visit 2 and 3). This procedure will be explained by the CI. ntake can be calculated. The participants physical activity levels for the immediate 48-hrs prior to the beginning of each main trial (Visit 2 and 3) will be asked to be replicated as closely as possible.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Menstrual Cycle (females only)</measure>
    <time_frame>7 - 21 days</time_frame>
    <description>Assessed through a self-reported menstrual cycle questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Self-reported Physical Activity level</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed by the International Physical Activity Questionnaire (long form)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting glucose concentration</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via plasma sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting lipid profiles (triglycerides / cholesterol)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via serum sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Adipose tissue derived hormone concentrations (leptin, adiponectin)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via plasma sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting catecholamine concentrations (epinephrine and norepinephrine)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via plasma sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting sex hormone concentrations (17 beta-estradiol, testosterone, progesterone)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via serum sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting pancreatic derived hormone concentrations (insulin and glucagon)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via plasma sample extracted from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hydration Status (urine specific gravity)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via analysis of urine sample with a refractometer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Age</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sex</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ethnicity</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Smoking Status</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Medication / supplement use</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dietary pattern / requirements (e.g. vegetarian, vegan, Celiac disease)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via a participant questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body Mass (kg)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via body weighing scales</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body Mass Index (kg/m2)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed by dividing body weight in kg by height in metres squared.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Waist circumference (cm)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via use of an anthropometric tape measure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hip Circumference (cm)</measure>
    <time_frame>7-21 days</time_frame>
    <description>Assessed via use of an anthropometric tape measure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body fat percentage</measure>
    <time_frame>1 day</time_frame>
    <description>Assessed via a dual energy xray absorptiometry scan at Visit 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body fat localisation</measure>
    <time_frame>1 day</time_frame>
    <description>Assessed via a dual energy xray absorptiometry scan at Visit 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lean body mass</measure>
    <time_frame>1 day</time_frame>
    <description>Assessed via a dual energy xray absorptiometry scan at Visit 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body fat percentage</measure>
    <time_frame>7-21 days</time_frame>
    <description>Bioelectrical Impedance Analysis from the body weighing scales</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Genotyping analysis</measure>
    <time_frame>7 - 21 days</time_frame>
    <description>Genotyping analysis will be assessed through the extraction of the buffy coat layer from the blood sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Skeletal Muscle sample (Optional)</measure>
    <time_frame>1 day</time_frame>
    <description>The optional muscle sample will be obtained from the quadriceps muscle using the Bergstrom technique on Visit 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adipose Tissue (Fat) sample (Optional)</measure>
    <time_frame>1 day</time_frame>
    <description>The optional fat sample will be obtained from the subcutaneous abdominal region (5 cm laterally of the umbilicus) via the 'lipoaspiration' technique on Visit 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fat mass index (body fat in kg/m2)</measure>
    <time_frame>7 - 21 days</time_frame>
    <description>Assessed by dividing body fat in kg by height in metres squared.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Lipid Metabolism</condition>
  <condition>Substrate Metabolism</condition>
  <condition>Exercise</condition>
  <arm_group>
    <arm_group_label>Male and Female Adults</arm_group_label>
    <description>Completion of Study Protocol</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Study Protocol</intervention_name>
    <description>Participants will complete three study protocols 7 - 28 days apart which includes:&#xD;
3 x main trial days (max. 150 mins) involving body composition analysis, indirect calorimetry, a blood sample, optional muscle and / or adipose tissue biopsies and a maximal cardiorespiratory fitness test.&#xD;
2 x lifestyle monitoring periods (physical activity and diet) for the prior 7 days before each main trial day.&#xD;
Maintenance of habitual habits, dietary and physical activity behaviour patterns&#xD;
We are observing biological / health parameters in a group of individuals who will be assessed under resting and exercising conditions. The current study does not involve an intervention.</description>
    <arm_group_label>Male and Female Adults</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma, serum and buffy coat layer extraction from blood samples. Skeletal muscle and adipose&#xD;
      tissue (fat) samples. Urine sample for immediate analysis and disposal.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adults&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  be between 18 - 65 years of age&#xD;
&#xD;
          -  male or female&#xD;
&#xD;
          -  body mass index between 18.9 - 35 kg/m2&#xD;
&#xD;
          -  be able and willing to give informed oral and written consent&#xD;
&#xD;
          -  complete and meet the defined criteria of pre-study questionnaires and screens&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently have or have a previous history of metabolic, cardio-pulmonary or&#xD;
             musculoskeletal disease&#xD;
&#xD;
          -  BMI below 18.9 or above 35 kg/m2&#xD;
&#xD;
          -  Have plans to change lifestyle (diet and/or physical activity) during the study period&#xD;
             ( 7 - 21 days)&#xD;
&#xD;
          -  Unwillingness or unable to sufficiently meet study demands&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Javier T Gonzalez, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Bath</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department for Health, University of Bath</name>
      <address>
        <city>Bath</city>
        <zip>BA2 7AY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000 May;49(5):677-83. doi: 10.2337/diabetes.49.5.677.</citation>
    <PMID>10905472</PMID>
  </reference>
  <reference>
    <citation>Kelley DE, Mandarino LJ. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999-2007. doi: 10.1172/JCI114935.</citation>
    <PMID>2123890</PMID>
  </reference>
  <reference>
    <citation>ANDRES R, CADER G, ZIERLER KL. The quantitatively minor role of carbohydrate in oxidative metabolism by skeletal muscle in intact man in the basal state; measurements of oxygen and glucose uptake and carbon dioxide and lactate production in the forearm. J Clin Invest. 1956 Jun;35(6):671-82. doi: 10.1172/JCI103324. No abstract available.</citation>
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    <citation>Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036. doi: 10.1016/j.cmet.2017.04.015.</citation>
    <PMID>28467922</PMID>
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  <reference>
    <citation>Rynders CA, Blanc S, DeJong N, Bessesen DH, Bergouignan A. Sedentary behaviour is a key determinant of metabolic inflexibility. J Physiol. 2018 Apr 15;596(8):1319-1330. doi: 10.1113/JP273282. Epub 2017 Jul 4.</citation>
    <PMID>28543022</PMID>
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  <reference>
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  <reference>
    <citation>Lanzi S, Codecasa F, Cornacchia M, Maestrini S, Salvadori A, Brunani A, Malatesta D. Fat oxidation, hormonal and plasma metabolite kinetics during a submaximal incremental test in lean and obese adults. PLoS One. 2014 Feb 11;9(2):e88707. doi: 10.1371/journal.pone.0088707. eCollection 2014.</citation>
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  <reference>
    <citation>Perez-Martin A, Dumortier M, Raynaud E, Brun JF, Fedou C, Bringer J, Mercier J. Balance of substrate oxidation during submaximal exercise in lean and obese people. Diabetes Metab. 2001 Sep;27(4 Pt 1):466-74.</citation>
    <PMID>11547220</PMID>
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  <reference>
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    <citation>Shook RP, Hand GA, Paluch AE, Wang X, Moran R, Hebert JR, Jakicic JM, Blair SN. High respiratory quotient is associated with increases in body weight and fat mass in young adults. Eur J Clin Nutr. 2016 Oct;70(10):1197-1202. doi: 10.1038/ejcn.2015.198. Epub 2015 Nov 25.</citation>
    <PMID>26603877</PMID>
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    <citation>Seidell JC, Muller DC, Sorkin JD, Andres R. Fasting respiratory exchange ratio and resting metabolic rate as predictors of weight gain: the Baltimore Longitudinal Study on Aging. Int J Obes Relat Metab Disord. 1992 Sep;16(9):667-74.</citation>
    <PMID>1328091</PMID>
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    <citation>Hopkins M, Blundell JE, King NA. Individual variability in compensatory eating following acute exercise in overweight and obese women. Br J Sports Med. 2014 Oct;48(20):1472-6. doi: 10.1136/bjsports-2012-091721. Epub 2013 May 10.</citation>
    <PMID>23666018</PMID>
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    <citation>Barwell ND, Malkova D, Leggate M, Gill JM. Individual responsiveness to exercise-induced fat loss is associated with change in resting substrate utilization. Metabolism. 2009 Sep;58(9):1320-8. doi: 10.1016/j.metabol.2009.04.016. Epub 2009 Jun 18.</citation>
    <PMID>19501861</PMID>
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  <reference>
    <citation>Dandanell S, Husted K, Amdisen S, Vigelso A, Dela F, Larsen S, Helge JW. Influence of maximal fat oxidation on long-term weight loss maintenance in humans. J Appl Physiol (1985). 2017 Jul 1;123(1):267-274. doi: 10.1152/japplphysiol.00270.2017. Epub 2017 May 25.</citation>
    <PMID>28546468</PMID>
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  <reference>
    <citation>Blaize AN, Potteiger JA, Claytor RP, Noe DA. Body fat has no effect on the maximal fat oxidation rate in young, normal, and overweight women. J Strength Cond Res. 2014 Aug;28(8):2121-6. doi: 10.1519/JSC.0000000000000512.</citation>
    <PMID>24796985</PMID>
  </reference>
  <reference>
    <citation>Croci I, Hickman IJ, Wood RE, Borrani F, Macdonald GA, Byrne NM. Fat oxidation over a range of exercise intensities: fitness versus fatness. Appl Physiol Nutr Metab. 2014 Dec;39(12):1352-9. doi: 10.1139/apnm-2014-0144. Epub 2014 Aug 1.</citation>
    <PMID>25356842</PMID>
  </reference>
  <reference>
    <citation>Ara I, Larsen S, Stallknecht B, Guerra B, Morales-Alamo D, Andersen JL, Ponce-Gonzalez JG, Guadalupe-Grau A, Galbo H, Calbet JA, Helge JW. Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans. Int J Obes (Lond). 2011 Jan;35(1):99-108. doi: 10.1038/ijo.2010.123. Epub 2010 Jun 15.</citation>
    <PMID>20548301</PMID>
  </reference>
  <reference>
    <citation>Horowitz JF, Klein S. Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity. J Appl Physiol (1985). 2000 Dec;89(6):2276-82. doi: 10.1152/jappl.2000.89.6.2276.</citation>
    <PMID>11090579</PMID>
  </reference>
  <reference>
    <citation>Goodpaster BH, Wolfe RR, Kelley DE. Effects of obesity on substrate utilization during exercise. Obes Res. 2002 Jul;10(7):575-84. doi: 10.1038/oby.2002.78.</citation>
    <PMID>12105277</PMID>
  </reference>
  <reference>
    <citation>Ellis AC, Hyatt TC, Hunter GR, Gower BA. Respiratory quotient predicts fat mass gain in premenopausal women. Obesity (Silver Spring). 2010 Dec;18(12):2255-9. doi: 10.1038/oby.2010.96. Epub 2010 May 6.</citation>
    <PMID>20448540</PMID>
  </reference>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 14, 2017</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>May 25, 2022</last_update_submitted>
  <last_update_submitted_qc>May 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Bath</investigator_affiliation>
    <investigator_full_name>Javier Gonzalez</investigator_full_name>
    <investigator_title>Lecturer (Assistant Professor) in Human Physiology</investigator_title>
  </responsible_party>
  <keyword>Maximal Fat Oxidation</keyword>
  <keyword>Exercise</keyword>
  <keyword>Intra-individual variability</keyword>
  <keyword>Determinants</keyword>
  <keyword>Whole-body fat oxidation</keyword>
  <keyword>Body composition</keyword>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 11, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT03029364/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03029364
org study id: 17/SW/0269
nct id: NCT03029364
lead sponsor: 
has dmc: No
The ability to upregulate fat oxidation at appropriate times such as during fasting, low to
      moderate intensity exercise and after a high fat meal, is popularly advocated. This is
      presumably due to the perception that a high capacity to utilise fat may improve (ultra)
      endurance performance and help in the regulation of body fat and metabolic diseases. In
      accordance, impaired fat use at rest has been associated with obesity and insulin resistance
      (Kelley et al., 1999). However, there is inconclusive and / or a lack of systematic evidence,
      especially in a large diverse range of adults, exploring:

      1) Whether whole body fat use during exercise is altered in individuals with overweight or
      obesity compared to lean individuals

      3) The intra-individual variability in whole-body fat use at rest and during exercise

      4) Physiological, metabolic, lifestyle and genetic characteristics that are associated with
      whole-body fat use at rest and during exercise

      Therefore, the objectives of this study are three-fold:

        1. To explore whether whole body fat use is associated with body composition

        2. To explore associations between whole-body fat use and physiological, metabolic,
           lifestyle and genetic variables

        3. To assess the intra-individual variability of whole-body fat use.

      This study is an observational, exploratory cross-sectional study. A wide range of 'healthy'
      and 'at-risk of metabolic disease' adults will be recruited.

      Participants will be asked to visit a laboratory at the University of Bath four times. Visit
      1 is a screening and study familiarisation visit. Visits 2 and 3 are to be completed within
      7-14 days and involve lifestyle monitoring (dietary and physical activity), a one-off urine
      and blood sample, assessment of fuel use at rest and during exercise (the latter through an
      incremental graded cycling exercise test to exhaustion). Visit 4 is to assess body
      composition via a dual-energy x-ray absorptiometry (DEXA) scan in addition to an optional
      skeletal muscle and / or fat tissue biopsy.
Metabolic flexibility broadly refers to the ability to utilize the right fuel source for
      energy (primarily either carbohydrate or fat) at the right time (Kelley and Mandarino, 2000).
      This was first conceptualised at the level of skeletal muscle (Kelley and Mandarino, 1990;
      Andres et al., 1956). A main tenant originally captured by 'metabolic flexibility' is the
      predominant utilization of fat as an energy source under rested post-absorptive conditions in
      'healthy' individuals (Kelley et al., 1999; Kelley and Mandarino, 1990). Recently, there has
      been a call to extend the concept of 'metabolic flexibility' to exercising conditions
      (Goodpaster and Sparks, 2017; Rynders et al., 2017). Similarly to at rest, fat provides an
      important source of energy during low-to-moderate intensity exercise (van Loon et al., 2001;
      Romijn et al., 1993). Thus, in healthy individuals at the whole-body and skeletal muscle
      level, it is robustly characterised and accepted that fat is an important and predominant
      fuel source for energy under such conditions.

      However, it is commonly proposed that a lower reliance upon fat as a fuel source is present
      in individuals with obesity and type 2 diabetes and consequently, has been implicated in the
      pathogenesis of such conditions (Rynders et al., 2017; Kelley and Mandarino, 2000).
      Alternatively, a high capacity to utilize fat under the aforementioned two situations is
      advocated to be a desirable trait for both athletes and non-athletes, presumably due to the
      perception that high rates of fat utilization may improve endurance performance and/or assist
      with the regulation of body fat and metabolic health. As such, much interest has been
      generated into upregulating fat utilization at appropriate times e.g. during fasting and
      low-to-moderate intensity exercise.

      Correspondingly, lower resting and exercising fat use has been reported in individuals with
      obesity vs lean (e.g. Lanzi et al., 2014; Perez-Martin et al., 2001; Kelley et al., 1999).
      Furthermore, greater fat use at rest has been associated with lower future body weight and
      fat gain / regain (e.g. Shook et al., 2016; Seidell et al., 1992), and during exercise with
      reduced short term post-exercise energy intake / balance (e.g. Hopkins et al., 2012),
      exercise-induced fat loss (Barwell et al., 2008) and weight loss / maintenance (Dandadell et
      al., 2017). Importantly, however, this relationship is not always apparent with similar (e.g.
      Blaize et a., 2014; Croci et al., 2014) or higher (e.g. Ara et al., 2011; Goodpaster et al.,
      2002; Horowtiz et al., 2000) rates of fat use at rest and during exercise reported in
      individuals with obesity compared to lean counterparts. Furthermore, cross-sectional and
      prospective associations do not always exist between lower fat use and greater body weight /
      fat mass gain or regain (e.g. Dandanell et al., 2017; Ellis et al., 2010). Thus, despite
      being popularly advocated, it is currently unclear whether lower fat use at rest or during
      exercise predisposes or is a characteristic of excess adiposity (i.e. obesity).

      The inconsistent findings could partly be due to numerous methodological discrepancies
      between studies such as participant characteristics, matching of comparative groups, the
      exercise protocol utilised and / or the assessment of body composition, lipid oxidation and
      cardio-respiratory fitness levels.

      Therefore, through the use of well-established and respected techniques, we aim to
      comprehensively and systematically explore whether whole-body fat use at rest and during
      exercise is:

        1. Altered in individuals with overweight or obesity compared to lean individuals

        2. Further determinants / factors that may influence fat use

        3. The intra-individual variation in fat use which will help to more confidently determine
           the above objectives.
observational model: Cohort
time perspective: Cross-Sectional
measure: Maximal rate of whole-body fat oxidation (mg/kg FFM/min)
time frame: 7 - 14 days
description: Fat free mass (FFM). Assessed during the incremental stage maximal cardio-respiratory fitness test
measure: Maximal rate of whole-body fat oxidation (g/min)
time frame: 7-14 days
description: Non-adjusted rate. Assessed during the incremental stage maximal cardio-respiratory fitness test
measure: FATmax (% of maximum oxygen consumption)
time frame: 7 - 14 days
description: The exercise intensity that maximal rate of whole-body fat oxidation occurs at. Expressed as % of VO2peak). Assessed during the incremental stage maximal cardio-respiratory fitness test.
measure: FATmax (% of Watt max)
time frame: 7 - 14 days
description: The exercise intensity that maximal rate of whole-body fat oxidation occurs at. Expressed as % of Watt max). Assessed during the incremental stage maximal cardio-respiratory fitness test.
measure: FATmax (% of Heart Rate max)
time frame: 7 - 14 days
description: The exercise intensity that maximal rate of whole-body fat oxidation occurs at. expressed either as % of heart rate max). Assessed during the incremental stage maximal cardio-respiratory fitness test
measure: Whole-body substrate oxidation rates (Carbohydrates and Lipid) during exercise
time frame: 7 - 14 days
description: Assessed during the incremental stage maximal cardio-respiratory fitness test via indirect calorimetry of expired gas samples.
measure: Whole-body substrate oxidation rates (Carbohydrates and Lipid) at rest
time frame: 7 - 14 days
description: Assessed at rest through the participant lying in a semi-supine position via indirect calorimetry of expired gas samples.
measure: Resting metabolic rate
time frame: 7 - 14 days
description: Assessed at rest through the participant lying in a semi-supine position via indirect calorimetry of expired gas samples.
measure: Cardiorespiratory fitness (VO2peak)
time frame: 7 - 14 days
description: Assessed during the incremental stage maximal cardio-respiratory fitness test
measure: Habitual Energy Intake
time frame: 7 - 21 days
description: Participants will be asked to complete a self-weighed food and drink diary before each main trial day (Visit 2 and 3) so that average daily calorie and macronutrient intake can be calculated. The procedure will be explained by the CI. This diet monitoring period must include 3 week-days, at least one 1 weekend day and the immediate 48-hrs prior to the beginning of each main trial (Visit 2 and 3). Additionally, the prior 48-hrs before Visit 2 will be replicated before Visit 3.
measure: Habitual Energy Expenditure / Physical Activity
time frame: 7 - 21 days
description: Physical activity will be measured by accelerometry and heart-rate monitoring for 7 days before each main trial day (Visit 2 and 3). This procedure will be explained by the CI. ntake can be calculated. The participants physical activity levels for the immediate 48-hrs prior to the beginning of each main trial (Visit 2 and 3) will be asked to be replicated as closely as possible.
measure: Menstrual Cycle (females only)
time frame: 7 - 21 days
description: Assessed through a self-reported menstrual cycle questionnaire
measure: Self-reported Physical Activity level
time frame: 7-21 days
description: Assessed by the International Physical Activity Questionnaire (long form)
measure: Fasting glucose concentration
time frame: 7-21 days
description: Assessed via plasma sample extracted from the blood sample
measure: Fasting lipid profiles (triglycerides / cholesterol)
time frame: 7-21 days
description: Assessed via serum sample extracted from the blood sample
measure: Fasting Adipose tissue derived hormone concentrations (leptin, adiponectin)
time frame: 7-21 days
description: Assessed via plasma sample extracted from the blood sample
measure: Fasting catecholamine concentrations (epinephrine and norepinephrine)
time frame: 7-21 days
description: Assessed via plasma sample extracted from the blood sample
measure: Fasting sex hormone concentrations (17 beta-estradiol, testosterone, progesterone)
time frame: 7-21 days
description: Assessed via serum sample extracted from the blood sample
measure: Fasting pancreatic derived hormone concentrations (insulin and glucagon)
time frame: 7-21 days
description: Assessed via plasma sample extracted from the blood sample
measure: Hydration Status (urine specific gravity)
time frame: 7-21 days
description: Assessed via analysis of urine sample with a refractometer
measure: Age
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Sex
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Ethnicity
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Smoking Status
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Medication / supplement use
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Dietary pattern / requirements (e.g. vegetarian, vegan, Celiac disease)
time frame: 7-21 days
description: Assessed via a participant questionnaire
measure: Body Mass (kg)
time frame: 7-21 days
description: Assessed via body weighing scales
measure: Body Mass Index (kg/m2)
time frame: 7-21 days
description: Assessed by dividing body weight in kg by height in metres squared.
measure: Waist circumference (cm)
time frame: 7-21 days
description: Assessed via use of an anthropometric tape measure
measure: Hip Circumference (cm)
time frame: 7-21 days
description: Assessed via use of an anthropometric tape measure
measure: Body fat percentage
time frame: 1 day
description: Assessed via a dual energy xray absorptiometry scan at Visit 4.
measure: Body fat localisation
time frame: 1 day
description: Assessed via a dual energy xray absorptiometry scan at Visit 4.
measure: Lean body mass
time frame: 1 day
description: Assessed via a dual energy xray absorptiometry scan at Visit 4.
measure: Body fat percentage
time frame: 7-21 days
description: Bioelectrical Impedance Analysis from the body weighing scales
measure: Genotyping analysis
time frame: 7 - 21 days
description: Genotyping analysis will be assessed through the extraction of the buffy coat layer from the blood sample
measure: Skeletal Muscle sample (Optional)
time frame: 1 day
description: The optional muscle sample will be obtained from the quadriceps muscle using the Bergstrom technique on Visit 4.
measure: Adipose Tissue (Fat) sample (Optional)
time frame: 1 day
description: The optional fat sample will be obtained from the subcutaneous abdominal region (5 cm laterally of the umbilicus) via the 'lipoaspiration' technique on Visit 4.
measure: Fat mass index (body fat in kg/m2)
time frame: 7 - 21 days
description: Assessed by dividing body fat in kg by height in metres squared.
arm group label: Male and Female Adults
description: Completion of Study Protocol
intervention type: Behavioral
intervention name: Study Protocol
description: Participants will complete three study protocols 7 - 28 days apart which includes:
3 x main trial days (max. 150 mins) involving body composition analysis, indirect calorimetry, a blood sample, optional muscle and / or adipose tissue biopsies and a maximal cardiorespiratory fitness test.
2 x lifestyle monitoring periods (physical activity and diet) for the prior 7 days before each main trial day.
Maintenance of habitual habits, dietary and physical activity behaviour patterns
We are observing biological / health parameters in a group of individuals who will be assessed under resting and exercising conditions. The current study does not involve an intervention.
arm group label: Male and Female Adults
Plasma, serum and buffy coat layer extraction from blood samples. Skeletal muscle and adipose
      tissue (fat) samples. Urine sample for immediate analysis and disposal.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Javier T Gonzalez, PhD
role: Principal Investigator
affiliation: University of Bath
facility: 
country: United Kingdom
citation: Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000 May;49(5):677-83. doi: 10.2337/diabetes.49.5.677.
PMID: 10905472
citation: Kelley DE, Mandarino LJ. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999-2007. doi: 10.1172/JCI114935.
PMID: 2123890
citation: ANDRES R, CADER G, ZIERLER KL. The quantitatively minor role of carbohydrate in oxidative metabolism by skeletal muscle in intact man in the basal state; measurements of oxygen and glucose uptake and carbon dioxide and lactate production in the forearm. J Clin Invest. 1956 Jun;35(6):671-82. doi: 10.1172/JCI103324. No abstract available.
PMID: 13319506
citation: Goodpaster BH, Sparks LM. Metabolic Flexibility in Health and Disease. Cell Metab. 2017 May 2;25(5):1027-1036. doi: 10.1016/j.cmet.2017.04.015.
PMID: 28467922
citation: Rynders CA, Blanc S, DeJong N, Bessesen DH, Bergouignan A. Sedentary behaviour is a key determinant of metabolic inflexibility. J Physiol. 2018 Apr 15;596(8):1319-1330. doi: 10.1113/JP273282. Epub 2017 Jul 4.
PMID: 28543022
citation: van Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ. The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol. 2001 Oct 1;536(Pt 1):295-304. doi: 10.1111/j.1469-7793.2001.00295.x.
PMID: 11579177
citation: Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, Wolfe RR. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol. 1993 Sep;265(3 Pt 1):E380-91. doi: 10.1152/ajpendo.1993.265.3.E380.
PMID: 8214047
citation: Lanzi S, Codecasa F, Cornacchia M, Maestrini S, Salvadori A, Brunani A, Malatesta D. Fat oxidation, hormonal and plasma metabolite kinetics during a submaximal incremental test in lean and obese adults. PLoS One. 2014 Feb 11;9(2):e88707. doi: 10.1371/journal.pone.0088707. eCollection 2014.
PMID: 24523934
citation: Perez-Martin A, Dumortier M, Raynaud E, Brun JF, Fedou C, Bringer J, Mercier J. Balance of substrate oxidation during submaximal exercise in lean and obese people. Diabetes Metab. 2001 Sep;27(4 Pt 1):466-74.
PMID: 11547220
citation: Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol. 1999 Dec;277(6):E1130-41. doi: 10.1152/ajpendo.1999.277.6.E1130.
PMID: 10600804
citation: Shook RP, Hand GA, Paluch AE, Wang X, Moran R, Hebert JR, Jakicic JM, Blair SN. High respiratory quotient is associated with increases in body weight and fat mass in young adults. Eur J Clin Nutr. 2016 Oct;70(10):1197-1202. doi: 10.1038/ejcn.2015.198. Epub 2015 Nov 25.
PMID: 26603877
citation: Seidell JC, Muller DC, Sorkin JD, Andres R. Fasting respiratory exchange ratio and resting metabolic rate as predictors of weight gain: the Baltimore Longitudinal Study on Aging. Int J Obes Relat Metab Disord. 1992 Sep;16(9):667-74.
PMID: 1328091
citation: Hopkins M, Blundell JE, King NA. Individual variability in compensatory eating following acute exercise in overweight and obese women. Br J Sports Med. 2014 Oct;48(20):1472-6. doi: 10.1136/bjsports-2012-091721. Epub 2013 May 10.
PMID: 23666018
citation: Barwell ND, Malkova D, Leggate M, Gill JM. Individual responsiveness to exercise-induced fat loss is associated with change in resting substrate utilization. Metabolism. 2009 Sep;58(9):1320-8. doi: 10.1016/j.metabol.2009.04.016. Epub 2009 Jun 18.
PMID: 19501861
citation: Dandanell S, Husted K, Amdisen S, Vigelso A, Dela F, Larsen S, Helge JW. Influence of maximal fat oxidation on long-term weight loss maintenance in humans. J Appl Physiol (1985). 2017 Jul 1;123(1):267-274. doi: 10.1152/japplphysiol.00270.2017. Epub 2017 May 25.
PMID: 28546468
citation: Blaize AN, Potteiger JA, Claytor RP, Noe DA. Body fat has no effect on the maximal fat oxidation rate in young, normal, and overweight women. J Strength Cond Res. 2014 Aug;28(8):2121-6. doi: 10.1519/JSC.0000000000000512.
PMID: 24796985
citation: Croci I, Hickman IJ, Wood RE, Borrani F, Macdonald GA, Byrne NM. Fat oxidation over a range of exercise intensities: fitness versus fatness. Appl Physiol Nutr Metab. 2014 Dec;39(12):1352-9. doi: 10.1139/apnm-2014-0144. Epub 2014 Aug 1.
PMID: 25356842
citation: Ara I, Larsen S, Stallknecht B, Guerra B, Morales-Alamo D, Andersen JL, Ponce-Gonzalez JG, Guadalupe-Grau A, Galbo H, Calbet JA, Helge JW. Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans. Int J Obes (Lond). 2011 Jan;35(1):99-108. doi: 10.1038/ijo.2010.123. Epub 2010 Jun 15.
PMID: 20548301
citation: Horowitz JF, Klein S. Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity. J Appl Physiol (1985). 2000 Dec;89(6):2276-82. doi: 10.1152/jappl.2000.89.6.2276.
PMID: 11090579
citation: Goodpaster BH, Wolfe RR, Kelley DE. Effects of obesity on substrate utilization during exercise. Obes Res. 2002 Jul;10(7):575-84. doi: 10.1038/oby.2002.78.
PMID: 12105277
citation: Ellis AC, Hyatt TC, Hunter GR, Gower BA. Respiratory quotient predicts fat mass gain in premenopausal women. Obesity (Silver Spring). 2010 Dec;18(12):2255-9. doi: 10.1038/oby.2010.96. Epub 2010 May 6.
PMID: 20448540
responsible party type: Principal Investigator
investigator affiliation: University of Bath
investigator full name: Javier Gonzalez
investigator title: Lecturer (Assistant Professor) in Human Physiology
sharing ipd: Undecided
provided document: 