Dietary Essential Fatty Acid Regulation of Omega-3 HUFA Metabolism; Satiety and Body Composition
Condition: Weight Gain; Healthy Subjects; Obesity; Women
MeSH terms: Weight Gain
Study type: Interventional

Summary: 
      Background:

      - Rates of obesity have increased dramatically in recent decades, and researchers are
      investigating how changes in diets and physical activity have contributed to this increase.
      To understand how weight might be controlled, it is important to learn what kinds of dietary
      changes can affect hunger and might lower body weight. Essential fatty acids, for instance,
      are an important part of a healthy diet, but researchers have not yet determined the ideal
      amount of essential fatty acids that people should eat. By studying how different diets
      affect body chemistry and hormone levels in women who are overweight or obese, researchers
      hope to be able to determine better diets or treatments to help people reach and maintain an
      optimum healthy weight.

      Objectives:

      - To examine how certain fats in the diet affect body metabolism, hormones, and weight
      regulation.

      Eligibility:

      - Healthy women between 18 and 50 years of age who are overweight or obese (body mass index
      between 25 and 35).

      Design:

        -  This study has an initial screening visit and three phases. All participants will be
           involved in the first two phases of the study, and some participants will be involved in
           the third phase.

        -  Participants will be screened with a physical examination and medical history, in
           addition to blood and urine tests and questionnaires about eating habits and other diet
           factors.

        -  Phase 1: Participants will have three visits to the National Institutes of Health over a
           4-week period. At the visits, participants will have blood and urine tests, complete
           questionnaires, and have other tests including brain and body imaging studies.
           Participants will then be assigned to one of three study diets.

        -  Phase 2: Participants will have a 12-week diet phase, with all foods supplied by the
           study researchers. Participants will keep a daily log of food and beverage intake, and
           will have three testing sessions with procedures similar to those performed in Phase 1.

        -  Phase 3: Participants assigned to a particular study diet (one-third of all
           participants) will be given the option of continuing the diet for an additional 36 weeks
           (9 months), with food consumption, monitoring, and testing procedures similar to those
           performed in Phase 2....
    

Detailed description: 
      Objective

      To evaluate the effects of lowering the dietary nutrient linoleic acid (LA) as a controlled
      variable on: 1) tissue accretion of omega-6 and omega-3 highly unsaturated fatty acids
      (HUFA); 2) bioactive endocannabinoids derived from the omega-6 HUFA arachidonic acid (AA); 3)
      insulin sensitivity; 4) satiety and hunger; and 5) body composition. Modifications in dietary
      LA will be offset with reciprocal changes in the nutrient oleic acid (OA) to maintain
      equivalency of calories and nutrients.

      Study Population

      Up to 180 overweight, but otherwise healthy pre-menopausal women volunteers (aged 18 through
      50) with body mass index (BMI) between 25 and 35 kg/m(2), will be enrolled.

      With the anticipated dropout rates described in Section 7.4, we anticipate that 84 of these
      subjects will be randomized to study diets, and 64 subjects will complete the 12 week diet
      phase.

      Three Group Comparative Analysis

      A total of 84 subjects will be randomized to one of 3 healthy and nutritionally complete
      diets that differ only in the fatty acid composition of added visible oils. All foods will be
      provided through the NIH metabolic kitchen, with subjects visiting the kitchen daily Monday
      through Friday to obtain foods. Each Friday, subjects will carry home foods packed for their
      weekend meals. Baseline testing battery will include: 1) blood composition of omega-6 and
      omega-3 HUFA; 2) endocannabinoid, eicosanoid, and docosanoid derivatives of omega-6 and
      omega-3 HUFA; 3) insulin function assessment; 4) body composition assessment; 4) functional
      satiety assessment; and 5) self-reported measures of satiety, hunger and affective states.
      The full baseline testing battery will be repeated after 84 days of randomized treatment. An
      abbreviated testing battery will be performed after 28 and 56 days of randomized treatment.

      A subset of participants will undergo additional inpatient testing in the 24-hour metabolic
      chamber as described in Section 3.3.2. The remaining subjects will remain ambulatory
      throughout the study. Participants will be advised to continue their usual medical care and
      medications throughout the study.

      36-Week Continuation (Gradient Dose Replacement) Sub Study

      At completion of the 84 day (12 week) study, participants in the low LA group (Group B) will
      have the option of continuing their study diets for another 252 days (36 weeks). During the
      continuation phase, the abbreviated testing battery will be completed after 6, 12, 18, 24 and
      30 weeks, and the full testing battery will be repeated after 36 weeks.

      Outcome Measures

      A Primary Dependent Variables

      The primary outcomes will be the proportion of omega-6 HUFA in total HUFA (%omega-6 in HUFA)
      and two endocannabinoids derived from omega-6 AA, 2-Arachidonoylglycerol (2-AG) and
      N-Arachidonoylethanolamine (Anandamide or AEA).

      Secondary Dependent Variables

      Secondary outcome measures will include blood concentrations of the omega-6 HUFA Arachidonic
      Acid (AA); the omega-3 HUFA Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA); the
      rates of change in %omega-6 in HUFA, AA, EPA, DHA, 2-AG and AEA over time; adipose and muscle
      tissue fatty acid composition; endocrine hormones; gene expression profiles; psychometrics;
      functional satiety; 24-hr energy metabolism and substrate utilization; and body composition,
      as follows: Omega-6 and omega-3 HUFA and total fat content will be measured in adipose and
      muscle tissue biopsies. Other endocannabinoid, eicosanoid and docosanoid derivatives of
      omega-6 and omega-3 HUFA will be measured in plasma via mass spectrometry.

      Psychometric outcomes will include self-reported measures of satiety and affective states.
      Functional satiety will be assessed via buffet-style food array testing. Body composition
      outcomes will include DEXA, 3T MRI, anthropometric measurements and bioelectrical impedance.
      Genotyping will also be performed to assess for interactions between selected gene variants
      and effects of the intervention.
    

Intervention name(s): Linoleic Acid; Docosahexaenoic Acid; Eicosapentaenoic Acid
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Allocation: Randomized
Intervention model: Parallel Assignment
Primary purpose: Treatment
Keywords: Lipids; Obesity; Omega-3 Fatty Acids; Overweight