Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)
Condition: Healthy Volunteers
MeSH terms: Thyroid Diseases
Intervention: Sincalide; Ursodiol; Fat Meal; Carb meal; Placebo
Intervention description: 600 calorie meal containing 72% fat, 8% protein, and 20% carbohydrate; 600 calorie meal containing 100% carbohydrate; IV and/or oral placebo
Intervention MeSH terms: Ursodeoxycholic Acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Deiodinase; Bile Acids; Cholecystokinin; Thyroid Hormones; Energy Expenditure; Healthy Volunteer

Summary:

      Postprandial thermogenesis, or thermic effect of food are terms that describe the increase in
      utilization of energy by the human body following a meal. The mechanisms involved in this
      process are believed to differ according to the type of food consumed, whether fat, protein
      or carbohydrate.

      The bile acids (BAs), unique substances secreted by the gall bladder into the gut after a
      meal, play an important role in the absorption of fat and the management of cholesterol
      stores in the body. Recent studies suggest that BAs may also serve as regulators of energy
      expenditure (consumption) in the cells of our body by increasing the production of T3, an
      active form of thyroid hormone. T3 in turn is believed to increase the efficiency with which
      our bodies burn calories thereby generating heat. Although this process has been shown to be
      effective in rodents who demonstrated weight loss after treatment, the role of BAs in humans
      is poorly understood. Thus we do not know whether endogenous (produced by the body) or
      exogenous (taken as medication) BAs play a significant role in the maintenance of body
      weight. We hypothesize that, similarly to rodents, humans will respond to BAs by increasing
      energy expenditure via the production of the active form of thyroid hormone.

      This randomized, cross-over study will look at changes in thyroid hormones and energy
      consumption in response to stimuli of endogenous BA secretion including dietary content, and
      to the intake of pharmacological doses of bile acids.

      Following a two-day period of equilibration diet, 30 healthy volunteers will be randomly
      assigned to receive either a high-fat or high-carbohydrate isocaloric meal followed by a
      6-hour metabolic chamber stay; the next day they will be crossed-over to the alternate
      intervention. During the following three days, the study subjects will again be randomized to
      receive either an intravenous injection of sincalide (the C-terminal octapeptide fragment of
      cholecystokinin) 0.04 mcg/kg or placebo and P.O. placebo, or I.V. placebo and 15 mg/kg of BA
      (ursodiol) with similar metabolic chamber stays and cross-over design.

      The data gathered from this study will provide greater insight into the physiological and
      molecular mechanism(s) regulating the relation between endogenous bile acid secretion and
      energy metabolism in response to meals, as well as the role of BAs per se on energy
      metabolism.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Age greater than or equal to18 years, male or female

        Written informed consent

        EXCLUSION CRITERIA:

        Hypo- or hyperthyroidism (history or serum thyroid-stimulating hormone (TSH) greater than
        5.0 or less than 0.4 miU/L)

        Blood pressure greater than 140/90 mmHg (26) or receiving antihypertensive therapy

        History of cardiovascular disease

        BMI less than or equal to 20 or greater than or equal to 27 Kg/m(2)

        Diabetes mellitus (fasting serum glucose greater than or equal to 126 mg/dL)

        Hyperlipidemia (serum total cholesterol greater than or equal to 240 mg/dL, triglycerides
        greater than or equal to 220 mg/dL, and/or use of antilipemic therapy)

        Liver disease or ALT serum concentrations greater than 1.5 times the upper laboratory
        reference limit

        Hyperbilirubinemia (serum total bilirubin greater than 1.5 mg/dL)

        Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min (MDRD
        equation)

        Anemia (Hemoglobin concentration less than or equal to 11.1 g/dL females, and 12.7 g/dL
        males)

        History of cholecystectomy or cholelithiasis (by ultrasound at screening).

        History of malabsorption, or food allergies/intolerances that would preclude participant
        from consuming foods required for study

        Claustrophobia

        History of illicit drug or alcohol abuse within the last 5 years; current use of illicit
        drugs (by history) or alcohol (CAGE greater than 3)

        Psychiatric conditions or behavior that would be incompatible with safe and successful
        participation in this study

        Current use of medications/dietary supplements/alternative therapies known to alter thyroid
        function, energy expenditure or bile acid secretion

        History of weight loss or weight gain of greater than 3 percent body weight over the past 2
        months (self-reported)

        Pregnancy/breastfeeding/hormonal contraceptive use and childbirth within the last 6 months

        Perimenopausal (as self-described within two years from onset of amenorrhea or current
        complaints of hot flashes)

        Current smoker