Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)

Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)

Thyroid Hormones Homeostasis and Energy Metabolism Changes During Stimulation of Endogenously Secreted Bile Acids (BAs)

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.

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 following parameters will be recorded and compared to placebo: Energy expenditure Substrate utilization Spontaneous movements Skin and core temperature Serial changes in circulating thyroid hormones Serial changes in bile acid serum concentrations 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.

Participants randomized to consume a 100% carbohydrate meal day 1, then a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 2, IV sincalide 0.04mcg/kg + PO placebo day 3, IV placebo + PO placebo day 4, and IV placebo + PO Ursodiol 15mg/kg day 5

Participants randomized to consume a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 1, then a 100% carbohydrate meal day 2, IV sincalide 0.04mcg/kg + PO placebo day 3, IV placebo + PO placebo day 4, then IV placebo + PO Ursodiol 15mg/kg day 5

Participants randomized to consume a 100% carbohydrate meal day 1, then a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 2, IV placebo + PO placebo day 3, IV sincalide 0.04mcg/kg + PO placebo day 4, then IV placebo + PO Ursodiol 15mg/kg day 5

Participants randomized to consume a high fat (72% fat, 8% protein, 20% carbohydrate) meal day 1, then a 100% carbohydrate meal day 2, IV placebo + PO placebo day 3, IV sincalide 0.04mcg/kg + PO placebo day 4, the IV placebo + PO Ursodiol 15mg/kg day 5

Energy expenditure is measured over 6 hours in a respiratory chamber for each intervention and placebo.

Bile acid is measured at 0, 60, 90 and 360 minutes during a 6 hour stay in in a respiratory chamber for each intervention and placebo. The mean of these 4 values is then calculated.

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

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