Secretin, the first hormone commencing the field of endocrinology, has been studied for its pleiotropic role in the body inclusive of its neuroactive and body water homeostatic and gastrointestinal functions. Yet, the metabolic effect of secretin remains elusive and is being proposed recently for a revisit. Recent discovery from our lab showed an anorectic response for secretin, while its role in lipid homeostasis remains largely unexplored. Exerting functions such as exocrine pancreatic secretion and gastric motility inhibition, intestinal fatty acid induced release of secretin was recently shown to be mediated by CD36. Fasting related increase in plasma secretin concentration has been proposed to be involved in lipolysis but evidences regarding lipolytic actions of secretin remain contradictory. Recent report has suggested that secretin stimulates both lipolysis and lipogenesis in adipose cells. Thus, we hypothesize that secretin modulates lipid homeostasis, which was examined under two opposite, energy deficient and energy excess, conditions. Under energy deficient/starved state, secretin level in circulation and secretin receptor level in epididymal adipose tissue were found to be upregulated. Using secretin receptor knockout (SCTR-/-) and secretin knockout (SCT-/-) mice as controls, it was found that secretin stimulated a dose- and time-dependent lipolysis in vitro and acute lipolysis in vivo. H-89, a protein kinase A (PKA) inhibitor, attenuated the lipolytic effects of secretin in vitro, while secretin induced an increase in cAMP dependent PKA activity in vivo. Using western blot analysis, secretin was found to phosphorylate hormone sensitive lipase (HSL) at serine residue 660. Additionally, immunofluorescent studies revealed that secretin stimulated translocation of HSL from cytosol to surface of lipid droplet subsequently leading to lipolysis. Under excess energy condition, when SCTR-/- mice and its littermates SCTR+/+ mice were subjected to high fat diet (HFD) feeding for 3 months, it was found that SCTR-/- mice gained lesser weight. Nuclear magnetic resonance imaging revealed that SCTR-/- mice exhibited lower body fat content. Additionally, HFD-associated hyperleptinaemia was alleviated in SCTR-/- mice along with metabolic syndrome as they performed better in insulin and glucose tolerance tests. Continuous monitoring by indirect calorimetry revealed similar food intake, energy expenditure and locomotor activity between SCTR-/- and SCTR+/+ mice. Interestingly, intestinal fatty acid absorption, measured by a noninvasive method, was impaired in HFD-fed SCTR-/- mice. While postprandial triglyceride release was reduced in SCTR-/- mice, it also had a significant reduction in transcript and protein levels of CD36 and its downstream mediator MTTP. Secretin, when incubated with isolated enterocytes, upregulated the expression of CD36. In summary, during starvation, secretin stimulates lipolysis through a HSL and PKA mediated pathway. When fed a HFD, SCTR-/- mice is resistant to diet induced obesity due to impaired intestinal lipid absorption. A novel short positive feedback pathway between CD36 and secretin, functioning to maximize lipid absorption, is also being proposed. Thus for the first time, two independent role of secretin in lipolysis and in intestinal lipid absorption were discovered along with their mechanistic insights. This study paves way for developing new therapeutic strategies against metabolic disorders associated with lipid metabolism. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

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Glycosaminoglycan-peptide complexes (GAG-P) and some proteoglycans from long bones, breast muscle, comb, crop, gizzard, heart, infundibulum, intestines, isthmus, kidney, leg muscle, liver, lung, magnum, oesophagus, ovary, pancreas, proventriculus, skin, shell gland, spleen, trachea, vagina, wattle, cecum, egg yolk and adipose tissue of the white leghorn hen were isolated and analysed for constituent units. Techniques of identification included infrared spectroscopy, cellulose acetate electrophoresis, colorimetric reactions, ion-exchange chromatography and scanning electron microscopy. The in vivo incorporation of {('14)C}-glucosamine (GlcN) and {('14)C}-galactosamine (GalN) for 1-, 2-, 120-, and 240-hour periods, and {('14)C}-glucose (Glc) and {('14)C}-galactose (Gal) for a 48-hour period into whole tissues, acetone-extracted tissues and GAG-P were investigated. Radioactivity in excreta was measured. ('14)CO(,2) from the {('14)C}-hexose treated birds was determined. In vitro incorporation of ('14)C from {('14)C}-Glc, {('14)C}-Gal, {('14)C}-GlcN, {('14)C}-GalN, {('14)C}-fructose and {('14)C}N-acetylneuraminic acid were studied.

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This study examined the trend of varying volumes of exercise on the risk factors embodying the metabolic syndrome in sedentary women (n=21, 49.2 ± 5.7 years). The following measurements: waist and hip circumference, weight, height, resting blood pressure, body composition, fasting levels of blood glucose, lipids, and insulin, peak V02 and treadmill time were measured at baseline and upon the completion of the study. Women were randomly assigned to one of three energy expenditure groups: 600 kcals/week (n=6), 800 kcals/week (n=8) or 1000 kcals/week (n=7). They were instructed to perform cardiovascular exercise three times a week for three months in a moderate exercise-training program with no modifications in their diet. The results revealed few significant changes in the risk factors embodying the metabolic syndrome. Nevertheless, these volumes of exercise were adequate in reducing at least one metabolic disorder in nearly half (48%) of our subject population. This impact of exercise on metabolic syndrome risk factors was clinically important because as metabolic disorders decreased so did the mortality risk from cardiovascular and coronary disease within these women. / School of Physical Education

Phenylketonuria (PKU) is an inherited metabolic disease that affects about one in 10,000 of the population worldwide. In the classical form of the condition, the hepatic enzyme phenylalanine hydroxlase is absent or much reduced. If untreated, severe or profound mental handicap customarily results due to the accumulation of dietary phenylalanine (phe) which is neurotoxic. The mechanism by which phe impairs growth in the immature nervous system is little understood, but myelin metabolism appears to be disturbed. Treatment is by reduction of phe in daily food intake. Treatment should ideally begin in the neonatal period if intellectual loss is to be avoided. However, the safe range of phe concentrations during treatment and the age at which treatment can be discontinued without further damage being inflicted are uncertain. The studies reported in this volume investigated neuropsychological outcomes of treatment control and cessation factors. In addition, the question of whether executive functions are especially vulnerable to elevated phe concentrations during treatment was addressed. Patient samples conformed to the practice adopted in the West of Scotland regional centre for the management of PKU of maintaining dietary treatment until age 10 or beyond. Almost exclusively, negative findings emerged. These suggested that, if control of phe intake conforms to current UK recommendations for the preschool and primary years, neither global nor specific intellectual deficit result. Furthermore, the data supported the view that cessation of treatment at 10 years of age does not have harmful consequences. These findings have direct implications for the formulation of clinical policy on the treatment of PKU, but it must be recognized that the history of the successful treatment of PKU and mass screening for the disease spans a mere three decades. Thus, treatment outcome research to date is based only on children and young adults. In future investigations, a life-span approach will be required before the issues raised in this thesis can be finally settled.

Pregnant and weanling rats were fed liquid diets with or without 30 percent of total kcal from ethanol and varying levels of copper in order to determine if ethanol ingestion would exaggerate a marginal copper status to an obvious copper deficiency. Pregnant albino rats were fed either 0.75 or 3.75 mg Cu/L throughout gestation and the first 15 days of lactation while female weanling rats received 0.5 or 2.5 mg Cu/L for 5 weeks. Ethanol consumption exaggerated a marginal copper status during reproduction as evidenced by significant reductions in maternal liver copper concentration and enzymatic activity of the copper metalloprotein Copper-Zinc superoxide dismutase in offspring liver. Ethanol had little or no effect upon copper status in weanling rats. In addition, serum copper failed to reflect a developing depletion of liver copper when ethanol was being consumed. Since it is known that the average American diet is just adequate in copper content, and that copper balance is difficult to achieve during times of increased metabolic demand, pregnant subjects may be at a great risk to develop a copper deficiency when ethanol is being consumed. This ethanol and copper interaction, however, will likely go undetected if only serum copper is used as an indicator of copper status. / Graduation date: 1989

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No description available.