Horses with high energy requirements are generally fed two large concentrate meals per day, either in the form of grain or pellets. The postprandial elevation of blood glucose resulting from this type of feeding has the potential to alter production of hormones such as leptin. Leptin is an adipose-derived protein that promotes satiety in normal animals. The objective of this study was to determine if feeding large amounts of concentrate twice each day would alter serum leptin concentration. Nine horses were placed into three groups (A, B, and C) and each group was rotated through three feeding schedules (2x, 3x, and 4x) in a 3 x 3 Latin square design. Horses were fed twice per day on the 2x schedule, three times per day on the 3x schedule, and four times per day on the 4x schedule. Horses were fed the same total amount of concentrate per day throughout the study, although meal size varied with the number of times the horse was fed per day. Horses were weighed and scored for body condition on the first day of each period. Each treatment period lasted for 11 days. Blood was drawn on days one, four, and seven of each period and leptin concentration was determined by radioimmunoassay. On the afternoon of the tenth day of each period, horses were fitted with jugular catheters and blood was drawn every two hours for 24-hours to determine the circadian rhythm of leptin secretion. Additionally, blood was taken 30 minutes prior to and every 30 minutes after the morning meal to determine postprandial plasma glucose concentrations. Mean and peak glucose values were higher on the 2x schedule than the 3x or 4x schedules (P < 0.05). Leptin concentration was highest in horses on the 3x schedule, although when these data were normalized to baseline (day one) values, leptin was highest on the 2x schedule (P < 0.05). Serum leptin concentration was highly correlated with body condition score (P < 0.01), but not gender (P = 0.82), and leptin increased throughout the study (P < 0.05). Data from the 24-hour collection showed that serum leptin concentration varied with time in horses on the 2x but not the 4x schedule (P < 0.05). Linear regression of data from the 2x schedule indicates that the pattern of change may be modeled by a quadratic equation (P < 0.05). This study demonstrates that feeding horses large carbohydrate meals twice per day disrupts the normal pattern of leptin in the horse, possibly affecting appetite and other physiological processes.

Thesis (Ph. D.)--University of Missouri, Columbia, 2001. / Includes abstract, bibliographical references (leaves 145-152) and vita. Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 75-79).

Thesis (Ph. D.)--University of Oklahoma Health Sciences Center, 1957. / Includes bibliographical references (leaves 45-51).

Thesis--M. Phil., University of Hong Kong, 1985.

Thesis--Ph. D., University of Hong Kong, 1984.

Thesis--Ph. D., University of Hong Kong, 1981.

Thesis (M. Sc.)--University of Hong Kong, 1970. / Typewritten.

SIRT1 (sirtuin 1), a mammalian ortholog of the longevity regulator yeast Sir2p, elicits diversified functions by mediating NAD+ -dependent deacetylation of protein targets. SIRT1 contributes to the beneficial effects of calorie restriction, the non-genetic intervention capable of promoting longevity and reducing the incidence of age-related disorders. In mammals, SIRT1 acts as a metabolic regulator in response to environmental stress signals. Activation of SIRT1 protects mice against diet-induced obesity and insulin resistance. However, the tissue specific metabolic functions of SIRT1 remain to be defined. The present study shows that over-expression of human SIRT1 selectively in adipose tissue decreases circulating lipid levels, reduces whole body fat mass, and elevates systemic insulin sensitivity. By contrast, over-expression of a dominant-negative human SIRT1 mutant H363Y in adipose tissue accelerates the development of aging-associated insulin resistance. Activation or down-regulation of adipose SIRT1 promotes lipid mobilization towards different metabolic organs and alters biotin homeostasis in opposite manners. Adipose SIRT1 positively regulates lipid metabolism, genes expression and adipokines secretion which are negatively influenced by SIRT1 H363Y mutant. Biotin is a water soluble vitamin and plays an important role in energy metabolism. The present study shows that biotin and its metabolites are the endogenous inhibitors of SIRT1 enzymatic activity. Chronic biotin supplementation abolishes adipose SIRT1-mediated beneficial effects on lipid metabolism. These effects are partly explained by the regulation of acetyl-CoA carboxylase (ACC), a key regulator of lipid metabolism and biotin homeostasis. SIRT1 selectively deacetylates and negatively regulate the protein stability of ACC. Over-expression of SIRT1 in fat cells persistently down-regulates ACC expression. The direct interaction between SIRT1 and ACC are subjected to rapid regulation by nutrient status which can explain the beneficial effect of SIRT1 in energy homeostasis. In mice subjected to chronic treatment with biotin, the interactions between SIRT1 and ACC were significantly inhibited. Taken in conjunction, the above findings reveal that SIRT1 in adipose tissue functions to regulate systemic energy metabolism and insulin sensitivity. In particular, it plays a critical role in modulating ACC protein levels and biotin homeostasis in adipose tissue, which in turn facilitate lipid storage and utilization in response to nutrient level changes. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

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