published_or_final_version / Anatomy / Master / Master of Science

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by Sea Man Mei, Mandy. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 203-214). / Abstract also in Chinese. / ACKNOWLEDGMENTS --- p.i / ABSTRACT --- p.ii / LIST OF ABBREVAIATIONS --- p.vi / TABLE OF CONTENTS --- p.vii / Chapter Chapter1 --- General Introduction / Chapter 1.1 --- DEFINITION --- p.2 / Chapter 1.2 --- MOTIVATION OF THE ONSET OF WEIGHT CYCLING --- p.3 / Chapter 1.3 --- PHYSIOLOGICAL EFFECTS OF WEIGHT CYCLING --- p.6 / Chapter 1.3.1 --- """Dieting-Induced Obesity"" Hypothesis" --- p.6 / Chapter 1.3.1.1 --- Food Efficiency --- p.6 / Chapter 1.3.1.2 --- Proposed Mechanisms for the Increase of Food Efficiency --- p.10 / Chapter 1.3.1.3 --- Change in Body Fat --- p.14 / Chapter 1.3.2 --- Association with Increased Mortality and Coronary Heart Disease (CHD) --- p.15 / Chapter Chapter2 --- Depletion of Linoleic Acid and α-Linolenic Acid Caused by Weight Cycling is Independent of the Extent of Calorie-Restriction / Chapter 2.1 --- INTRODUCTION --- p.18 / Chapter 2.1.1 --- Nomenclature of Fatty Acids --- p.18 / Chapter 2.1.2 --- Metabolism and Physiological Roles of LA and α-LnA --- p.19 / Chapter 2.1.2.1 --- "LA, α-LnA and their Derivatives as Structural Components" --- p.21 / Chapter 2.1.2.2 --- Production of Eicosanoids from LA and α-LnA --- p.22 / Chapter 2.1.2.3 --- Other Physiological Roles --- p.23 / Chapter 2.1.3 --- Dietary LA and α-LnA Relative to CHD --- p.24 / Chapter 2.1.3.1 --- Dietary LA and CHD --- p.24 / Chapter 2.1.3.2 --- Dietary α-LnA and CHD --- p.26 / Chapter 2.1.4 --- WC-Induced Alteration in the Composition of Tissue Lipids --- p.27 / Chapter 2.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.29 / Chapter 2.3 --- MATERIALS AND METHODS --- p.30 / Chapter 2.3.1 --- Animals and Diets --- p.30 / Chapter 2.3.2 --- Lipid Analysis --- p.32 / Chapter 2.3.3 --- Triacylglycerol Species Analysis --- p.34 / Chapter 2.3.4 --- Other Assays --- p.35 / Chapter 2.3.5 --- Statistics --- p.35 / Chapter 2.4 --- RESULTS --- p.36 / Chapter 2.4.1 --- Food Intake --- p.36 / Chapter 2.4.2 --- Change of Body weight --- p.38 / Chapter 2.4.3 --- Weight of Liver and Adipose Tissues --- p.40 / Chapter 2.4.4 --- Serum Cholesterol and Triglycerides --- p.41 / Chapter 2.4.5 --- Carcass Total Fatty Acids --- p.42 / Chapter 2.4.6 --- Adipose Tissue Fatty Acids --- p.44 / Chapter 2.4.7 --- Liver Fatty Acids --- p.47 / Chapter 2.5 --- DISSCUSION --- p.50 / Chapter Chapter3 --- Influence of Dietary Fat Level on Fatty Acid Composition and Adiposity in Weight-Cycled Rats / Chapter 3.1 --- INTRODUCTION --- p.56 / Chapter 3.1.1 --- Fat Preference and Intake in Humans --- p.56 / Chapter 3.1.2 --- Alteration of Lipid Metabolism Induced by Dietary Fat --- p.58 / Chapter 3.1.3 --- Interaction Between Weight Cycling and Fat Intake --- p.60 / Chapter 3.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.62 / Chapter 3.3 --- MATERIALS AND METHODS --- p.63 / Chapter 3.3.1 --- Animals and Diets --- p.63 / Chapter 3.3.2 --- Analysis of Adipocytes --- p.66 / Chapter 3.3.3 --- Fatty Acid Analysis --- p.67 / Chapter 3.3.4 --- "Determination of Serum Cholesterol, Triglycerides and Glucose" --- p.68 / Chapter 3.3.5 --- Statistics --- p.68 / Chapter 3.4 --- RESULTS --- p.69 / Chapter 3.4.1 --- Body Weight --- p.69 / Chapter 3.4.2 --- Food Intake and Food Efficiency --- p.71 / Chapter 3.4.3 --- Weight of Liver --- p.74 / Chapter 3.4.4 --- Weight of Adipose Tissue --- p.74 / Chapter 3.4.5 --- Number and Size of Adipocytes --- p.81 / Chapter 3.4.6 --- "Serum Triglycerides, Cholesterol and Glucose" --- p.85 / Chapter 3.4.7 --- Fatty Acid Composition --- p.92 / Chapter 3.5 --- DISCUSSION --- p.145 / Chapter 3.5.1 --- Weight Cycling-Induced Obesity Only with a High-Fat Diet --- p.145 / Chapter 3.5.1.2 --- Effect of Weight Cycling on the Size of Adipocytes --- p.147 / Chapter 3.5.1.3 --- Food Efficiency during Weight Cycling --- p.148 / Chapter 3.5.2 --- Weight-Cycling Induced Specific Alteration of Fatty Acid Metabolism --- p.149 / Chapter Chapter4 --- Weight Cycling Altered the Activities of Lipoprotein Lipase and Lipogenic Enzymes in Rats / Chapter 4.1 --- INTRODUCTION --- p.152 / Chapter 4.1.1 --- Fatty Acid Metabolism --- p.152 / Chapter 4.1.1.1 --- Fatty Acid Synthesis --- p.152 / Chapter 4.1.1.2 --- Fatty Acid Storage --- p.155 / Chapter 4.1.1.3 --- Fatty Acid Oxidation --- p.156 / Chapter 4.1.2 --- Hormonal Control of Fatty Acid Metabolism During Fasting and Refeeding --- p.158 / Chapter 4.1.2.1 --- Fatty Acid Metabolism During Fasting --- p.158 / Chapter 4.1.2.2 --- Fatty Acid Metabolism During Fed-State --- p.160 / Chapter 4.2 --- OBJECTIVE OF THE PRESENT STUDY --- p.161 / Chapter 4.3 --- MATERIALS AND METHODS --- p.162 / Chapter 4.3.1 --- Samples --- p.162 / Chapter 4.3.2 --- Enzymatic Analysis --- p.162 / Chapter 4.3.2.1 --- Lipoprotein Lipase (LPL; EC 3.1.1.34) --- p.162 / Chapter 4.3.2.2 --- Fatty Acid Synthase (FAS; EC 2.3.1.85) --- p.165 / Chapter 4.3.2.3 --- Malic Enzyme (ME; EC 1.1.1.40) --- p.166 / Chapter 4.3.2.4 --- Pyruvate Kinase (PK; EC 2.7.1.40) --- p.166 / Chapter 4.3.2.5 --- Acetyl-CoA Carboxylase (ACC; EC 6.4.1.2) --- p.167 / Chapter 4.3.2.6 --- "Phosphoenolpyruvate Carboxykinase (PEPCK, EC 4.1.1.32)" --- p.168 / Chapter 4.3.2.7 --- Determination of Protein Content --- p.169 / Chapter 4.3.3 --- Determination of Serum Insulin and Serum Glucagon --- p.169 / Chapter 4.3.4 --- Statistics --- p.169 / Chapter 4.4 --- RESULTS --- p.170 / Chapter 4.4.1 --- Enzymatic Analysis --- p.170 / Chapter 4.4.1.1 --- Lipoprotein Lipase --- p.170 / Chapter 4.4.1.2 --- Fatty Acid Synthase --- p.175 / Chapter 4.4.1.3 --- Malic Enzyme --- p.182 / Chapter 4.4.1.4 --- Pyruvate Kinase --- p.182 / Chapter 4.4.1.5 --- Acetyl-CoA Carboxylase --- p.187 / Chapter 4.4.1.6 --- Phosphoenolpyruvate Carboxykinase --- p.187 / Chapter 4.4.2 --- Level of Serum Insulin and Glucagon --- p.192 / Chapter 4.5 --- DISCUSSION --- p.196 / Chapter 4.5.1 --- Effect of Weight Cycling on Activity of Lipoprotein Lipase and Lipogenic Enzymes Activity --- p.196 / Chapter 4.5.2 --- The Overshoot of Enzymatic Activities in Relation to Tissue Fatty Acid Composition --- p.198 / Chapter 4.5.3 --- No Elevation of Plasma Insulin in Weight Cycled Rats --- p.199 / Chapter Chapter5 --- Conclusion --- p.200 / References --- p.203

Digitized by Kansas Correctional Industries

Leptin is an adipocyte-derived hormone which circulates in concentrations that are closely correlated with amounts of body fat. It provides a chronic signal to the central nervous system (CNS) regarding quantity of stored body fat and as such it is involved in the regulation of long term energy homeostasis. Leptin also declines abruptly when negative energy is imposed, providing a signal of incipient threats to the adequacy of fat stores. Humans and mice maintain body weight (fat) at remarkably stable levels without conscious effort to adjust food intake or energy expenditure. Changes in body weight induced by either overfeeding or dietary restriction are rapidly reversed when free feeding is resumed, indicating that altered body weight is accompanied by physiological adjustments that oppose this change. The “set-point” that is being defended depends on individuals’ genetic makeup and developmental environment during the perinatal period. Several aspects of leptin physiology were investigated in the work presented in this dissertation including:  the effects of transient hyperleptinemia at specific developmental periods on subsequent body weight set point in mice;  regulation of body weight in the absence of leptin in mice;  genetic contributors to circulating leptin concentrations in human and mice, and;  the efficacy of an MC4R agonist – a downstream target of leptin – on maintenance of reduced body weight in mice. Chapter 2 and 3. The effects of transient hyperleptinemia at specific developmental periods on subsequent body weight set point in mice To assess whether leptin per se influences the body weight set point and whether there is a critical time window for such effects, we generated a transgenic mouse in which non-invasive induction of transient hyperleptinemia is dissociated from adiposity. This transgenic mouse uses a TET-ON system in which transgenic (CMV-driven) leptin expression is regulated by exposure to doxycycline (dox) in a dose-responsive manner that can be rapidly turned on and off. Circulating leptin concentrations can be elevated to those in a high fat-fed obese mouse within one day and either sustained indefinitely or restored to baseline concentrations within 24 hours. Acute overexpression of leptin in the adult transgenic mice reduces food intake and causes transient weight loss – confirming that the transgenic leptin is bioactive and capable of triggering anticipated physiological responses. This leptin transgenic mouse enables reversible increases in circulating leptin to virtually any level at any point in development. Using this system we investigated the physiological consequences of developmentally timed transient hyperleptinemia on subsequent apparent set point for adiposity. Specifically, we evaluated the physiological effects of elevated leptin during adulthood, “adolescence” and the immediate postnatal period on the defense of body weight (adiposity) later in life and on the susceptibility to gain weight when offered a highly palatable diet ad libitum. We showed that inducing chronic hyperleptinemia in adult or “adolescent” mice does not increase the set point of defended body weight when excess leptin is removed; however, transient elevation of circulating leptin in the immediate postnatal period increases the hyperphagic response of the offspring to a highly palatable diet 7 weeks later, and renders animals more susceptible to obesity as adults. We demonstrated that leptin per se is capable of influencing the susceptibility of mice to gain weight on high fat diet; however, these effects are restricted to a critical time window which we identified to be the immediate postnatal period. Chapter 4. Regulation of body weight in the absence of leptin in mice Leptin-deficient Lepob/ob mice show metabolic compensation for lost weight and they appear to defend body fat by leptin-independent mechanisms. We attempted to identify mechanisms involved in leptin-independent regulation of body weight. Lepob/ob mice were either fed ad libitum or calorie restricted to lose 20% of body weight. Calorie-restricted mice reduced energy expenditure and, when released to ad libitum feeding, regained fat and lean mass (to the levels of ad libitum controls) within 5 weeks. Calorie-restricted mice did so while their ad libitum caloric intake was equal to that of the control animals. These results confirm that, in congenitally leptin deficient animals, leptin is not required for compensatory reduction in energy expenditure accompanying weight loss, but suggest that the hyperphagia of the weight-reduced state is leptin-dependent. Chapter 5. Genetic contributors to circulating leptin concentrations in human and mice While circulating leptin concentrations correlate closely with body fat, at any given level of adiposity, there is substantial variation in circulating leptin. We collaborated with Dr. Ruth Loos – professor of Environmental Medicine & Public Health at Icahn School of Medicine at Mount Sinai – and her associates who carried out a genome-wide association study of circulating leptin concentrations adjusted for body mass and composition, and identified five loci associated with reduced circulating leptin concentrations [1]. The aim of the study was to identify and functionally assess potentially causal gene(s) within each implicated region. Our aim was to identify genes that modify leptin production/release in a manner that might account for reduced circulating leptin concentrations and hence predisposition to obesity. We developed an assay to directly measure effects of the candidate genes in ex vivo adipose tissue explants on production and secretion of leptin. Using siRNAs, we knocked down expression of these genes in perigonadal adipose tissue explants from mice fed high fat diet and demonstrated that Adig, located in the SLC32A1 locus, modulates leptin production and secretion [1]. These studies provide a prototype for the functional deconvolution of groups of genes identified by genome-wide association studies in which a specific cell type can be implicated. Chapter 6. The efficacy of an MC4R agonist – a downstream target of leptin – on maintenance of reduced body weight in mice Finally, we investigated the efficacy of an MC4R agonist in maintenance of reduced body weight in mice [2]. Weight loss is difficult to maintain due to physiological adaptations in energy expenditure and drive to eat that accompany this state. Exogenous leptin sufficient to restore circulating levels to those preceding weight (fat) loss reverses many of the relevant phenotypes. MC4R is a downstream target of leptin signaling and is central in energy homeostasis. In collaboration with scientists at AstraZeneca, we studied the effectiveness of a novel peptide MC4R agonist in maintenance of reduced body weight compared to its use in inducing weight loss. In the weight reduced state, 5x lower doses of the same molecule were comparably efficacious to a higher dose in the ad libitum state [2]. This protocol provides a model for evaluating the mechanisms and quantitative efficacy of weight-maintenance strategies and agents. These data support the concept that the pharmacology of the weight reduced state may be more tractable than that designed to induce weight loss. Overall, the major conclusions from these studies are that:  transient hyperleptinemia during the postnatal period can influence the susceptibility of mice to diet-induced obesity in adulthood;  factors other than leptin contribute to body weight regulation in leptin deficient mice;  functional, biological assays can be used to identify causal genes in genome-wide association study identified loci, and;  pharmacological agents to maintain reduced weight may be a tractable target for treatment of obesity.

This study examined attitudes and behavioral intentions of eight-grade students toward figures (representing hypothetical peers) of varying body weight (average, overweight, and obese). The primary aim of this study was to investigate how weight impacts students’ attitudes toward and interactions with peers. Second, impact of the rater’s gender was explored. It was hypothesized that girls would rate average-weight figures more positively than overweight figures and overweight figures more positively than obese figures. It was also hypothesized that boys would rate average-weight figures more positively than overweight and obese figures, with less discrepancy between their ratings of overweight and obese figures. One-hundred seventy primarily Caucasian, eight-grade students (72 male, 98 female; mean age = 13.61, SD = .49) were identified as part of a convenience sample from a public elementary school and were randomly assigned to view a target photo of their same gender in one of three conditions: average-weight, overweight, obese. Participants rated attitudes toward the figures on the Adjective Checklist and behavioral intentions on the Shared Activity Questionnaire-B (SAQ-B). Results showed the hypotheses to be partially supported. Students’ responses on the SAQ-B showed they were statistically significantly more willing to interact with an overweight peer (M = 16.33, SD = 4.19) than an obese peer (M = 14.30, SD = 3.83) for active-recreational activities. The overall effect size (males and females combined) was moderate (.51), with a small effect size for females (.42) and a moderate effect size for males (.64). There were no other statistically significant differences on the SAQ-B subscales of active-recreational, academic, and social, or on the Adjective Checklist. Although differences were not significant, effect sizes for social domain for average versus obese and overweight versus obese were mostly small to medium. Conversely, almost all effect sizes for academic were nonmeaningful. Therefore, it appears weight has less impact in academic interactions than the other two areas. Effect sizes were larger for males than females for overweight versus obese on the Adjective Checklist and SAQ-B social and active recreational, showing that males tended to hold more negative views of obesity than females in these areas.

Thesis (M.S.)--Eastern Illinois University. / Includes bibliographical references (leaves 37-40).

Thesis (M.Sc.-Res.)--University of Wollongong, 2009. / Typescript. Includes bibliographical references: leaf 60-80.

Thesis (Ph. D. in Psychology)--Vanderbilt University, 2004. / Title from PDF title screen. Includes bibliographical references.