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The Role of Leptin in Body Weight RegulationSkowronski, Alicja Anna January 2017 (has links)
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.
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Short and long-term effectiveness of a weight loss programMann, Janet G. 02 October 2001 (has links)
The purpose of this study was to determine that a behavioral lifestyle modification
approach to weight loss changes participants' dietary intake and physical activity
levels and that these changes were associated with weight loss and weight loss
maintenance. Behavioral factors important in other weight control studies were also
investigated to see if they are important indicators of successful weight control in
this program as well. A group of previously validated questionnaires, along with a
weight history written for this study, was administered to current participants in
Providence Health System's Smart CHOICES program both before and after
program participation. The same questionnaires were administered to past
participants in a one-time follow-up for the CHOICES program approximately 2
years after program completion. The study found that current participant successful
weight losers did decrease their percentage of energy intake from fat more than did
non-successful weight losers over the course of the program. Also, successful
weight losers decreased their caloric intake and increased physical activity levels
during the program and these changes did not occur in non-successful weight
losers. The Eating Inventory scales for cognitive restraint and Westenhoefer's
flexible control showed expected increases and disinhibition and hunger scores
showed expected decreases among successful weight losers. However, non-successful
weight losers showed these same changes except for the hunger scores,
which did not decrease during the program. There were no differences found
between past participant weight loss maintainers and non-maintainers in caloric
intake, percentage fat intake, physical activity levels, Eating Inventory scales, or
flexible and rigid control. When compared to successful weight losers among the
current participants, there were suggestions that past participant weight loss
maintainers and non-maintainers regressed toward their pre-treatment levels in
percentage of fat intake, physical activity levels, and flexible control scores over
time. While the Smart CHOICES program is effective in bringing about short-term
behavior change to produce weight loss, maintenance of weight loss is a problem in
this program as it is in other lifestyle modification programs. The factors
differentiating successful weight maintenance from weight regain after loss in this
program were not identified. / Graduation date: 2002
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Prediction of minimum wrestling weight in adolescent wrestlers by using anthropometric measuresDe Vos, Alphons Cornelius, 1962- January 1987 (has links)
Fifty-five wrestlers from Tucson, Arizona were studied to develop equations using anthropometric measurements to predict a wrestler's minimum wrestling weight (MWW). This sample was also used to cross-validate seven equations that predict MWW by using anthropometric measures. All estimates of percent fat and MWW were validated by densitometry. The mean age, weight, percent fat and MWW for this sample, with standard deviations, were 16.8 ± 1.1 yrs, 63.7 ± 12.7 kg, 8.8 ± 5.49 percent, and 60.6 ± 9.49 kg. Using multiple regression analysis, the best combination of variables predicted MWW with an adjusted R2 of.93 and standard error of estimate (SEE) of 2.45 kg. The next best equation from this sample predicted MWW with an adjusted R2 of.91 and SEE of 2.8 kg. All seven of the equations from other samples were successfully cross validated on this sample. These equations predicted the criterion MWW with respective adjusted R2's and SEE's ranging from.91 and 2.84 kg to.79 and 4.28 kg.
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A study of the effect of progesterone on the body weight regulation in intact female ratsRavelingien, Jo January 1992 (has links)
It is the aim of this study to elucidate the influence of progesterone on body weight regulation in intact female rats. A study of the literature includes a description of the body weight regulation and the effects of ovarian hormones on it. The controlled-system approach tries to link behavioral and physiological factors altering energy balance. The experimental study is subdivided into food-intake - and food-selection studies, a locomotor activity study, a study eliciting a possible role of thermogenesis, and finally rat liver studies which consist of a gas chromatography analysis of hepatic fatty acids and an electron microscopy study examining the ultrastructure of hepatocytes. It can be concluded that the effect of progesterone treatment on the body weight of intact female rats depends on the route of administration. There is a significant increase in body weight after subcutaneous progesterone injections without changes in total caloric intake and nutrient selection habits, indicating the importance of energy expenditure. But changes in spontaneous activity make no contribution in the progesterone-induced energy storage. It is also concluded that peripherally located brown adipose tissue thermogenesis is not changed, without ruling out the effect of more centrally located thermogenic organs as the liver. In this organ, small but significant changes in the fatty acid profile occur during the subcutaneous progesterone treatment.
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Characterizing the secretome of adipose tissue in metabolic stressGoodman, Joshua January 2024 (has links)
Adipose tissue is a crucial organ that sits at the nexus of organismal metabolism. Evolutionary systems seemingly developed to regulate weight such that the risk of starvation accompanying low weight was balanced against the risk of predation accompanying high weight, but the molecular underpinnings of these systems have not been fully elucidated.
The modern obesogenic diet has led these processes to become dysregulated, resulting in increased rates of obesity and associated metabolic disorders, making a full understanding of the mechanisms underlying weight regulation even more important. Parabiosis experiments support the existence of an uncharacterized anorectic factor that opposes weight gain. A previously established system of murine overfeeding recapitulates the defense of body weight against rapid weight gain and uncovers a non-inflammatory adipose tissue environment in the setting of obesity.
Building on this past work, this thesis sets out to characterize the protein secretome of adipose tissue from overfed mice in order to provide insight into possible candidate anorectic factors and better understand the physiology of adipose tissue in this experimental form of obesity.In doing so, we uncover a previously unappreciated phenomenon of mitochondrial secretion from adipose tissue depending on metabolic state. We find that mitochondria are secreted in greater number from overfed adipose tissue and that these mitochondria are enriched for enzymes related to de novo lipogenesis.
We also demonstrate that mitochondria are released intact. We find that some of these phenotypes are shared in genetically obese db/db mice, pointing toward potential physiological roots. We also characterize the plasma proteomes of overfed mice, finding that in overfed mice, inflammatory pathways are increased in the absence of induction of canonical inflammatory cytokines and in the absence of inflammation in the adipose tissue.
Collectively, this work demonstrates the utility and importance of using experimental models in order to better disentangle phenomena of feeding, obesity, and inflammation. It offers direction for future studies that can positively identify an adipocyte-secreted anorectic factor peptide and work to define the manner in which local and systemic inflammation can be uncoupled from adipose tissue hypertrophy.
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Oral contraceptives, weight control, and fat patterning in young college womenLitchfield, Ruth Edson January 2011 (has links)
Typescript (photocopy). / Digitized by Kansas State University Libraries / Department: Foods and Nutrition.
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A personal health planning tool: diet and exercise.January 2003 (has links)
by Hung Chi-Wai, Pang Kin-Wah. / Thesis (M.B.A.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 51-52). / ABSTRACT --- p.ii / TABLE OF CONTENTS --- p.iii / ACKNOWLEDGEMENTS --- p.vi / Chapter CHAPTER I --- INTRODUCTION --- p.1 / Chapter CHAPTER II --- METHODOLOGY --- p.4 / Chapter CHAPTER III --- TARGET USERS --- p.6 / Chapter CHAPTER IV --- OBJECTIVES --- p.7 / Aim at Fitness --- p.7 / Build a Healthy Base --- p.7 / Plan a Diet Sensibly --- p.8 / Chapter CHAPTER V --- HEALTHY WEIGHT & OVERWEIGHT --- p.10 / Chapter CHAPTER VI --- BODY MASS INDEX --- p.12 / General Guideline of BMI --- p.13 / BMI is a Diagnostic Tool --- p.14 / BMI Measures Body Fat --- p.14 / Chapter CHAPTER VII --- DAILY CALORIE REQUIREMENT --- p.16 / Basal Metabolic Rate --- p.17 / Activity Level --- p.17 / Losing Weight and Increasing Weight --- p.18 / Limitation of Basal Metabolic Rate Calculation --- p.18 / Chapter CHAPTER VIII --- PHYSICALLY ACTIVE --- p.20 / Physical Activity and Nutrition --- p.22 / Chapter CHAPTER IX --- FOOD PYRAMID --- p.23 / Grains --- p.25 / Fruits and Vegetables --- p.25 / Know More About Fat --- p.25 / Chapter CHAPTER X --- CORRECTING OR AVOIDING BAD EATING HABITS --- p.28 / Skip Breakfast --- p.28 / Eat Too Fast --- p.29 / Eat Too Much Fast Food --- p.29 / Have Unhealthy Snacks and Drinks --- p.29 / Chapter CHAPTER XI --- DESCRIPTION OF PERSONAL HEALTH PLANNING MODEL --- p.30 / Personal Health Planning Model flow --- p.32 / Data Input --- p.33 / Database --- p.34 / Calculation --- p.34 / Optimization --- p.35 / Constraints --- p.35 / Report --- p.35 / Chapter CHAPTER XII --- LIMITATIONS OF OUR MODEL --- p.35 / Chapter CHAPTER XIII --- CONCLUSION --- p.35 / APPENDIX 1 --- p.35 / APPENDIX II --- p.35 / APPENDIX III --- p.35 / APPENDIX IV --- p.35 / APPENDIX V --- p.35 / REFERENCES --- p.35
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Chronic green tea consumption on body fat accumulation in rats fed with hypercholesterol diet潘雅縈, Poon, Nga-ying, Pauletta. January 2003 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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Photoperiodic and diurnal regulation of WNT signalling in the arcuate nucleus of the 1 female Djungarian hamster, Phodopus sungorusBoucsein, A., Benzler, J., Hempp, C., Stöhr, S., Helfer, Gisela, Tups, A. 08 December 2015 (has links)
Yes / The WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal.
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Mathematical modeling of the hormonal regulation of food intake and body weight : applications to caloric restriction and leptin resistance / Modélisation mathématique de la régulation hormonale de la prise alimentaire et de la prise de poids : Applications à la restriction calorique et la résistance à la leptineJacquier, Marine 05 February 2016 (has links)
Réguler la prise alimentaire et la dépense énergétique permet en général de limiter d'importants changements de poids corporel. Hormones (leptine, ghréline, insuline) et nutriments sont impliqués dans ces régulations. La résistance à la leptine, souvent associée à l'obésité, limite la régulation de la prise alimentaire. La modélisation mathématique de la dynamique du poids contribue en particulier à une meilleure compréhension des mécanismes de régulation (notamment chez l’humain). Or les régulations hormonales sont largement ignorées dans les modèles existants.Dans cette thèse, nous considérons un modèle de régulation hormonale du poids appliqué aux rats, composé d'équations différentielles non-linéaires. Il décrit la dynamique de la prise alimentaire, du poids et de la dépense énergétique, régulés par la leptine, la ghréline et le glucose. Il reproduit et prédit l'évolution du poids et de la prise alimentaire chez des rats soumis à différents régimes hypocaloriques, et met en évidence l'adaptation de la dépense énergétique. Nous introduisons ensuite le premier modèle décrivant le développement de la résistance à la leptine, prenant en compte la régulation de la prise alimentaire par la leptine et ses récepteurs. Nous montrons que des perturbations de la prise alimentaire, ou de la concentration en leptine, peuvent rendre un individu sain résistant à la leptine et obèse. Enfin, nous présentons une simplification réaliste de la dynamique du poids dans ces modèles, permettant de construire un nouveau modèle combinant les deux modèles précédents / The regulation of food intake and energy expenditure usually limits important loss or gain of body weight. Hormones (leptin, ghrelin, insulin) and nutrients (glucose, triglycerides) are among the main regulators of food intake. Leptin is also involved in leptin resistance, often associated with obesity and characterized by a reduced efficacy to regulate food intake. Mathematical models describing the dynamics of body weight have been used to assist clinical weight loss interventions or to study an experimentally inaccessible phenomenon, such as starvation experiments in humans. Modeling of the effect of hormones on body weight has however been largely ignored.In this thesis, we first consider a model of body weight regulation by hormones in rats, made of nonlinear differential equations. It describes the dynamics of food intake, body weight and energy expenditure, regulated by leptin, ghrelin and glucose. It is able to reproduce and predict the evolution of body weight and food intake in rats submitted to different patterns of caloric restriction, showing the importance of the adaptation of energy expenditure. Second, we introduce the first model of leptin resistance development, based on the regulation of food intake by leptin and leptin receptors. We show that healthy individuals may become leptin resistant and obese due to perturbations in food intake or leptin concentration. Finally, modifications of these models are presented, characterized by simplified yet realistic body weight dynamics. The models prove able to fit the previous, as well as new sets of experimental data and allow to build a complete model combining both previous models regulatory mechanisms
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