Maternal weight during pregnancy has an important impact on multiple aspects of health for both mothers and their children. This dissertation investigated whether pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) independently impact a child’s health service utilization. Methods: This dissertation included four studies. The study population for the first three studies was all women who delivered a singleton, live infant in Ontario between 2012-2014 and have information contained in the Better Outcomes Registry and Network (BORN) Ontario registry. Health service data in the first 24 months following birth were collected via health administrative databases housed at ICES. I investigated whether there was an association of pre-pregnancy BMI (Chapter 2) or GWG (Chapter 3) with pediatric health service use. I then investigated whether adverse birth outcomes, specifically small for gestational age (SGA) or preterm birth (PTB), mediated this relationship (Chapter 4). Finally, I developed a cost effectiveness evaluation framework for the implementation of a maternal weight intervention program to limit the impact on the child (Chapter 5).Findings: Children born to women with pre-pregnancy obesity relative to normal weight experienced higher rates of hospitalization (adjusted incidence rate ratio [aIRR]: 1.20, 95% CI:1.17,1.24), physician visits (aIRR: 1.05, 95% CI: 1.04,1.05) and emergency department (ED)visits (aIRR: 1.27, 95% CI: 1.25,1.29). Children born to normal weight (aIRR: 1.07, 95% CI:1.05,1.09) or overweight (aIRR: 1.04, 95% CI: 1.01,1.07) mothers with above recommended (versus recommended) GWG had increased ED visits. Children born to underweight women with below recommended GWG had increased hospitalizations (aIRR: 1.31, 95% CI: 1.14,1.51) and physician visits (aIRR: 1.14, 95% CI: 1.10,1.17). PTB (56.74%), and SGA (6.83%)iv mediated the relationship of below recommended GWG and pediatric hospitalizations only. Adetailed cost effectiveness framework is outlined to investigate an intervention plan targeting GWG to limit adverse pediatric health outcomes. Discussion: The findings of this dissertation indicate that below or above optimal maternal weight is associated with pediatric health service use. This dissertation serves as a call to action to better inform clinical practice and impact health service policy related to maternal weight via early intervention.

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.

No description available.

Patients with severe heart failure (HF) are often excluded from exercise training studies due to their potentially unstable nature and severe exercise intolerance. Steady state cycling and walking have been the most common interventions and it is unknown whether these training modalities are appropriate and safe for patients with severe HF as they can produce significant cardiovascular stress. Body-weight supported treadmill (BWST) training may be beneficial in patients with severe HF by improving the periphery while minimizing cardiac loading. The purpose of this study was to: 1) assess the safety and feasibility of BWST training in severe HF patients and 2) to evaluate the effect of BWST training on functional capacity, health-related quality of life (HRQL ), cardiopulmonary function, and blood vessel function. Three male patients with severe HF participated in the study. On study entry and at the end of 24 sessions of physician supervised BWST training, patients completed a cardiopulmonary exercise test, two HRQL questionnaires, a 6-Minute Walk Test (6-MWT), and a Doppler ultrasound study. Although there were no study-related adverse events, only one subject (Patient 1) was able to complete post-testing. However, all three patients seemed to demonstrate a general trend towards increased exercise tolerance. By the seventeenth exercise session, the BWS was reduced to zero for Patient 1. In addition, Patient 1 achieved an average walking speed of2.0 km/hr and was completing 34 minutes ofwalking with minimal rest periods by the end of the training program. Patients 2 and 3 also responded to the training as evidenced by a slight increase in exercise duration. However due to fluctuations in their health status, they did not have any substantial improvement. Patient 1 experienced substantial increases in functional capacity: a 64% increase in V02 peak (7.2 to 11.7 ml/kg/min); a 33% increase in peak power output (300 to 400 kpm/min); a 37% increase in VE peak (28 to 39 L/min); and a 28% increase in 6-MWT distance (223. 5 to 286m). In addition, Patient 1 's NYHA-FC improved after training from class III to II. A significant training effect was also evident by reductions in HR at rest (96 to 79 bpm) and during submaximal exercise (100 kpm/min) (105 to 84 bpm). HRQL also tended to improve for Patient 1. Based on these findings and observations, two conclusions can be made. First, patients with severe HF can safely participate in BWST training and may derive considerable benefits. Second, the feasibility of training patients with severe HF is highly dependent on their cardiac condition and other co-morbidities remaining stable enough to allow consistent training. / Thesis / Master of Science (MS)

No description available.

Type 2 diabetes (T2D) is one of the fasting growing chronic diseases, caused by insulin resistance and pancreatic β-cell dysfunction. While over thirty medications were approved to treat T2D in the United States, less than one in four patients treated with anti-diabetic drugs achieved the glycemic target. Thus, identifying more effective anti-diabetic drugs is still needed for improving glycemic control in T2D patients. Incretins are gut hormones that possess potent insulinotropic action, which have drawn considerable attention in research and developing treatment strategy for T2D. Specifically, glucagon like peptide 1 (GLP-1), the most important incretin that is secreted from enteroendocrine L-cells in response to food ingestion, plays a vital role in maintaining glycemic homeostasis via potentiating glucose stimulated insulin secretion (GSIS) and promoting pancreatic β-cell proliferation and survival. Therefore, targeting L-cells to induce GLP-1 secretion would be an alternative strategy for treating T2D. The goal of this research was to identify low-cost and safe naturally occurring agents as a primary or adjuvant treatment for T2D. Here, I found that a small molecule, elenolic acid (EA), which was generated in our lab but is also present in mature olive and extra virgin olive oil, dose-dependently stimulated GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts. EA induced a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling. Consistently, inhibition of (PLC) ablated EA-stimulated increase of [Ca2+]i and GLP-1 secretion in L-cells. In addition, EA-triggered GLP-1 secretion from L-cells was blocked by YM-254890, a Gαq inhibitor. Consistent with our in vitro study, a single dose of EA acutely stimulated GLP-1 secretion in mice, accompanied with an improved oral glucose tolerance. Chronic administration of EA restored the impaired glucose and lipid homeostasis in DIO mice, which may be partially due to promoting GLP-1 secretion and reduced hepatic gluconeogenesis. In addition, EA suppressed appetite, reduced food intake and gastric emptying rate, as well as promoted weight loss in obese mice, demonstrating that it is also an anti-obesity agent. Further, EA treatment reduced lipid absorption, and promoted hepatic fatty acid oxidation, and reversed abnormal plasma lipid profiles in DIO mice. Consistently, EA exerted potent anti-diabetic action in db/db mice, and its blood glucose-lowering effect is comparable with that of liraglutide in blood glycemic control but is better than that of metformin in this overt diabetic model. Collectively, I have identified for the first time, as to the best of our knowledge, that EA could be a dual-action compound that exerts anti-diabetic effects via activation of the GLP-1 mediated metabolic pathway and suppression of hepatic gluconeogenesis, leading to effective control on food intake, body weight gain, and glycemia in T2D mice. / Doctor of Philosophy / Type 2 diabetes (T2D) is one of the fasting growing chronic diseases, which results from insulin resistance and pancreatic β-cell dysfunction. Even though there have been over thirty drugs approved to treat T2D in the United States, less than 25% of patients treated with anti-diabetic drugs achieved the glycemic target. Thus, more effective anti-diabetic drugs are still needed for improving glycemic control in patients with T2D. Incretins are a group of gut hormones and responsible for over 50% postprandial insulin secretion in humans, which have drawn considerable attention in research and developing a treatment strategy for T2D. Specifically, glucagon-like peptide 1 (GLP-1), the most important incretin that is secreted from enteroendocrine L-cells in response to food ingestion, plays a vital role in controlling blood glucose via potentiating glucose-stimulated insulin secretion (GSIS) and promoting pancreatic β-cell proliferation and survival. Therefore, targeting L-cells to induce GLP-1 secretion would be an alternative strategy for treating T2D. The goal of this research was to identify low-cost and safe naturally occurring agents as a primary or adjuvant treatment for T2D. Here, I found that a small molecule, elenolic acid (EA), which was synthesized in our lab but is also present in mature olive and extra virgin olive oil, dose-dependently stimulated GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts (containing L-cells). Further experiments showed that EA induced a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate (IP3) in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling, as IP3 is a direct product of PLC. Consistently, inhibition of PLC ablated EA-stimulated increase of [Ca2+]i and GLP-1 secretion in L-cells. In addition, EA-triggered GLP-1 secretion from L-cells was blocked by YM-254890, a Gαq inhibitor. In line with the in vitro study, a single dose of EA acutely elevated plasma GLP-1 concentration in mice, accompanied by improved oral glucose tolerance. Chronic administration of EA restored the impaired glucose and lipid homeostasis in diet-induced obese (DIO) mice, which may be partially due to promoting GLP-1 secretion and reduced hepatic gluconeogenesis. In addition, EA suppressed appetite, reduced food intake, and gastric emptying rate, as well as promoted weight loss in the DIO mice, demonstrating that it is also an anti-obesity agent. Further, EA treatment reduced lipid absorption and promoted hepatic fatty acid oxidation, as well as reversed abnormal plasma lipid profiles in the DIO mice. Consistently, EA exerted potent anti-diabetic action in predisposed diabetic mice (db/db), and its blood glucose-lowering effect is comparable with that of liraglutide, a commercial GLP-1 receptor agonist, in blood glycemic control but is better than that of metformin, a widely used first-line anti-diabetic drug, in this overt diabetic model. Collectively, I have identified for the first time, as to the best of our knowledge, that EA could be a dual-action compound that exerts anti-diabetic effects via activation of the GLP-1 mediated metabolic pathway and suppression of hepatic gluconeogenesis, leading to effective control on food intake, body weight gain, and glycemia in T2D mice.

The beef cattle industry has placed increased focus on mature cow size as a result of its influence on production efficiency and profitability. The objectives of this study were to evaluate relationships among lifetime measures of body weight (BW) and frame score (FS) in commercial beef females, and to assess the value of immature measures as predictors of mature cow size. Measurements of BW, hip height (HH), body condition score (BCS), and calculated FS were recorded at weaning (WN), breeding at 13 mo age (BR), and 8 subsequent periods, ceasing at approximately 5 yr of age for 232 Angus-cross females born 2004 through 2008. Correlation analysis revealed significant (P < 0.001) relationships among BW taken at WN and BR with BW measurements taken at 2.5, 3.8, and 4.8 yr of age (WN r = 0.70, 0.51, 0.61; BR r = 0.65, 0.57, 0.64, respectively). Significant relationships (P < 0.001) existed between FS collected at WN and BR, and FS at 2.5 and 3.8 yr (WN= 0.70, 0.72; BR= 0.79, 0.82, respectively). Repeatability of lifetime FS measures was 0.73. BCS was a significant (P < 0.001) source of variation in mature BW, with a unit change in BCS accounting for 41 kg BW change at 4.8 yr (P < 0.001). BW and FS were moderately to strongly related (P < 0.001) at WN, BR, 2.5, 3.8, and 4.8 yr (r = 0.62, 0.49, 0.62, 0.62, and 0.47 respectively). Prediction models for BW at 4.8 yr were similar using weaning BW alone, or with inclusion of both weaning BW and HH (R2 = 0.57 and 0.56). Similarly, breeding BW and HH were non-additive for prediction of 4.8 yr BW (R2 = 0.68, 0.58, and 0.68 for BW, HH, and BW +HH respectively). Performance at immature ages proves to be a satisfactory indicator of mature size, supporting continued incorporation of immature BW and HH and/or FS measurements into selection practices. / Master of Science

The purpose of this retrospective study was to determine if physiological performance measures were associated with staying in or dropping out of a medically supervised exercise program. In a retrospective file analysis, three subject groups of 35 subjects each were defined by their length of participation in the program. One group, the early drop outs, included subjects who participated in the program for a period of less than six months, another group, the late drop outs, participated for 6-12 months, and the third group, the compliers, was comprised of subjects who complied with the program beyond one year. Measurements were made on the following variables at entry and again after six months of participation: maximal oxygen uptake, resting heart rate, resting blood pressure, serum cholesterol and body weight. U sing analysis of variance for paired groups, the three groups were found not to differ on any performance variable at entry (p > .05). No significant differences were observed between the late drop outs and compliers when identical performance measures were compared at the time of the six month GXT. A paired t-test analysis to determine physiological changes within both the late drop outs and complier groups revealed that neither group had made significant improvements in the physiological indicators over the six month period, except in the oxygen consumption measurement for both the late drop outs and the complier groups, / Master of Science

The relationships among artificial sweetener consumption, body weight, and energy intake were examined using a rat model and a survey of college students. The rats were divided into four treatment groups and one control group (n=10 per group). Group 1 was provided with a 10% sucrose solution; group 2, a 50% sucrose solution; group 3, a 0.05% aspartame solution; and group 4, a 0.25% aspartame solution. All groups were provided with rat chow and water ad libitum. Analysis of variance (ANOVA) and Duncan's multiple range test were used to evaluate the data from the rat study. No differences existed among the groups for weight gain or total energy intake. Differences did exist among the groups for solution and food intake with the two groups given sucrose consuming the greatest amount of sweetened solution and the least amount of food. In the survey of college students, the human subjects' gender, perception of their weight, weight status, dieting status, weight consciousness, weight change over a one year period, and total caloric intake/ total energy expenditure were examined in relation to their consumption of diet soda and packets of table top artificial sweeteners. / Master of Science

Chickens from lines that have been divergently selected for either low (LWS) or high (HWS) body weight at 56 days of age for more than 57 generations serve as unique models to study eating disorders. The LWS have different severities of anorexia while all HWS become obese. Over the past decade our groups has demonstrated that these lines have differential food intake threshold responses to a range of intracerebroventricular (ICV) injected neurotransmitters. The major brain region regulating homeostatic regulation of appetite is the hypothalamus, and hence this dissertation was focused on understanding how the hypothalamus is different between LWS and HWS lines. Experiments 1 and 2 were performed as follows: whole hypothalamus as well as individual hypothalamic nuclei, respectively, were collected from 5 day-old chicks that had been fasted for 180 min or had free access to food. The hypothalamic nuclei included those primarily associated with appetite including the lateral hypothalamus, paraventricular nucleus (PVN), ventromedial hypothalamus, dorsomedial nucleus, and arcuate nucleus (ARC). Total RNA was isolated, reverse transcribed, and real time PCR performed. Hypothalamic expression of anorexigenic factors was greater in LWS than HWS, those factors including calcitonin, corticotropin-releasing factor receptor 1, leptin receptor, neuropeptide S, melanocortin receptor 3 (MC3R), and mesotocin. The gene expression data from individual hypothalamic nuclei revealed that mesotocin from the PVN may play an important role in the inhibition of appetite in the LWS. Experiment 3 was then designed to evaluate the effects of stress on food intake: besides the differences in hypothalamic gene expression between the lines, they also have different feeding responses when stressed: ICV injection of neuropeptide Y (0.2 nmol, NPY) did not increase food intake in LWS on day 5 after stress exposure. Experiment 4 was thus designed to study the molecular mechanisms underlying conditional feeding responses to exogenous NPY after stress in the LWS. The melanocortin system (AgRP and MC3R) changed in the hypothalamus after stress in the LWS, and hence may be responsible for the loss of responsiveness to exogenous NPY in stressed LWS. Experiment 5 was designed to evaluate whether hypothalamic differences exist at the protein level: label-free liquid chromatography coupled to tandem-mass spectrometry was used to measure the abundance of proteins in the hypothalamus. Hypothalamus was obtained from fed and 180 minute-fasted 5 day-old male LWS and HWS chicks. Proteins involved in energy metabolism were different between the lines. Differences were also found in proteins involved in GABA synthesis and uptake as well as protein ubiquitination. In conclusion, these results suggest that different feeding behaviors of LWS and HWS may be due to differences in gene and protein expression in the hypothalamus. / Ph. D.