Obesity is a major predictor for type 2 diabetes. The etiology and comorbidities of these two diseases are associated. Diabetics are twice as likely to contract any type of infection and at greater risk of worse clinical outcomes to infection. However, the individual effects of diet, glycemia and obesity on risk and severity of enteric infection has not been elucidated. Here we show that high blood glucose (i.e. hyperglycemia), independent of obesity, is sufficient to promote mortality during infection with Citrobacter rodentium, a diarrhea-causing pathogen in mice. Mortality was caused by dehydration as a result of excessive Wnt/β-catenin signalling. Our findings highlight the importance of glucose lowering and fluid therapy as opposed to immunological dysfunction, gut barrier defects or bacteraemia as modifiers of outcomes from enteric infection during diabetes. Future work should develop a more comprehensive understanding of the molecular changes that connect hyperglycemia, Wnt/β-catenin pathway and fluid balance during infection. We used the most common model to cause diet-induced obesity in mice to study another enteric pathogen. We showed that long- and short-term high-fat diet (HFD) feeding promoted the colonization and expansion of adherent-invasive Escherichia coli. Higher pathogen burdens in the intestinal tissues and feces were detected in diet-induced obese mice, which coincided with increased distal gut pathology. Initiating the diet one day prior or after infection was sufficient to promote the expansion of adherent-invasive E. coli in the absence of robust weight gain implicating components of diet as a major determinant of pathogen burden. We isolated the dietary factor and found that low fibre content of the high-fat diet was partially responsible for the increased intestinal pathogen burden. Future work should determine how lower fibre alters host and bacterial metabolism in order to promote overgrowth of adherent-invasive E. coli in the gut. / Thesis / Doctor of Philosophy (PhD) / Obesity and diabetes are major public health issues that are connected in many ways, including how diet changes glucose metabolism. Diabetics have a higher risk of contracting infections and also have worse outcomes from infections. It was unknown what factors of obesity or diabetes influence how the immune system combats bacterial infections. The gut is an important site as it is where diet, the immune system, and metabolism all directly interact. We discovered that high blood sugar was associated with death related to dehydration in diabetic, but not necessarily obese mice infected with a diarrhea causing bacteria. Diet-induced obesity in mice infected with bacteria associated with Crohn's disease, showed an overgrowth of bacteria and worse intestinal damage. We isolated the key dietary factor responsible, which was low fibre rather than high fat or sugar. Even one day of lower dietary fibre promoted overgrowth of infectious bacteria in the gut.

Electrolytic lesions of the ventromedial hypothalamus produce an obesity syndrome in experimental animals characterized by behavioural and metabolic disturbances. Historically, theories of VMH obesity have considered a single disturbance, either behavioural or metabolic, to be the primary effect of the lesion, which in turn causes other components of the syndrome. An alternative view suggests that VMH lesions simultaneously disturb both behavioural and metabolic mechanisms due to the anatomical proximity of these mechanisms in the hypothalamus. Therefore, more discrete lesions in the VMH may produce some syndrome components but not others. This thesis presents a series of experiments that test this "dissociative" perspective of the VMH obesity syndrome. First, rats having different hypothalamic ablations were compared on: caloric intakes on a series of test diets, body weight changes, and body fat. Bilateral parafornical hypothalamic knife cuts (PFKC) that spared the ventromedial hypothalamic nucleus (VMN), produced overeating and weight gain characteristic of VMH lesions. However, measurement of percentage body fat (i.e. level of obesity) indicated that PFKC rats were less obese than VMH rats, even though PFKC lesions produced a greater hyperphagia and weight gain than VMH lesions. In contrast, lesions restricted to VMN produced obesity, but did not produce hyperphagia or weight gain. Since parafornical knife cuts produced a greater hyperphagia than VMH lesions, it is possible that VMN damage actually reduces caloric intake in VMH rats. To test this hypothesis, the effects of VMH, PFKC, and combined PFKC/VMN lesions on caloric intake and body weight were compared. PFKC and VMH lesions produced hyperphagia and weight gain. However, knife cuts were not significantly more effective than VMH lesions for producing these disturbances in this experiment. Therefore, PFKC lesions do not invariably produce a greater hyperphagia than VMH lesions. Furthermore, VMN lesions had no effect on the level of overeating or weight gain in rats bearing PFKC lesions. Therefore, damage to VMN does not reduce the hyperphagia produced by PFKC lesions. Finally, the effects of these different hypothalamic manipulations on metabolic measures were determined. To eliminate the confound of hyperphagia on metabolic variables, all lesion rats were fed a daily food ration sufficient to maintain their body weight at the level of controls. VMH and PFKC lesions resulted in elevated parasympathetic tone, indicated by elevated basal gastric acid secretion. VMN lesions did not affect gastric acid secretion. In contrast, only VMH and VMN lesions produced obesity when overeating was prevented. PFKC rats did not become obese. These experiments demonstrate that separate hypothalamic mechanisms underly the hyperphagia and obesity characteristic of VMH lesions. Furthermore, different mechanisms underly obesity and elevated parasympathetic tone following VMH lesions. Therefore, these observations support a dissociative model of the VMH obesity syndrome. / Thesis / Doctor of Philosophy (PhD)

Modifiable health behaviors are a leading cause of mortality and chronic disease in the United States. Engagement in maladaptive health behaviors is linked to poor physical, psychological, and cognitive outcomes including increased risk of cardiovascular disease, Alzheimer's disease, anxiety, and depression. Using a neurobehavioral approach, I examined the hypothesis that neurobehaviors are impaired in clinical populations, and that exercise improves these neurobehaviors as well as the underlying mechanisms. In the first study, I found that a range of neurobehaviors are affected in individuals with obesity, indicating hyperactivity of the reward system and hypoactivity of the executive system. Using these neurobehaviors as predictors, I created a neurobehavioral model predicting obesity with an accuracy of 65%. In the second study, I examined neurobehaviors in a population of individuals in recovery from substance misuse. I found that neurobehaviors are altered in this population suggesting heightened activity of the executive system supports success in recovery. In the third study, I examined the effects of a long-term exercise program on a range of neurobehaviors and neurophysiology as measured through electroencephalography. I found that long-term exercise improved psychological state, memory, and attention. Additionally, I found that decreased cortical activity in response to exercise is associated with improvements in psychological state. Collectively, these findings suggest that there is a bi-directional relationship between the body and brain, with optimal physical health promoting optimal mental functioning. Additionally, these findings suggest that interventions that support improved neurobehaviors and neural circuitry are critical to promote engagement in positive health behaviors. / Doctor of Philosophy / Modifiable health behaviors are a leading cause of mortality and chronic disease in modern industrialized societies. Engagement in poor health behaviors is linked to increased risk of chronic disease affecting the body and brain including cardiovascular disease, Alzheimer's disease, anxiety, and depression. This dissertation explores the psychological and cognitive factors influencing engagement in healthy behaviors, and the ability of an exercise intervention to improve these factors as well as the underlying mechanisms. In the first study, I found that a range of neurobehavioral factors are impaired in individuals with obesity, and that these factors can be used to predict obesity. In the second study, I examined similar outcomes in a population of individuals in recovery from substance misuse, and found that neurobehaviors are altered in this population suggesting heightened activity of the executive system which supports successful recovery. In the third study I found that long-term exercise improved psychological and cognitive outcomes. Additionally, I found that changes in the electrical activity of the brain in response to exercise are associated with improvements in psychological state. Collectively, these findings suggest that there is a bi-directional relationship between the body and brain, with optimal physical health promoting optimal mental functioning. Additionally, these findings suggest that interventions that support improved neurobehaviors and neural circuitry are critical to promote engagement in positive health behaviors.

Glucose and lipid metabolism are dysregulated in obese horses. Altered glucose metabolism is evidenced by the development of insulin resistance and increased fasting plasma insulin concentrations (hyperinsulinemia) while altered lipid metabolism is evidenced by increased plasma lipid concentrations. Obesity in horses also increases the risk of the painful hoof disease, laminitis. Three experiments were performed to investigate the regulation of nutrient metabolism in skeletal muscle and adipose tissue of lean, healthy horses. Adipose tissue was found to be the primary lipogenic tissue of horses, with acetate being the primary lipogenic substrate. Secondly, ten, lean horses were used to investigate the effects of acute hyperinsulinemia on nutrient metabolism. Increasing plasma insulin concentrations to >1,000 mIU/L for six hours decreased transcript abundance of glucose transporters and the insulin receptor in adipose tissue, and decreased protein abundance of the insulin receptor in skeletal muscle, potentially indicating that hyperinsulinemia potentiates insulin resistance. Insulin infusion also reduced mRNA abundance of lipid transporters in adipose tissue while increasing them in skeletal muscle. The final experiment investigated the influence of the insulin-sensitizing drug, pioglitazone, and lipopolysaccharide, on nutrient metabolism in skeletal muscle and adipose tissue, and their association with insulin sensitivity. Pioglitazone treatment did not increase insulin sensitivity; however it did increase skeletal muscle transcript abundance of the insulin receptor and the non-insulin sensitive glucose transporter and adipose tissue protein abundance of the insulin-sensitive glucose transporter (GLUT4). Lipopolysaccharide decreased insulin sensitivity regardless of pioglitazone pre-treatment, which was associated with decreased transcript abundance of GLUT4 in skeletal muscle and adipose tissue of untreated horses, but not adipose tissue of pioglitazone treated horses. / Ph. D.

Since the 1990s, medical and media articles containing the word "obesity" inevitably included the word "epidemic" as well. These articles usually pointed to the exponential growth in overweight and obese persons in high-income and low-income countries alike. A recent field of literature called "fat studies" has sought to question this so-called epidemic, bringing to light inconsistencies or down-right falsehoods present in obesity research. While researchers in this field have importantly uncovered many myths surrounding obesity and overweight, examinations of the rhetorical strategies used to approve potentially dangerous weight loss or weight maintenance procedures remain few. This thesis project hopes to cover just a portion of that gap by examining two groups targeted most directly by obesity researchers: women and children. Particularly, this research examines potentially dangerous recommendations made by doctors and the media to pregnant obese women and obese adolescents. Ultimately, this project uncovers dualisms of wrong versus right bodies and fat stigmatization in the "objective" language of health about obesity. This polemic leaves pregnant women and adolescents little choice except either to conform or to face a world of media and medicine that blames these two groups for the "choice" to remain fat. / Master of Arts

Type 2 diabetes (T2D) is a major public health issue worldwide and it currently affects nearly 26 million people in the United States. It is estimated that one third of Americans will have diabetes by 2050. T2D is a result of chronic insulin resistance and loss of beta-cell mass and function. Both in experimental animals and people, obesity is a leading pathogenic factor for developing insulin resistance, which is always associated with the impairment in energy metabolism, causing increased intracellular fat content in skeletal muscle, liver, fat, as well as pancreatic islets. Constant insulin resistance will progress to T2D when beta-cells are unable to secret adequate amount of insulin to compensate for decreased insulin sensitivity. In the present study, I investigated whether sulforaphane, a natural compound derived from cruciferous vegetables, can prevent high-fat (HF) diet-induced obesity and diabetes in C57BL/6 mice. Dietary intake of sulforaphane (250 mg/kg diet) prevented hyperglycemia and increased insulin sensitivity in HF diet-induced obese mice. Mice treated with sulforaphane had significant lower serum insulin levels (1.93±0.11 μg/dl) as compared to those without treatment (3.09±0.27 μg/dl, P<0.05). In second study, administration of sulforaphane (40 mg/kg body weight daily via gavage) in obese mice enhanced body weight loss and improved insulin sensitivity. Moreover, sulforaphane increased pyruvate oxidation by 28.85% (P<0.05) and enhanced fatty acid oxidation efficiency by 2.2 fold (P<0.05) in primary human muscle cells. These results suggest that sulforaphane may be a naturally occurring insulin-sensitizing agent that is capable of preventing T2D. / Master of Science

Falls due to slipping are a serious occupational concern. Slipping is estimated to cause 40-50% of all fall-related injuries. In 2011, falls resulted in 22% of injuries requiring days away from work. Epidemiological data indicates that older and obese adults experience more falls than young, non-obese individuals. An increasingly heavier and older workforce may be exacerbating the problem of slip-induced falls in the workplace. The purpose of this study was to examine the effects of obesity and age on slip severity and fall outcome following an unexpected slip. Four groups of participants (young obese, young non-obese, older obese, older non-obese) were exposed to an unexpected slip perturbation. Slip severity (slip distance, slip duration, average slip velocity and peak slip velocity) and slip outcome (fall or recovery) were compared between groups. Obese individuals experienced 8.25% faster slips than non-obese individuals in terms of average slip velocity (p=0.022). Obesity did not affect slip distance, slip duration or peak slip velocity. Obese individuals also experienced more falls; 33.3% of obese individuals fell compared to 8.6% of non-obese (p=0.005). Obese individuals were 8.24 times more likely to experience a fall than non-obese individuals, when adjusting for age, gender and gait speed. No age effects were found for slip severity or slip outcome. This study revealed that obese participants experienced faster slips and more falls than their non-obese counterparts. These results, along with epidemiological data reporting higher fall rates among the obese, indicate that obesity may be a significant risk factor for experiencing slip-induced fall. / Master of Science

Occurrence of obesity has steadily increased in the human population and, along with it, associated health complications such as systemic insulin resistance, which can lead to the development of type 2 diabetes mellitus. Obesity is a complex metabolic disorder that often leads to chronic inflammation and an overall decline in human and animal health. In mouse skeletal muscle, obesity has been shown to impair muscle regeneration after injury, however, the mechanism underlying these changes in satellite cell (SC) biology have yet to be explored. To test the negative impacts of obesity on SC behaviors, we fed C57BL/6 mice normal chow (NC, control) or high-fat diet (HFD) for 10 wks and performed SC proliferation and differentiation assays in vitro. SCs from HFD mice formed colonies with smaller numbers (P < 0.001) compared to those isolated from NC mice, and this observation was confirmed (P < 0.05) by BrdU incorporation. Moreover, in vitro differentiation assays consisting of equally seeded SCs derived from NC and HFD muscles showed that HFD SCs exhibited compromised (P < 0.001) differentiation capacity compared to NC SCs. Immunocytochemical staining of cultured SCs demonstrated that the percentage of Pax7+/MyoD- (self-renewed) SC subpopulation decreased (P < 0.001) with HFD treatment group compared to the control. In single fiber explants, a higher ratio of SCs experienced apoptotic events as revealed by the expression of cleaved caspase 3 (P < 0.001). To investigate further the impact of obesity on SC quiescence and cycling properties in vivo, we used an inducible H2B-GFP mouse model to trace the turnover rate of GFP and thus cell division under normal and obese conditions. Flow cytometric analysis revealed that SCs from HFD treatment cycled faster (P < 0.001) than their NC counterparts, as reflected by the quicker loss of the GFP intensity. To test for SC muscle regenerative capacity in vivo, we used cardiotoxin (CTX) to induce wide-spread muscle damage in the tibialis anterior muscle. After analysis we found that HFD leads to a compromised, though mild, impairment in muscle regeneration. Taken together, these findings suggest that obesity negatively affects SC quiescence, proliferation, differentiation, and self-renewal in vitro, ex vivo and in vivo. / MS / The prevalence of obesity in the human population has steadily increased over the past decades and, along with it, associated health complications such as systemic insulin resistance, which can lead to the development of type 2 diabetes mellitus. Obesity is a complex metabolic disorder that often leads to chronic inflammation and an overall decline in human and animal health. Along with the multitude of health disorders associated with obesity, in mouse skeletal muscle, obesity has been shown to impair muscle regeneration after injury. The mechanisms underlying the impairment in muscle regeneration as seen in obesity are unknown. To better understand how obesity affects skeletal muscle, we looked at satellite cells (SC). Satellite cells, or muscle stem cells, are skeletal muscle resident cells that play a vital role in muscle repair after damage. To test the negative impacts of obesity on SC behaviors, we fed mice normal chow (NC, control) or high-fat diet (HFD) for 10 wks to obtain an obesogenic mouse model. Our first experiments involved culturing the SCs derived from the HFD and NC mouse muscles and growing them in an artificial environment. These experiments showed SCs derived from HFD mice had a decreased ability to replicate and divide compared to those isolated from NC mice. Moreover, the SCs from the HFD mice exhibited compromised capacity to form myotubes in culture, an essential part in muscle regeneration after damage. Our next set of experiments conducted looked at individual muscle fibers isolated from mouse muscle. In these experiments the SCs on the HFD muscle fibers had a higher ratio of SCs experiencing cell death in comparison to the control. To test the SC cycling properties in the living mouse we used a mouse model to trace the activity and cell division of SCs under normal and obese conditions. Using this model revealed that SCs from HFD treatment cycled faster than their control counterparts, even in the absence of notable muscle damage. To test for SC muscle regenerative capacity after muscle damage, we used cardiotoxin (CTX) to induce wide-spread muscle damage in the tibialis anterior muscle (leg muscle) of the living mouse. After analysis we found that HFD leads to a compromised, though mild, impairment in muscle regeneration. Taken together, these findings suggest that obesity negatively affects SC behaviors and function.

Obesity is a major and growing health concern associated with an increased risk of falls. The majority of falls are thought to result from some kind of postural perturbation, yet the biomechanical mechanisms as to why obese individuals fall more often is unclear. Therefore, the goal of this study was to investigate the effects of obesity on balance recovery in response to small forward postural perturbations. Twenty male participants, including 10 lean (mean BMI ± SD: 21.9 ± 1.4) and 10 obese (BMI: 33.2 ± 2.3), were exposed to two types of postural perturbations (force impulses applied with a pendulum and angular displacements administered with a release mechanism). Participants attempted to recover balance with only an ankle strategy such that neither a step nor hip flexion was utilized. Quiet standing trials were also conducted for comparison with the literature. Obese individuals exhibited less center of mass (COM) displacement and a slower COM velocity compared to lean individuals when exposed to identical force perturbations. When exposed to the force perturbations relative to body weight, and when released from identical lean angles, no differences in COM performance were found. During quiet standing, no differences in center of pressure (COP) velocity were observed between obese and lean groups. In all tasks, the obese generated higher ankle torque than the lean. Overall, the obese participants exhibited no differences in movement or less/slower movement than the lean participants when recovering from small forward postural perturbations as well as during quiet standing. These results imply that obesity in young adult males did not impair balance recovery for the tasks investigated. / Master of Science

Body representation disorders have a key role in the characterization of obesity. So far, the literature consistently pointed to a negative attitudinal body image. Conversely, after reviewing the pertinent literature, it emerges that more incoherent results have been reported for the self-perceived body size. Chapter 2 tries to clarify this issue by adopting a more innovative theoretical framework (i.e., the implicit/explicit model; Longo, 2015). For the first time, we probed the implicit representation underlying position sense in obesity, reporting a similar representation to healthy weight participants. Importantly, this result shows that not all components of body representation are affected by obesity. Chapter 3 addresses another aspect of body representation that has been neglected in obesity, namely bodily self-consciousness. The Rubber Hand Illusion has been traditionally used to investigate the mechanisms underlying body awareness. Our results show that individuals with obesity have comparable subjective experience of the illusion, while the effect of the illusion on self-location is reduced. This dissociation can be interpreted as the result of a preserved visuo-tactile integration and an altered visuo-proprioceptive integration in obesity. However, in Chapter 4 we reported that individuals with obesity have a reduced temporal resolution of visuo-tactile integration, meaning that they integrated stimuli over an extended range of asynchronies than healthy weight participants. In fact, this evidence predicts that in the RHI individuals with obesity might perceive more synchronously the asynchronous stimulation, showing a greater effect of the illusion also in this condition. Nevertheless, we failed to show this pattern of results in our study with an interval of asynchronous stimulation of 1000 ms (usually adopted in the RHI paradigm). We hypothesized that smaller time-lags, which are inside the temporal binding window of individuals with obesity and outside the temporal binding widow of healthy weight participants, might not be perceived by individuals with obesity but detected by healthy weight individuals. Accordingly, a dissimilar susceptibility to the illusion should be observed. Chapter 5 investigates this issue by adopting a modified version of the RHI that enables a parametrical modulation of the timing of the stimulation. However, we could not replicate the RHI even in healthy weight participants. The possible methodological reasons for this failure are discussed. Overall, this work tries to fill some gaps in the previous literature about body representation in obesity. Moreover, our findings provide an important clue about the possible cognitive mechanisms involved in body representation disorders in obesity. However, many questions still need an answer: due to the complexity of the domain a comprehensive knowledge of the topic might be challenging. A deep understanding of obesity is fundamental to develop multidisciplinary and efficacious rehabilitative protocols. Indeed, better treatments would significantly ameliorate individuals’ well-being but also contribute to reduce the huge health costs related to obesity comorbidities.