The focus of this thesis was leptin and its role in the development of obesity and non-insulin-dependent diabetes mellitus (NIDDM). Studies in Psammomys obesus, a polygenic animal model of obesity and NIDDM, showed that ob gene expression and plasma leptin concentration correlated significantly with body weight, percentage body fat and plasma insulin concentration. In addition, plasma leptin concentrations were significantly elevated in insulin resistant Psammomys obesus independent of body weight. Dietary energy restriction from weaning in Psammomys obesus prevented excessive body weight gain, hyperleptinemia and hyperglycemia compared with ad libitum fed animals. Interestingly, 19% of the energy-restricted animals still developed hyperinsulinemia and tended to have increased plasma leplin compared with normoinsulinemic energy-restricted Psammomys obesus. Fasting for 24 hours significantly reduced plasma leptin concentration in lean, insulin-sensitive but not obese, insulin-resistant P. obesus, suggesting a dysregulation in the response of leptin to acute caloric deprivation in these animals. The effects of leptin administration to P. obesus were also investigated. Single daily intraperitoneal injection of 5 mg leptin/kg body weight for 14 days had no significant effect in lean or obese P. obesus. This dose had previously been shown to rapidly and significantly reduce food intake and body weight in ob/ob and wild-type mice, suggesting relative leptin resistance in P. obesus. Acute (8 hour) effects of administration of 5 mg leptin/kg body weight were also investigated. No significant effects on food intake or plasma insulin were detected, however blood glucose concentrations were significantly elevated in obese, glucose intolerant P. obexus, suggesting an exacerbation of insulin resistance in susceptible animals. Treatment of lean, healthy P. obesus with 45 mg leptin/kg body weight/day for 7 days resulted in significant decreases in food intake and percentage body fat, showing that the leptin resistance observed in this species could be overcome by the administration of very large doses of leptin. In another study, leplin was shown to significantly inhibit maximal insulin binding to isolated adipocytes, suggesting that leptin may respresent an important link between obesity and NIDDM. Links between aspects of obesity and NIDDM and polymorphisms in the ob and p3-adrencrgic receptor genes were also investigated in two human populations.

The research presented within this thesis has focused on the complex and interrelated gastrointestinal mechanisms involved in the regulation of appetite and energy intake. The suppression of appetite and energy intake is mediated, at least in part, by a number of gastrointestinal factors, including gastric distension, the modulation of gastric emptying, gastrointestinal motility and gastrointestinal peptides, including cholecystokinin ( CCK ), glucagon - like peptide - 1 ( GLP - 1 ), peptide tyrosine - tyrosine ( PYY ) and ghrelin. An understanding of these mechanisms is important to determine the pathophysiology of obesity and to allow the identification of targets for the treatment of obesity. The effects of the fat on gastrointestinal function and appetite are dependent upon the digestion of fat to free fatty acids. Animal studies indicate that the effects of free fatty acids on energy intake are more potent than those of triglycerides. The comparative effects of a free fatty acid and a triglyceride on gastric emptying, appetite and energy intake were assessed in healthy lean male subjects. Free fatty acids slowed gastric emptying, stimulated the secretion of CCK, suppressed hunger, increased fullness and suppressed energy intake more potently than triglyceride ( Chapter 5 ). These observations suggest that small amounts of free fatty acids in the small intestine potently modulate gastrointestinal function and energy intake. We had previously demonstrated that intraduodenal infusion of the free fatty acid, lauric acid ( C12 ) ( at 0.375 kcal / min, 106 mM ), stimulates isolated pyloric pressure waves ( IPPWs ), inhibits antral and duodenal pressure waves ( PWs ), stimulates the release of cholecystokinin ( CCK ) and glucagon- like peptide - 1 ( GLP - 1 ), and suppresses energy intake, and that these effects are much greater than those seen in response to isocaloric decanoic acid ( C10 ) infusion. However, C12 was associated with nausea, confounding interpretation of these results. In order to determine whether the effects we had observed were physiological, or related to nausea, we assessed the effects of a range of doses of C12 ( 0.1 - 0.4 kcal / min ) on the above parameters. Intraduodenal infusion of very small amounts of C12, potently modulate gastrointestinal motility, gut hormone secretion and suppresses energy intake at a subsequent meal in a dose - dependent fashion, in the absence of nausea ( Chapter 6 ). However, as both the load and the concentration of the infusions varied, it was unclear whether these effects were load -, or concentration -, dependent. We, therefore, examined the independent effects of load, and concentration, of C12 on these variables, and demonstrated that the effects of C12 on gastrointestinal motility, gut hormone release and energy intake are dependent upon the load, but not the concentration of C12 administered to the small intestine in humans ( Chapter 7 ). Animal studies have indicated that the effects of nutrients on gastrointestinal function and energy intake are dependent upon the length of small intestine exposed to nutrient. In humans, we demonstrated that the modulation of gastrointestinal motility and gut hormone secretion by small intestinal glucose is dependent upon the length of small intestine exposed to nutrient, specifically, the suppression of antral motility, the release of GLP - 1 and the suppression of plasma ghrelin concentrations is dependent upon greater than 60 cm of the small intestine being exposed to glucose ( Chapter 8 ). The inhibitory action of glucagon - like peptide - 1 ( GLP - 1 ) on gastric emptying GE is likely to be important in mediating its effects on glycaemia, appetite and upper gastrointestinal symptoms. In healthy subjects ( i ) the slowing of solid and liquid gastric emptying by exogenous GLP - 1 is associated with increased retention of both solid and liquid in the distal stomach and, even when administered in a " low " dose can induce " gastroparesis " and ( ii ) the effects of GLP - 1 on postprandial glycaemic and insulinaemic responses are predictable on the basis of its effect on gastric emptying, supporting the concept that gastric emptying is a major target mechanism for the clinical use of incretin mimetics ( Chapter 9 ). The feeding inhibitory effects of GLP - 1 are likely to relate to the increased antral meal retention, as a close relationship has previously been demonstrated between antral area ( and content ) with the perception of fullness and subsequent energy intake. An understanding of the physiological adaptations that occur in obesity is essential to enable the development of successful therapies for this condition. There is increasing evidence that consumption of a high - fat diet is associated with the development of obesity. The precise mechanisms by which this occurs are unclear, however, studies in animals suggest that adaptations in the gastrointestinal mechanisms involved in the regulation of appetite and energy intake occur, and may, therefore, predispose to obesity. In particular, studies have demonstrated that the acute effects of exogenous CCK, a hormone that potently suppresses energy intake, are attenuated following exposure to a high - fat diet in rats. In our study, healthy lean male volunteers were exposed to a high - fat diet for a period of 3 weeks, following which the effects of an intravenous infusion of CCK on gastrointestinal motility and energy intake were evaluated. Fasting concentrations of CCK were greater following the high - fat diet, however, we did not demonstrate any differences in the antropyloroduodenal motility or energy intake response to exogenous CCK following ingestion of either diet, suggesting, that at least in the short - term, in healthy lean male subjects consumption of a high - fat diet does not alter the sensitivity to the effects of CCK on antropyloroduodenal motility and energy intake ( Chapter 10 ). The studies reported in this thesis have provided new insights into the mechanisms by which nutrients present within the gastrointestinal tract modulate gastrointestinal function and energy intake. Future studies in obese subjects will be required to determine whether sensitivity of the gastrointestinal tract to nutrients is modulated in the obese state. / Thesis (Ph.D.)--School of Medicine, 2006.

Context: Young women are at high risk of weight gain but there has been limited knowledge on weight management in this group. Hyperandrogenemia and menstrual abnormalities are common co-morbidities of obesity in young women but their associations with food cravings are not known. Metformin has been shown to reduce body weight and improve metabolic outcomes in older adults but its effects on healthy overweight and obese young women have not been investigated. Quantitative lifestyle advice has been shown to be effective in inducing weight loss but its psychological effects on young women have not been extensively studied. The overall objective of this study was to investigate the effectiveness of metformin, quantitative lifestyle advice and internet-based intervention on weight management in young. Methods: In the first 12-weeks, 203 overweight and obese young women (BMI 33.3±0.3 kg/m² , age 28±0.3 years; age range:17-37) were randomized to one of three treatment arms to receive metformin (Diabex XR 1500mg a day) plus qualitative lifestyle advice (M-QL), placebo plus qualitative lifestyle advice (P-QL) or a structured lifestyle program (L-QT). L-QT consisted of an energy restricted diet with quantitative lifestyle advice (6000KJ; 40% protein, 40% carbohydrate, 30% fat), structured exercise program, and behavioural therapy. From weeks 13 to 48, all participants were placed on the structured lifestyle program conducted through a website. Outcome measures include body weight, fasting lipids, insulin, glucose, psychological distress, self-esteem, food cravings, energy intake and physical activity. Primary analyses were conducted using linear mixed models. Results: At baseline, psychological distress and hyperandrogenemia were associated with increased food cravings (P<0.01). At 12-weeks, L-QT group had greater weight loss (-4.2±0.4 kg) compared to M-QL (-1.0±0.4 kg) and P-QL groups (-0.2±0.3 kg) (P<0.001). Attrition at week 12 was high particularly in L-QT group, ie 48% (28/59) for L-QT group, 34% (22/65) for M-QL group and 29% (23/79) for P-QL group (P=0.08). Baseline psychological distress and food cravings predicted attrition at week 12. At week 12, L-QT group had significantly greater improvements in psychological distress (-3.0+0.9 vs -0.84+0.52, P=0.013) and self-esteem (3.2±0.8 vs -0.04±0.4, P<0.001) compared to the M-QL and P-QL groups. At 48 weeks, both QT and QL groups maintained significant weight loss (-4.8±0.1 kg vs -1.3±0.4 kg respectively, P=0.0005). Weight changes from week 13 to 48 were similar between the groups (P>0.05). Attrition was similarly high in both groups by week 48 (78%; 159/203) (P=0.003). Being married or having children predicted attrition at week 48. Conclusions: A structured lifestyle intervention program was more effective than metformin in achieving weight loss in young women. Quantitative lifestyle advice produced greater improvements in psychological outcomes compared to qualitative lifestyle advice. Internet-based weight loss program was effective in maintaining weight loss in young women independent of initial weight loss. High attrition rates were seen throughout the study, particularly among those who had greater psychological distress or food cravings, and those who were married or had children. Strategies on managing issues relating to psychological distress, food cravings and family responsibilities may allow better tailoring of weight management programs for this group. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1523605 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009

Thesis (M.A.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (February 6, 2007) Vita. Includes bibliographical references.

Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Valpha/betarepertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNgamma-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with anti-CD3 antibody or its F(ab’)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. CD4+ T cells impact the progression of obesity-associated metabolic abnormalities and can be manipulated by immunotherapy.

Overweight and obesity, one of the most common public health problems in affluent societies, have become epidemic not only in Canada but also throughout the world. Obesity is also a major contributor to the global burden of chronic disease and disability such as diabetes, hypertension, and cardiovascular disorders. <p>Studies have demonstrated clearly that higher intake of cholesterol and saturated fats and generally higher intake of energy-dense food are a key determinant of increasing levels of obesity and overweight in children. Physical activity is also recognized as a major factor in preventing obesity among children. Environmental factorsby which we mean both social (such as social support, social networks) and physical environment (such as access to physical activity amenities, roads and trails, grocery stores)in generally believed to have a powerful influence on either limiting or enhancing the effects of fundamental determinants (diet and physical activity) of obesity in children. This thesis focuses on one of the key determinants, physical activity, and in turn examines factors that are related to changing physical activity in children. <p>This research was designed to examine two major questions: (1) How do physical activity and overweigh/obesity change over time in a cohort of adolescents in Saskatoon? Are there differences in the patterns of change in overweight/obesity and physical activity between boys and girls? (2) What are the effects of family/friends and physical environments on the changing patterns of physical activity in this sample? <p>The data used in this study was taken from the in motion studies longitudinal data. Study participants include 837 adolescents from12-18 years of age from two high schools and five elementary schools from two diverse geographic areas in Saskatoon (low and high socioeconomic status). Physical activity patterns of adolescents were investigated over a five-month period (e.g., type, frequency, and duration). Participants were also asked to respond to questions on demographics, social support, perceived benefits and barriers of physical activity, and health practices. <p>The results of this study indicated that overweight/obesity increased with age, while physical activity decreased with age for both boys and girls. Boys overall were more likely to be physically active than were girls. Adolescents who received greater direct support from family members were 21% more likely to sustain their physical activity levels (relative odds 1.21; 95% CI 1.17, 1.24); in contrast, the more the familys indirect support the 5.4% less sustaining were the adolescents physical activity (relative odds 0.94; 95% CI 0.91, 0.98). Home environments which were rich in resources relevant to physical activity had 4% greater influence on adolescents physical activity levels, and this relationship was stronger than that of the influence of living in certain neighbourhoods (relative odds 1.04; 95% CI 1.03, 1.05). <p>This research shed some greater understanding of the impact of familys support and physical environment factors on adolescents continued physical activity levels. The implications of results for further research, targeted programs, and social policy is discussed in the thesis.

Aboriginal Canadians (First Nations, Métis, and Inuit) have the highest prevalence of overweight and obesity compared to other ethnic groups in Canada. In order to assess the evolution of the problem over time and to understand potential risk factors, three studies were conducted using nationally-representative survey data. Direct comparisons between Aboriginal and non-Aboriginal Canadians from the same surveys provide important perspectives on the magnitude of health disparities that cannot be obtained by small regional studies that dominate the current available literature. Body mass index (BMI) trajectories from 1994 to 2009 were estimated for Aboriginal and non-Aboriginal Canadians. Aboriginal Canadians experienced higher rates of BMI increase over the 14-year period between 1994 and 2009. Rate of BMI increase was specifically higher for Aboriginal adults born in the 1960s and 1970s when compared with non-Aboriginal adults, and later-born cohorts had consistently higher BMI compared with earlier-born cohorts. The role of potentially modifiable lifestyle factors in obesity among Aboriginal and non-Aboriginal youth was also investigated. Compared to non-Aboriginal youth, consumption of fruits/vegetables and dairy products was lower, and more Aboriginal youth were "high" TV watchers. Physical activity participation did not differ between "high" and "low" TV watchers for both groups, and was associated with lowered odds for obesity only among Aboriginal youth. The complex relationship between obesity and socioeconomic status for Aboriginal and non-Aboriginal Canadians was explored. Employment status was strongly and negatively associated with obesity among Aboriginal men and women. Aboriginal men of high socioeconomic status (SES) were most likely to be obese, whereas Aboriginal women of high SES were least likely to be obese. Important descriptive and analytical information on an emerging and serious public health issue among Aboriginal people in Canada can inform the design and planning of intervention programs and development of public health strategies targeted at obesity.

Aboriginal Canadians (First Nations, Métis, and Inuit) have the highest prevalence of overweight and obesity compared to other ethnic groups in Canada. In order to assess the evolution of the problem over time and to understand potential risk factors, three studies were conducted using nationally-representative survey data. Direct comparisons between Aboriginal and non-Aboriginal Canadians from the same surveys provide important perspectives on the magnitude of health disparities that cannot be obtained by small regional studies that dominate the current available literature. Body mass index (BMI) trajectories from 1994 to 2009 were estimated for Aboriginal and non-Aboriginal Canadians. Aboriginal Canadians experienced higher rates of BMI increase over the 14-year period between 1994 and 2009. Rate of BMI increase was specifically higher for Aboriginal adults born in the 1960s and 1970s when compared with non-Aboriginal adults, and later-born cohorts had consistently higher BMI compared with earlier-born cohorts. The role of potentially modifiable lifestyle factors in obesity among Aboriginal and non-Aboriginal youth was also investigated. Compared to non-Aboriginal youth, consumption of fruits/vegetables and dairy products was lower, and more Aboriginal youth were "high" TV watchers. Physical activity participation did not differ between "high" and "low" TV watchers for both groups, and was associated with lowered odds for obesity only among Aboriginal youth. The complex relationship between obesity and socioeconomic status for Aboriginal and non-Aboriginal Canadians was explored. Employment status was strongly and negatively associated with obesity among Aboriginal men and women. Aboriginal men of high socioeconomic status (SES) were most likely to be obese, whereas Aboriginal women of high SES were least likely to be obese. Important descriptive and analytical information on an emerging and serious public health issue among Aboriginal people in Canada can inform the design and planning of intervention programs and development of public health strategies targeted at obesity.

Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Valpha/betarepertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNgamma-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with anti-CD3 antibody or its F(ab’)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. CD4+ T cells impact the progression of obesity-associated metabolic abnormalities and can be manipulated by immunotherapy.

Overweight and obesity, one of the most common public health problems in affluent societies, have become epidemic not only in Canada but also throughout the world. Obesity is also a major contributor to the global burden of chronic disease and disability such as diabetes, hypertension, and cardiovascular disorders. <p>Studies have demonstrated clearly that higher intake of cholesterol and saturated fats and generally higher intake of energy-dense food are a key determinant of increasing levels of obesity and overweight in children. Physical activity is also recognized as a major factor in preventing obesity among children. Environmental factorsby which we mean both social (such as social support, social networks) and physical environment (such as access to physical activity amenities, roads and trails, grocery stores)in generally believed to have a powerful influence on either limiting or enhancing the effects of fundamental determinants (diet and physical activity) of obesity in children. This thesis focuses on one of the key determinants, physical activity, and in turn examines factors that are related to changing physical activity in children. <p>This research was designed to examine two major questions: (1) How do physical activity and overweigh/obesity change over time in a cohort of adolescents in Saskatoon? Are there differences in the patterns of change in overweight/obesity and physical activity between boys and girls? (2) What are the effects of family/friends and physical environments on the changing patterns of physical activity in this sample? <p>The data used in this study was taken from the in motion studies longitudinal data. Study participants include 837 adolescents from12-18 years of age from two high schools and five elementary schools from two diverse geographic areas in Saskatoon (low and high socioeconomic status). Physical activity patterns of adolescents were investigated over a five-month period (e.g., type, frequency, and duration). Participants were also asked to respond to questions on demographics, social support, perceived benefits and barriers of physical activity, and health practices. <p>The results of this study indicated that overweight/obesity increased with age, while physical activity decreased with age for both boys and girls. Boys overall were more likely to be physically active than were girls. Adolescents who received greater direct support from family members were 21% more likely to sustain their physical activity levels (relative odds 1.21; 95% CI 1.17, 1.24); in contrast, the more the familys indirect support the 5.4% less sustaining were the adolescents physical activity (relative odds 0.94; 95% CI 0.91, 0.98). Home environments which were rich in resources relevant to physical activity had 4% greater influence on adolescents physical activity levels, and this relationship was stronger than that of the influence of living in certain neighbourhoods (relative odds 1.04; 95% CI 1.03, 1.05). <p>This research shed some greater understanding of the impact of familys support and physical environment factors on adolescents continued physical activity levels. The implications of results for further research, targeted programs, and social policy is discussed in the thesis.