An extensive literature has linked off-time pubertal maturation to adverse health outcomes among adults. Childhood adversities are also linked to both pubertal development and cardiometabolic disease. Despite the racial and ethnic disparities in pubertal timing and cardiometabolic health in midlife, few studies have investigated if off-time pubertal maturation is associated with Latino individuals' metabolic syndrome. Furthermore, there exists limited data assessing early life risk factors affecting the association between timing of pubertal maturation and metabolic syndrome by sex and in young adults. This dissertation used a life course perspective to test developmental hypotheses of stress on reproductive strategies and cardiometabolic health to address these limitations. The three primary aims of this dissertation research were to 1) estimate the association between family dysfunction and timing of pubertal maturation in Latino boys and girls, 2) systematically review the impact of the timing of pubertal maturation on metabolic syndrome in young adults age 18-40 years, and 3) estimate the association between timing of pubertal maturation and metabolic syndrome in young adult Latino men and women. The analytic aims were explored using data from two population-based cohorts that include different age groups: the Hispanic Community Health Study/Study of Latinos (HCSH/SOL) Youth Ancillary Study (cross-sectional design) (8-16 years), and the Boricua Youth Study Health Assessment Ancillary Study (prospective design) (5-10 years and 18-23 years). The first empirical study, using HCHS/SOL Youth data, found that the presence of family dysfunction may be associated with delayed pubertal maturation in Latino children and adolescents. The systematic review highlighted the lack of diversity by sex, measurements, and racial/ethnic representation in this area of research, but also suggested that childhood BMI may account for much of the association between pubertal timing and metabolic syndrome. The second empirical study, based on the BYS HA study, did not find meaningful associations between timing of pubertal maturation and metabolic syndrome and cardiometabolic traits in young adults. These results do not support the prevailing hypotheses nor quantitative evidence linking off-time pubertal maturation to poorer cardiometabolic health. Overall, this dissertation utilized a life course perspective to advance understanding and support of the origins of adulthood cardiovascular risk that may begin in childhood. Future investigations should be designed to be longitudinal and include measures characterizing childhood body size, health behaviors, and environmental exposures. Future studies should also explore the specific mechanisms explaining the observed associations, particularly the complex interaction between hormonal and metabolic factors that appear to affect adult health among individuals with off-time pubertal maturation adversely.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18130号 / 医博第3850号 / 新制||医||1001(附属図書館) / 30988 / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 横出 正之, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19402号 / 医博第4053号 / 新制||医||1012(附属図書館) / 32427 / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 小川 誠司, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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16 Abstract The rising prevalence in noncommunicable diseases worldwide calls for the effort to determine their underlying causes. Common metabolic disorders in particular overwhelm the healthcare systems and are a one of the leading causes of poor quality of life of patients. Metabolic syndrome is represented by concurrence of several conditions - dyslipidaemia, obesity, hypertension or impaired glucose tolerance - altered metabolic phenotypes related to genetic and environmental factors. Recent studies suggest that early-life exposure to certain environmental stimuli is particularly capable of changing the mammalian phenotypes. Nutrition, as one of the major factors influencing health, is naturally a focus of research, which studies the link between parental diets and phenotypic alterations in offspring. The developmental origins of health and disease were historically more focused on maternal undernutrition, it is, however, more important to focus on surplus of macronutrients considering the westernization of modern diets. We propose the relevancy of not only the amount of macronutrients in maternal diet, but also their sources, as they may increase disease risk in offspring. Here we report, that sucrose as an alternative carbohydrate in maternal diet, has a marked impact on metabolism of the offspring...

Atherosclerosis and symptoms of metabolic syndrome such as obesity, high cholesterol, and insulin resistance often coincide and exacerbate one another, but the cellular and molecular events in common with these conditions have not yet been fully elucidated. Low density lipoprotein receptor adaptor protein 1 (LDLRAP1) is an adaptor protein which interacts with the cytoplasmic tail of the LDL receptor, internalizing the receptor when it engages with LDL. Mutations in this gene lead to LDLR malfunction and cause Autosomal Recessive Hypercholesterolemia (ARH) in humans; however, direct causality on atherogenesis or metabolism in a defined pre-clinical model has not been reported. The aim of this study was to test the hypothesis that deletion of LDLRAP1 would lead to hypercholesterolemia and atherosclerosis. LDLRAP1-/- mice fed a high fat, western diet (HFD) for 16 weeks had significantly increased plasma cholesterol and triglyceride concentrations, accompanied with significantly increased plaque burden compared with wild-type controls. Unexpectedly, LDLRAP1-/- mice gained significantly more weight compared to the wild-type, LDLRAP1-/- mice were insulin resistant, and calorimetric studies suggested an altered metabolic profile. We determined that LDLRAP1 is highly expressed in white adipose tissue (WAT), and LDLRAP1-/- adipocytes are significantly larger and have reduced glucose uptake and AKT phosphorylation, but increased CD36 expression. WAT from LDLRAP1-/- mice is hypoxic, and has gene expression signatures of dysregulated lipid storage and energy homeostasis. These data indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice, and also are the first to suggest that LDLRAP1 plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 deletion leads to systemic effects, and may act as a molecular link which regulates dyslipidemia, atherosclerosis, insulin resistance, and obesity. / Biomedical Sciences

Obesity is a disease that increases risk of developing metabolic diseases including insulin resistance (IR), metabolic syndrome (MS), and type 2 diabetes (T2D). Adipose tissue expansion during obesity leads to immune cell infiltration, causing local inflammation and disruption of lipid homeostasis. There is an association between exposure to environmental chemicals, like p,p’-DDE, a metabolite of p,p’-DDT, and diagnosis of obesity, dyslipidemia, IR, and prevalence of MS and T2D. DDE accumulates in fatty tissues and has been shown to have immunomodulatory properties, affecting macrophage and T cell populations. Potential mechanisms were studied by which DDE could modulate adipocyte and immune cell function and facilitate an increased risk of obesity and immune dysregulation, potentially through cyclooxygenase-2 (COX-2). 3T3-L1 preadipocytes and J774A.1 macrophages were studied for the effects of DDE on adipogenesis and macrophage reactivity, respectively. 3T3-L1 cells were induced to differentiate to adipocytes using a sub-optimal differentiation cocktail with increasing concentrations of DDE (0.5uM-100uM). It was determined that DDE enhanced adipogenesis in a concentration dependent manner and the expression of adipogenic and lipogenic genes, indicating that DDE enhances adipogenesis. In J774A.1 cells, the ability of DDE or 10uM NS-398, a specific COX-2 inhibitor, to inhibit the production of the prostaglandins PGE2, PGD2, PGF2a, was assessed in vitro and in a cellree system. DDE or NS-398 followed by immune challenge reduced cellular PG secretion and reduced PG production in a cell free system, indicating that DDE may interfere with lipid mediator signaling. Additionally, DDE or NS-398 exposure altered gene expression in J774A.1 cells following M1 or M2 polarization stimulus. Lastly, male C57Bl mice were exposed to 2mg/kg DDE for 5 days and the macrophage population of the adipose stromal vascular fraction was analyzed by flow cytometry. Adipose from DDE treated animals contained approximately 40% F4/80+CD11b+ macrophages. These results indicate that DDE may alter the homeostasis of adipose tissue by both enhancing adipogenesis and altering the reactivity of the resident macrophage population in a manner that may contribute to adipose dysfunction. These data suggest a possible mechanism by which DDE exposure may contribute to adiposity and adipose tissue dysfunction commonly seen in metabolic disease.

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. Our Centre previously generated a renin-dependent hypertensive/ type 1 diabetic mouse model and lead to the development of several signs associated with human diabetic kidney disease (DKD), however the extent and impact of dyslipidemia in this model remains unknown. We hypothesized that combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice. An 8-week-old male genetically hypertensive mice (Lin+) were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive) to induce hyperglycemia. Four-weeks later hypertensive/ diabetic mice (Lin+ mouse with induced beta cells death, also known as LinSTZ) were fed a 60% kCal HFD for 8 weeks. This study shows that HFD-fed LinSTZ mice developed less glomerular hypertrophy, scarring and albuminuria and hepatocytes fat accumulation at endpoint than regular-diet fed littermates. Moreover, antidiabetic drug Canagliflozin, dosed at 30 mg/kg body weight, showed reno-protection in the LinSTZ mice model. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS induced CKD. In fact, several indices of renal injury were reduced by feeding LinSTZ mice a HFD or treating them with Canagliflozin.

Indiana University-Purdue University Indianapolis (IUPUI) / Risk of coronary artery disease (CAD), the leading cause of death, greatly increases in metabolic syndrome. Metabolic syndrome (MetS; obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is increasing in prevalence with sedentary lifestyles and poor nutrition. Non-alcoholic steatohepatitis (NASH; i.e. MetS liver) is progressive and decreases life expectancy, with CAD as the leading cause of death. Pathogenic Ca2+ regulation transforms coronary artery smooth muscle from a healthy, quiescent state to a diseased, proliferative phenotype thus majorly contributing to the development of CAD. In particular, store-operated Ca2+ entry (SOCE) in vascular smooth muscle is associated with atherosclerosis. Genetic predisposition may render individuals more susceptible to Ca2+ dysregulation, CAD, NASH, and MetS. However, the metabolic and cellular mechanisms underlying these disease states are poorly understood. Accordingly, the goal of this dissertation was to investigate the role of dyslipidemia within MetS in the development of Ca2+ dysregulation, CAD, and NASH. The overarching hypothesis was that dyslipidemia within MetS would be necessary for induction of NASH and increased SOCE that would primarily mediate development of CAD. To test this hypothesis we utilized the Ossabaw miniature swine model of MetS. Swine were fed one of five diets for different lengths of time to induce varying severity of MetS. Lean swine were fed normal maintenance chow diet. F/MetS swine were fed high Fructose (20% kcal) diet that induced normolipidemic MetS. TMetS were fed excess high Trans-fat/cholesterol atherogenic diet that induced mildly dyslipidemic MetS and CAD. XMetS were TMetS swine with eXercise. DMetS (TMetS + high fructose) were moderately dyslipidemic and developed MetS and extensive CAD. sDMetS (Short-term DMetS) developed MetS with mild dyslipidemia, but no CAD. MMetS (Mixed-source-fat/cholesterol/fructose) were severely dyslipidemic, exhibited NASH, and developed severe CAD. Dyslipidemia in MetS predicted NASH severity (all groups < DMetS << MMetS), CAD severity (i.e. Lean, F/MetS, sDMetS < XMetS < TMetS < DMetS < MMetS), and was necessary for STIM1/TRPC1-mediated SOCE, which preceded CAD. Exercise ameliorated SOCE and CAD compared to TMetS. In conclusion, dyslipidemia elicits TRPC1/STIM1 SOCE that mediates CAD, is necessary for and predictive of NASH and CAD, and whose affects are attenuated by exercise.

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