京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13230号 / 論医博第2170号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 松田 文彦, 教授 富樫 かおり / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Pregnancy induces a dramatic change in hemodynamics due to increased blood volume and metabolic demands. The adaptation of the heart leads to physiological cardiac hypertrophy remodeling in healthy individuals during pregnancy. Metabolic syndrome (MetS) is known to predispose individuals to adverse cardiovascular event. Cardiac remodeling during pregnancy in obese individuals with or without MetS remains unclear. This study first observed differences in cardiac remodeling in human patients with excess weight during pregnancy. The pathophysiology of cardiac remodeling with pregnancy was then studied in a diet-induced animal model that recapitulates features of human MetS. Female mice fed with high fat diet (HFD) (45%kcal) for 4 months had increased body weight, impaired glucose tolerance and dyslipidemia. Pregnant female mice were kept on this HFD and were compared to nonpregnant females and normal diet (10%kcal fat) controls. HFD induced early-stage MetS led to cardiac hypertrophy at term that had features of pathological hypertrophy (PH), including fibrosis and upregulation of fetal genes associated with PH. Hearts from pregnant animals on the HFD had a distinct gene expression profile that likely underlies their pathological remodeling. Post-partum mice with preexisting MetS are also more susceptible to future pathological stimuli, with exacerbated cardiac hypertrophy and impaired cardiac function. These results suggested that preexisting MetS could change physiological into pathological cardiac remodeling during pregnancy, and predispose the heart to future cardiovascular risks. / Biomedical Sciences

Metabolic Syndrome (MetS) is a condition affecting over one third of U.S. adults and is characterized by risk factors that promote inflammation and result in chronic disease. Indicated by high visceral adiposity, dyslipidemia, insulin resistance and hypertension, MetS has been associated with increased risk for future cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality. Recognizing the need for population-specific dietary and lifestyle guidance is crucial for reversing the exponential growth in chronic diseases. Self-reported behavior and directly measured anthropometric and laboratory data from 4,627 adults in the 2007-2010 National Health and Nutrition Examination Survey were analyzed. The objectives were 1) determine the prevalence of MetS using the AHA/NHLBI criteria for specific cohorts in U.S. adults 2) determine whether macronutrient composition, micronutrient adequacy and energy balance differ between adults age 20-59 with and without MetS 3) investigate dietary patterns reported using food groups and their relationships with MetS in adults age 20-59. Agejusted prevalence of MetS was 36.8 percent (95 percent CI 34.7 percent-39.0 percent). Prevalence increased with age groups and BMI categories. Odds Ratios (OR) for MetS compared to normal weight were 4.33 (95 percent CI 3.43-5.47) for overweight individuals and 17.98 (95 percent CI 13.29-24.31) for obese individuals. Average daily moderate activity was 45 minutes less in adults with MetS (p<0.05). Within races, black women had a higher prevalence of MetS than black men (p<0.05) and white men had a higher prevalence than white women (p<0.05). Overall, there were few clinically significant differences in nutrient intake between those with and without MetS in race/gender cohorts, however nutrient intake differed between cohorts. Nutrient intake relative to caloric needs was lower in those with MetS, which may suggest lower metabolic rate than predicted. White men and women consumed more of most food groups than the other races. Women with MetS consumed more meat, seafood and eggs, and solid fat and less legumes, nuts, and seeds and grains than women without MetS (p<0.05). Men without MetS consumed more alcohol than men with MetS (p<0.05). Dietary intake was not predictive of MetS, however total volume of physical activity and BMI are factors that can be modified.

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A pig model of childhood obesity was used to study the effects of dietary energy on body adiposity, and blood parameters associated with impaired glucose clearance. Prepubertal female pigs weaned at 21 d of age were fed control (CON), refined sugar (SUG), fat (FAT), and sugar-fat (SUGFAT) diets in a completely randomized arrangement for 16 wk. Calories from fat were 8.9% for CON, 5.6% for SUG, 35.5% for FAT and 32.3% for SUGFAT. Calories from sugar were 36.0% for SUG and 30.7% for SUGFAT. Adding fat, sugar or both to diets increased (P < 0.003) calorie intake. Percentage body fat was higher (P < 0.0001) in all treatments compared to CON, and in SUGFAT and FAT compared to SUG. Ultrasound back fat depth was positively correlated (r2 = 0.909; P < 0.001) with percentage body fat and negatively (r = 0.912; P-value ) with percentage body protein. Area under the curve (AUC) in response to oral glucose tolerance at 14 wk was higher (P < 0.03) in FAT (+14.6%) and SUGFAT (+25.5%) pigs compared to CON. Glucose AUC from sugar-fed pigs was not different (P = 0.2) from fat alone-fed pigs. Adding sugar, fat, or their combination to diets increased (P < 0.008) blood glucose and decreased (P < 0.0009) plasma insulin AUC. These data show that inclusion of fat and refined sugar in pig diets increases body adiposity and impairs glucose homeostasis and suggests that the composition of calories consumed may have different effects than simply consumption of excess of calories. / Master of Science

Metabolic Syndrome (MetS) is a cluster of metabolic disorders that substantially increase the risk of developing other chronic diseases such as cardiovascular disease and type II diabetes. Diet is known to play a crucial role in the development of MetS and dietary intervention studies are a useful tool to investigate the effect of diet on MetS. However, the slow onset of MetS and difficulties associated with adhering to new diets, especially for long-term, makes it challenging to perform extensive dietary intervention studies on humans. To overcome this limitation, we sought to investigate the impact of diet on the risk of MetS by taking an in silico systems biology approach. We employed a whole-body model (WBM) of metabolism that accounts for 26 organs, including six sex organs, to computationally evaluate, at genome-scale, the effect of ten different diets on the serum levels of five key metabolites implicated in MetS namely glucose, triacylglycerides (TAG), LDL-C, HDL-C, and palmitoyl-CoA. We performed separate simulations for males and females using the sex specific WBMs. Our analyses elucidated molecular mechanisms that support the current hypothesis that an unhealthy diet can significantly elevate the risk of developing MetS while a healthy diet helps promote metabolic homeostasis. Furthermore, our investigation uncovered novel insights into the contribution of specific organs and tissues to the risk of MetS under these diets in males and females. For example, we found that glucose and TAG secretion by adipocytes into the blood are substantially lower and higher, respectively, under the unhealthy diet compared to other diets. Striking differences were also observed between the unhealthy diet and other diets for LDL-C, HDL-C, and palmitoyl-CoA in males. In females, we observed patterns that resembled those in males although other organs, such as the breast or uterus, also contributed to the serum levels of these key metabolites. Our study offers a promising strategy for investigating the effect of various dietary regimens on human metabolism and MetS at organ-level resolution. This paves the way for the in silico design of new dietary interventions to treat MetS. / 2026-02-12T00:00:00Z

Cardiometabolic diseases are the leading causes of worldwide mortality, of which metabolic syndrome is a major contributor. Increased sedentary behavior and decreased physical activity have been independently associated with increased risk of developing metabolic syndrome and subsequent maladies. Likewise, the development of more contemporary methodologies of measuring metabolic syndrome allow for a more nuanced examination of risk. However, these new methodologies lack extensive utilization among the physical activity epidemiology literature. The scarcity of research incorporating the independent relations between sedentary behavior, physical activity, and contemporary methodologies to measure metabolic syndrome warrants additional investigation. This dissertation aimed to further discern these relations using three different cohort data sets. Data from the National Health and Nutritional Examination Survey (NHANES), the Jackson Heart Study (JHS), and the Coronary Artery Risk Development in Young Adults (CARDIA) Study were utilized to further elucidate the relations between sedentary behavior, physical activity, and metabolic syndrome in three separate studies. The studies observed the majority of waking hours were spent engaged in sedentary behaviors; although, each cohort also appeared to meet the Physical Activity Guidelines for Americans. Metabolic syndrome positive individuals from NHANES engaged in similar amounts of physical activity as the general population. While the diversity of physical activity type was less, the physical activities engaged in were typically at the same prevalence among metabolic syndrome positive and the general populations. Sedentary behaviors were associated with increased metabolic syndrome severity score, but this relation was attenuated when moderate-to-vigorous physical activity and cardiorespiratory fitness were added to the model for both JHS and CARDIA studies. Decreasing sedentary time and with an equivalent amount of physical activity, of any intensity, is beneficial for cardiometabolic health. Understanding which physical activities subpopulations engage in can be paired with culturally competent interventions to increase physical activity engagement. Exceeding the minimum requirements for the Physical Activity Guidelines for Americans can produce increases in cardiorespiratory fitness, which have an independent positive impact on cardiometabolic health. Strategies should aim to increase physical activity among sedentary individuals, while limiting sedentary time among those physically active.

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