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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24795号 / 医博第4987号 / 新制||医||1066(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 小林 恭, 教授 波多野 悦朗, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>  </p> <p>In modern society, continuous light exposure and obesity are increasingly prevalent, especially in women of childbearing age. Circadian, metabolic, and reproductive systems have a complex, inter-regulated relationship. Thus, the disruption of one system likely impedes another. Excessive adiposity and circadian disruption alter normal behavior and physiology and disrupt the endocrine milieu. The overall goal of the studies described in this thesis was to develop and test a model system that could tease apart the influence of prepregnancy obesity and circadian disruption, as well as study the combined effects on female reproductive competence. </p> <p>The first study focuses on the prepregnancy period and aims to determine the effect of high fat diet feeding on diurnal eating pattern, body weight over the four-week period, the body composition at the end of the four-week period, hair corticosterone levels, and circadian fecal corticosterone patterns on female ICR mice. Five-week-old female ICR mice were randomly assigned to control (CON; 10% fat) or high fat (HF; 60%) diets and fed for four weeks to achieve adequate adiposity. During this four-week time period, mice had routine light exposure of 12h light and 12h dark. Feed was weighed at 0600 and 1745 Monday-Friday to determine diurnal feed intake. The mice were weighed on a weekly basis. After four weeks on respective diets, mice were anesthetized with isoflurane to measure crown-rump length to calculate BMI and hair was shaved for corticosterone extraction. Once mice recovered from anesthesia, body composition was measured with EchoMRI. After 1 week on diets, HF mice consumed more (P<0.05) during the day than CON mice, which is typically when mice are inactive. After two weeks on diets, HF mice weighed more (P<0.05) than CON, as well as had higher BMI and percent body fat (P<0.05) than CON after four weeks on diets. After four weeks on diets, HF mice had high hair corticosterone (P<0.05). Sampling feces over a 48h period at the end of the four weeks demonstrated that HF mice had elevated basal corticosterone, attenuated circadian rhythms, and a shift in corticosterone amplitude. The prepregnancy period demonstrated that high fat diets alone alter circadian eating pattern and corticosterone rhythms.</p> <p>The remainder of the study continued the dietary treatments assigned during the prepregnancy period, as well as implemented light conditions to create a 2Χ3 factorial study design. There were three light conditions: 12h light and 12h dark (LD), 24h dim light (L5), or 24h bright light (L100). Mice were moved into experimental light conditions after the observation of a vaginal plug or after 5 days with males. This portion of the study aimed to determine the effect of diet (CON or HF) and light exposure (LD, L5, or L100) on gestation length, number of pups born, milk composition, litter weight on postnatal day 12, as well as dam feed intake, hair corticosterone levels, and plasma prolactin. Continuous light exposure increased gestation length, with L5 (19.1 d ± 0.23) and L100 (18.9 d ± 0.21) having longer gestation lengths (P<0.05) than LD (18.1 d ± 0.25). Diet affected the number of pups born (P<0.05), with HF dams having fewer pups (9.99 ± 0.4) than CON (11.4 ± 0.4). Despite no difference in birth weight of standardized litters (n=8 pus/litter), litters of HF dams weighed more than CON by day 4 postnatal. The greater litter weight of HF dams continued until the end of the study on day 12 of lactation (P<0.05). Light had a tendency to increase litter weight (P=0.07). Diet, light, and stage of reproduction influenced dam feed intake (P<0.05). L100 dams had higher plasma prolactin, as well as final dam and mammary wet weights (P<0.05). Constant light exposure decreased ATP content in the mammary gland (P<0.05) and decreased milk lactose concentration (P<0.05). Pearson’s correlation analysis showed a positive relationship between mammary weight, fat pad weight, BMI, kcal of feed intake, and gestation length (P<0.05). In CON mice, hair corticosterone was negatively correlated with litter weight on lactation day 12. Liver weight was positively correlated with d 12 litter weight in HF mice. Together, these studies demonstrate that feeding high fat diets and continuous light alter maternal behavior and physiology, which may impact offspring health and development, however continuous light may not be the best approach to studying circadian disruption. Elevated maternal plasma prolactin and increased dam weight suggests a long day photoperiod was likely induced, thus potentially mitigating the circadian disruptive effects from constant light. Other model systems should be considered, such as using a chronic jet lag model that changes the light exposure every 3 d. </p>

Yes / Evidence suggests vitamin D3 (VD) supplementation can reduce accumulation of adipose tissue and inflammation and promote myogenesis in obese individuals, and thus could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. However, this is yet to be directly investigated. This study, using the work-loop technique, examined effects of VD (cholecalciferol) supplementation on isolated SkM contractility. Female mice (n = 37) consumed standard low-fat diet (SLD) or high-fat diet (HFD), with or without VD (20,000 IU/kg-1 ) for 12 weeks. Soleus and EDL (n = 8-10 per muscle per group) were isolated and absolute and normalized (to muscle size and body mass) isometric force and power output (PO) were measured, and fatigue resistance determined. Absolute and normalized isometric force and PO of soleus were unaffected by diet (P > 0.087). However, PO normalized to body mass was reduced in HFD groups (P  0.588). HFD reduced EDL isometric stress (P = 0.048) and absolute and normalized PO (P  0.493). Cumulative work during fatiguing contractions was lower in HFD groups (P  0.060). This study uniquely demonstrated that high-dose VD had limited effects on SkM contractility and did not offset demonstrated adverse effects of HFD. However, small and moderate effect sizes suggest improvement in EDL muscle performance and animal morphology in HFD VD groups. Given effect sizes observed, coupled with proposed inverted U-shaped dose-effect curve, future investigations are needed to determine dose/duration specific responses to VD, which may culminate in improved function of HFD SkM. NEW FINDINGS: What is the central question of this study? Can vitamin D supplementation alleviate detrimental effects of high-fat diet (HFD) consumption on contractile performance of isolated skeletal muscles? What is the main finding and its importance? The present study is the first to examine the synergistic effects of HFD consumption and vitamin D supplementation on the contractile performance of isolated skeletal muscle. These findings suggest high dose vitamin D has limited effects on force, power or fatigue resistance of isolated mouse soleus and extensor digitorum longus.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24109号 / 農博第2514号 / 新制||農||1093(附属図書館) / 学位論文||R4||N5400(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 佐藤 健司, 教授 菅原 達也, 准教授 木下 政人 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

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