京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第19629号 / 医科博第67号 / 新制||医科||5(附属図書館) / 32665 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 椛島 健治, 教授 岩井 一宏, 教授 渡邊 直樹 / 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20238号 / 医博第4197号 / 新制||医||1019(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 長船 健二, 教授 河本 宏, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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IGF1 and its receptor IGF1R have been correlated with the proliferation of granulosa cells as well as steroid synthesis. Studies have shown that conditional ablation of Igf1r in granulosa cells leads to follicular arrest at a secondary stage, absence of ovulation and infertility. With a high homology between IGF1R and INSR, the full effects of insulin signaling could be masked by just a single receptor knockout. Therefore, utilizing Esr2-iCre we generated a granulosa specific double knockout mouse model. These mice have severely disrupted follicular development, with a block at a primary stage. Granulosa cells do not proliferate, while the oocytes appear activated resulting in reduction of ovarian size, absence of estrous cyclicity and infertility. Since an early granulosa cell knockout leads to block in follicular development, it masks the receptor function during ovulation, and CL formation. With the use of Pgr-Cre, the follicular development goes undisturbed until the periovulatory stages. Pgr-Cre knockout of Insr and Igf1r results in reduced ovulation, and progesterone synthesis. Few oocytes, that do escape, get fertilized but fail to thrive, and do not implant. Pgr-Cre is also active in the uterine endometrium. Ablation of Insr and Igf1r in the uterus results in reduced endometrial proliferation during the preimplantation period, complete absence of implantation and decidualization. Collectively, these results indicate the importance of INSR and IGF1R during follicular development, and ovulation, as well as in uterine proliferation, implantation, and decidualization.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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TGFβ ligands, activin and myostatin have been shown to stimulate insulin production and secretion. Antagonists, Follistatin (FST) and Follistatin like 3 (FSTL3) were partially and fully ablated, respectively, creating hyperinsulinemic mice with fatty liver. Much research has surfaced on the connection between hepatic steatosis and hepatic insulin resistance. We present two different models, each with a different mechanism behind the development of fatty liver. FST288-only mice have increased synthesis of mRNA and proteins responsible for hepatic triglyceride (TG) uptake, while our double mutants have increased synthesis of mRNA and proteins responsible for TG synthesis. This alteration was likely independent of hepatic insulin resistance as livers from both mouse lines were insulin sensitive. Experiments conducted in this study to realize the causal factor of hepatic steatosis can be performed on adipose and muscle tissues in the future to better characterize the phenotype.

Controversy exists concerning the possible involvement of serotonin in the pituitary-adrenocortical response to stress. In the present research, a variety of physiological and pharmacological manipulations were used in male rats to study the role of this neurotransmitter in the adrenocortical response to insulin- induced hypoglycemia. First, the effect of insulin stress on hypothalamic 5-HT metabolism was examined, and an increased turnover was found as determined by an enhanced accumulation of 5-HT following monoamine oxidase inhibition. The corticos terone response to insulin was potentiated by prior administration of L-tryptophan, and blocked by pretreatment with valine, an amino acid that competes with tryptophan for transport across the blood-brain barrier. Treatment with the 5-HT receptor blocker methysergide, or serotonin depletion by intraventricular injection of 5 , 7-dihydroxy tryptamine significantly attenuated the insulin- induced rise in circulating corticosterone.