The biological function of sex and sex-steroid hormones in intestinal lipid and incretin metabolism

在我的NSERC计划（2013-2018）中，我发现肠道是通过雄激素受体（AR）对雄激素敏感的器官，雄激素可以调节全身脂质代谢。肠分泌肠促胰岛素，其也被证明调节脂质代谢。在这个新兴领域，我们对性作为一个生物变量和性类固醇激素如何调节肠道生物学的理解有限。 我的新数据显示，睾丸激素（T）通过AR增加脂肪酸和胆固醇吸收到肠淋巴中。我还发现饮食中的脂质会降低血浆睾酮水平。肠道可以代谢性类固醇，膳食脂质和肠促胰岛素可能会影响这些途径。我的初步数据构成了我的新发现计划的基本原理。我的总体工作假设是，性类固醇是肠道脂质吸收和肠促胰岛素分泌的调节剂，饮食脂质影响肠道性类固醇代谢。将使用多模型和综合生物学方法解决以下目标;主要目标I（短期）：确定性别和性类固醇对肠促胰岛素分泌和脂质吸收的影响。 我将使用性腺切除和性类固醇治疗的雄性和雌性啮齿动物模型，使用尿道淋巴管插管方法确定性别与性类固醇对肠促肠激素分泌和脂质吸收的影响。AR和ER的基因沉默和促进RNA将用于确定这些受体在这些途径中的直接作用。预期的结果将是证实性类固醇、雄激素和雌激素直接通过AR和ER上调脂质吸收和肠促胰岛素分泌。主要目的II（中期）：确定性类固醇如何调节肠促胰岛素和脂肪生成分子信号通路的分子机制。 我将使用肠组织和原代肠上皮细胞来测量AR、ER和脂肪生成核受体、肠促胰岛素和脂质合成蛋白和转运蛋白的基因和蛋白表达。预期的结果将是AR和ER调节核转录因子和参与这些途径的蛋白质的活性。主要目的III（长期）：确定膳食脂质对性类固醇激素的影响，以及与肠道类固醇生成、肠促胰岛素和脂质代谢的关系。我将测试高脂肪和低脂肪饮食对淋巴和血浆脂质、肠促胰岛素和性类固醇的影响。主要的预期结果将是高脂肪饮食通过调节肠道中的类固醇生成来降低血浆性类固醇水平。意义和影响：这项研究旨在解释男性和女性在脂质代谢和肠道生理学方面的差异，并将转化为了解性类固醇如何调节肠道功能和适应性，可应用于生物医学和农业部门。

In my NSERC program(2013-2018) I have discovered that the intestine is an androgen-sensitive organ via the androgen receptor (AR), and androgens can modulate whole-body lipid metabolism. The intestine secretes incretins which have also been shown to modulate lipid metabolism. In this emerging field we have limited understanding of how sex as a biological variable and sex-steroid hormones modulate intestinal biology.   My new data shows testosterone (T) via the AR increases fatty acid and cholesterol absorption into intestinal lymph. I have also shown dietary lipid reduces plasma testosterone levels. The intestine can metabolize sex-steroids, and dietary lipids and incretins may impact these pathways. My preliminary data forms the rationale of my new discovery program. My overall working hypothesis is that sex-steroids are regulators of intestinal lipid absorption and incretin secretion, and dietary lipids impact intestinal sex-steroid metabolism. The following objectives will be addressed using multi-model and integrative biological approaches; Primary Objective I (short-term): To determine the effect of sex and sex-steroids on intestinal incretin secretion and lipid absorption. I will use gonadectomized and sex-steroid treated male and female rodent models to determine the effect of sex vs sex-steroids on intestinal incretin secretion and lipid absorption using intestinal-lymphatic cannulation methods. Gene silencing and promoting RNA for AR and ER will be used to determine the direct role of these receptors in these pathways. The expected outcome will be to confirm sex-steroids, androgens and estrogens, upregulate lipid absorption and incretin secretion directly via the AR and ER. Primary Objective II (mid-term): To determine the molecular mechanisms of how sex-steroids regulate intestinal incretin and lipogenic molecular signalling pathways. I will use intestinal tissue and primary enterocytes to measure gene and protein expression of AR, ER and lipogenic nuclear receptors, incretins and lipid synthesis proteins and transporters. The expected outcome will be that the AR and ER regulate nuclear transcription factors and the activity of proteins involved in these pathways. Primary Objective III (long-term): To determine the effect of dietary lipids on sex-steroid hormones, and the relationship to intestinal steroidogenesis, incretin and lipid metabolism. I will test the effect of diets high and low in fat on lymph and plasma lipids, incretins and sex-steroids. The primary expected outcome will be that diets high in fat reduce plasma sex-steroid levels by modulating steroidogenesis in the intestine. Significance and Impact: This research aims to explain differences between the male and female sex in lipid metabolism and intestinal physiology, and will translate to understanding how sex-steroids regulate intestinal function and adaptation which can be applied in biomedical and agricultural sectors.