Estrogen and coordinated carbohydrate and lipid metabolism in obesity

 说明(申请人提供)：肥胖会损害血糖和脂肪代谢，增加患冠心病的风险。绝经前肥胖女性的冠心病风险约为肥胖男性的1/2；当绝经后卵巢功能丧失时，这种保护作用就会减弱。了解这种保护的机制有一个重要的治疗机会。这个项目的目标是确定女性预防肥胖引起的血糖和血脂异常的机制，并看看我们是否可以在男性身上增强这一途径。在肝脏中，肥胖时糖脂生物学受损的存在被归因于胰岛素诱导的调节血糖的AKT信号的缺陷，但促进脂肪生成的SREBP1c信号完整。这个模型不足以解释肥胖引起的血脂异常。我们已经开发了体内方法来了解脂肪、肌肉和肝脏的整合关系，这使我们能够提供肥胖的脂肪和血糖异常的统一模型：脂肪酸(FA)向肝脏的过量输送是由于胰岛素对脂解的抑制受损造成的。作为对这种FA流量的响应，肝脏将FA重新酯化为甘油三酯(TG)，导致脂肪肝和VLDL-TG的输出。脂肪肝会导致葡萄糖代谢的胰岛素调节受损。虽然这些步骤中的每一个都得到了文献的支持，但决定健康和疾病之间平衡的综合控制一直难以实现。此外，女性免受FA诱导的胰岛素抵抗的影响，我们认为这是由雌激素调节肌肉和肝脏的FA代谢所介导的。我们已经发现，雌激素可以纠正肥胖中的葡萄糖和脂肪缺陷--促进胰岛素调节葡萄糖代谢，同时阻止血脂异常。利用一种创新的体内葡萄糖和脂通量双重示踪剂，我们发现这种保护作用需要雌激素通过雌激素受体α(ERα)发出信号。我们将其与肝脏中缺乏ERα的小鼠相结合，发现ERα影响许多参与糖脂代谢的肝脏基因，并通过诱导负转录调节因子小杂二聚体伙伴(SHP)间接调节这些途径。这种肝脏雌激素途径对男性也很重要--而且很可能被增强以预防CHD。我们假设雌激素通过ERα介导的三个关键作用：1)它通过促进肌肉FA氧化来限制FA向肝脏的输送(AIM1)；2)它通过SHP激活肝脏中的转录网络，促进胰岛素抑制糖异生，促进FA氧化，并阻止FA驱动的极低密度脂蛋白的产生(AIM2)。雄性有低ERα信号，但这种保护作用可以增强(AIM3)。我们的研究具有重要意义，因为它们有望：1)确定女性性行为降低冠心病风险的生理基础，并为将这种保护转化为医疗保健提供基础；2)确定男性体内有益的睾酮效应通过转化为雌激素而介导的程度，以及增强男性肝脏ERα通路是否可以防止FA介导的血脂异常和糖耐量异常。

 DESCRIPTION (provided by applicant): Obesity impairs glucose and lipid metabolism, and increases the risk of coronary heart disease (CHD). Obese pre-menopausal females have ~1/2 the CHD risk of obese males; this protection is reduced when ovarian function is lost with menopause. There is an important therapeutic opportunity in understanding the mechanisms of this protection. The goal of this project is to define mechanisms by which female sex protects against obesity-induced glucose and lipid abnormalities, and see if we can augment this pathway in males. In the liver, the presence of impaired glucose and lipid biology in obesity has been attributed to a defect in insulin-induced AKT signaling to regulate glucose, but intact SREBP1c signaling to promote lipogenesis. This model is not sufficient to explain dyslipidemia with obesity. We've developed in-vivo approaches to understand the integrated relationships of adipose, muscle and liver, which allow us to provide a unifying model of both lipid and glucose abnormalities of obesity: Excess delivery of fatty acids (FA) to the liver arises due to impaired suppression of lipolysis by insulin. In response to this FA flux, the liver re-esterifies FA into triglyceride (TG) resulting in fatty liver and export of VLDL-TG. Fatty liver results in impaired insulin-regulation of glucose metabolism. While each of these steps is supported in the literature, the integrated control that determines the balance between health and disease has been elusive. Additionally, females are protected from FA-induced insulin resistance, which we propose is mediated by estrogen-regulated FA metabolism in muscle and liver. We've discovered that estrogen corrects both the glucose and lipid defects in obesity -promoting insulin- regulation of glucose metabolism, while blocking dyslipidemia. Using an innovative in vivo approach with dual tracers for glucose and lipid flux, we discovered that this protective effect requires estrogen signaling through estrogen receptor alpha (ERα). We coupled mRNA sequencing and mice lacking ERα in the liver and found that ERα influences numerous liver genes involved in glucose and lipid metabolism, and also indirectly regulates these pathways by induction of the negative transcriptional regulator Small Heterodimer Partner (SHP). This liver estrogen pathway is also important in males -and can likely be augmented to prevent CHD. We hypothesize three critical actions of estrogen mediated through ERα: 1) it limits FA delivery to the liver by promoting muscle FA oxidation (AIM1), 2) it activates via SHP a transcriptional network in the liver that promotes insulin suppression of gluconeogenesis, promotes FA oxidation, and prevents FA-driven VLDL production (AIM2). Males have low ERα signaling, but this protection and can be augmented (AIM3). Our studies are significant because they are expected to: 1) identify the physiological basis by which female sex reduces CHD risk and provide a foundation for translating this protection into healthcare, 2) define the extent that beneficial testosterone effects in males are mediated through its conversion to estrogen, and if augmenting the liver ERα pathway in males can prevent FA-mediated dyslipidemia and glucose intolerance.