Estrogen and coordinated carbohydrate and lipid metabolism in obesity

 描述（由申请人提供）：肥胖损害葡萄糖和脂质代谢，并增加冠心病（CHD）的风险。绝经前肥胖女性患冠心病的风险约为肥胖男性的1/2;当绝经后卵巢功能丧失时，这种保护作用就会降低。了解这种保护机制是一个重要的治疗机会。该项目的目标是确定女性保护肥胖诱导的血糖和血脂异常的机制，并看看我们是否可以在男性中增强这一途径。 在肝脏中，肥胖症中葡萄糖和脂质生物学受损的存在被归因于胰岛素诱导的AKT信号转导调节葡萄糖的缺陷，但完整的SREBP 1c信号转导促进脂肪生成。该模型不足以解释血脂异常伴肥胖。我们已经开发了体内方法来了解脂肪，肌肉和肝脏的综合关系，这使我们能够提供肥胖症的脂质和葡萄糖异常的统一模型：由于胰岛素对脂肪分解的抑制作用受损，导致脂肪酸（FA）向肝脏的过度输送。作为对这种FA通量的响应，肝脏将FA再结晶为甘油三酯（TG），导致脂肪肝和VLDL-TG的输出。脂肪肝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，但决定健康与疾病之间平衡的综合控制却一直难以捉摸。此外，女性受到保护，从FA诱导的胰岛素抵抗，我们建议是由雌激素调节的脂肪酸代谢在肌肉和肝脏介导。 我们发现雌激素可以纠正肥胖症中的血糖和血脂缺陷--促进胰岛素--调节葡萄糖代谢，同时阻止血脂异常。通过使用葡萄糖和脂质流量双示踪剂的创新体内方法，我们发现这种保护作用需要通过雌激素受体α（ERα）进行雌激素信号传导。我们将mRNA测序与肝脏中缺乏ERα的小鼠相结合，发现ERα影响许多参与葡萄糖和脂质代谢的肝脏基因，并通过诱导负转录调节因子小异源二聚体伴侣（SHP）间接调节这些途径。这种肝脏雌激素途径在男性中也很重要-并且可能被增强以预防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（AIM 1）限制FA向肝脏的递送，2）它通过SHP激活肝脏中的转录网络，促进胰岛素抑制胰岛素生成，促进FA氧化，并阻止FA驱动的VLDL产生（AIM 2）。男性ERα信号较低，但这种保护作用可以增强（AIM 3）。 我们的研究意义重大，因为它们有望：1）确定女性降低CHD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）确定男性中有益的睾酮效应通过其转化为雌激素介导的程度，以及是否增加男性中肝脏ERα通路可以预防FA介导的血脂异常和葡萄糖耐受不良。

 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.