Interrelationship between the GH-axis and metabolism

描述（由申请人提供）： 摘要/总结肝脏中脂肪的不适当积累会导致肝脏胰岛素抵抗和炎症，进而导致肝纤维化。因此，了解调节肝脏脂质代谢的机制对于优化退伍军人人群中常见的代谢性疾病（包括肥胖、糖尿病和高脂血症）的诊断和治疗至关重要。由于肝脏是生长激素（GH）的主要靶点，再加上生长激素分泌/作用的发育和疾病相关变化与肝脏脂质蓄积的改变相关，因此了解GH如何调节肝脏脂质代谢具有临床意义。GH对肝脏脂质加工的直接影响的清晰图像被以下事实所掩盖：GH还改变全身胰岛素敏感性、胰岛素产生和底物利用率（葡萄糖和游离脂肪酸），所有这些都是已证实的肝脏脂质代谢调节剂。分离出GH和胰岛素的相对作用是进一步复杂的事实，胰岛素，以及GH，支持肝GH信号和胰岛素样生长因子I（IGF-I）的生产，IGF-I和胰岛素作为GH分泌的负反馈调节剂。鉴于GH和胰岛素之间复杂的相互关系，实验性改变其中一个的输出或信号将不可避免地导致另一个的变化。为了避免这些问题，拟议的一系列实验将利用我们实验室开发的独特的基因工程小鼠模型，该模型“抑制”GH和输入肝脏的胰岛素。在该提案中，我们将使用基因工程动物模型来实现1）GH和胰岛素的受控升高，2）在不存在肝胰岛素信号传导的情况下的高/正常GH和3）在不存在肝GH信号传导的情况下的高/正常胰岛素。这些体内模型将与原代肝细胞培养物结合使用，以解决以下特定目的：A）确定GH是否改变胰岛素介导的肝脏脂质代谢变化，B）检测胰岛素是否对GH介导的肝脏脂质代谢调节至关重要，以及C）检查成人发作的肝脏GH抵抗对脂质代谢的影响。所获得的知识将有助于更好地了解代谢性疾病的发展，进展，诊断和治疗。

DESCRIPTION (provided by applicant): Abstract/Summary Inappropriate accumulation of fat in the liver leads to hepatic insulin resistance and inflammation which can progress to liver fibrosis. Therefore, understanding the mechanisms regulating hepatic lipid metabolism is critical in optimizing the diagnosis and treatment of metabolic diseases that are common in the Veteran population including obesity, diabetes mellitus and hyperlipidemia. In that the liver is a major target of growth hormone (GH), coupled with the fact that developmental- and disease-associated changes in GH secretion/action are associated with alterations in hepatic lipid accumulation, understanding how GH regulates hepatic lipid metabolism is clinically relevant. A clear picture of the direct effectsof GH on hepatic lipid processing is clouded by the fact that GH also alters whole body insulin sensitivity, insulin production and substrate availability (glucose and free fatty acids), all of wich are confirmed modulators of hepatic lipid metabolism. Separating out the relative roles of GH and insulin is further complicated by the fact that insulin, as well as GH, supports hepatic GH signaling and insulin-like growth factor I (IGF-I) production, and IGF-I and insulin serve as negative feedback regulators of GH secretion. Given the complex interrelationship between GH and insulin, experimental alteration in the output or signaling of one will inevitably lead to changes in the other. In order to circumvent these problems, the proposed series of experiments will take advantage of unique genetically engineered mouse models, developed by our laboratory, that "clamp" GH and insulin input to the liver. In this proposal, we will use genetically engineered animal models to achieve 1) controlled elevation of both GH and insulin, 2) high/normal GH in the absence of hepatic insulin signaling and 3) high/normal insulin in the absence of hepatic GH signaling. These in vivo models will be used in conjunction with primary hepatocyte cultures to address the following SPECIFIC AIMS: A) Determine if GH modifies insulin-mediated changes in hepatic lipid metabolism, B) Test if insulin is essential for GH-mediated regulation of hepatic lipid metabolism, and C) Examine the impact of adult-onset hepatic GH resistance on lipid metabolism. The knowledge gained will aid in the better understanding of the development, progression, diagnosis and treatment of metabolic diseases.