Effects of recombinant human leptin in nonalcoholic fatty liver disease (NAFLD)

描述(申请人提供)：脂肪细胞激素瘦素具有广泛的作用范围，包括调节体重和胰岛素敏感性。我们发现，瘦素治疗非HIV脂肪营养不良可以逆转胰岛素抵抗、高甘油三酯血症和非酒精性脂肪肝(NAFLD)。随后，我们通过显示体重指数和性别匹配的NHANES III队列中瘦素水平的第25个百分位数，表明40%的非酒精性脂肪性肝炎(NASH，NAFLD最严重的形式)男性患者有相对瘦素缺乏(RLD)。我们最近完成了一项初步研究，调查了瘦素治疗对NASH和RLD的影响。初步数据令人鼓舞地表明，男性RLD患者实际上是瘦素反应的，因为他们表现出有益的代谢效应，以及开放标记瘦素治疗对肝脏组织病理学的改善。我们现在建议在更广泛的范围内探索NASH中的RLD。在目标1中，我们将在40名患有NAFLD/NASH和RLD的男性中测试重组瘦素治疗的疗效，并与安慰剂对照，他们的饮食将以双盲设计进行适度热量限制，为期1年。在目标2中，我们将研究我们观察到的静息能量消耗(REE)变化的时间进程。我们还将通过FDG-PET扫描研究自主神经功能、甲状腺轴和棕色脂肪质量来探讨REE变化的机制。如果这项提议成功完成，结果可能会为瘦素在人类中的作用提供新的临床和分子方面的见解。在目标3中，我们将确定肝脏基因表达的差异以及血清代谢组学的差异。初步数据显示，瘦素在肝脏FXR/RXR途径中的调节作用具有有趣的线索。我们将有机会在使用控制饮食和对照安慰剂对照的更多患者中更详细地研究这一点。 与公共卫生相关：肥胖的一个日益严重的并发症是脂肪肝，一般人口中至少有三分之一受到这种疾病的困扰。了解肥胖信号(如瘦素)和脂肪肝之间的联系可能有助于我们改进肥胖和胰岛素抵抗的治疗方法。如果我们的假设是正确的，20%的脂肪肝患者(那些相对缺乏瘦素的人)可能会从我们的研究中获得直接的临床益处。

DESCRIPTION (provided by applicant): The adipocyte hormone leptin has a wide-scope of actions including regulation of weight and insulin sensitivity. We showed that leptin therapy in the setting of non-HIV lipodystrophy reverses insulin resistance, hypertriglyceridemia and nonalcoholic fatty liver disease (NAFLD). Subsequently, we have shown that 40% of male patients with nonalcoholic steatohepatitis (NASH, the most severe form of NAFLD) have relative leptin deficiency (RLD) by demonstrating a leptin level < 25th percentile of BMI- and-gender-matched NHANES III cohort. We have recently completed a pilot study that investigated effects of leptin therapy in NASH and RLD. Preliminary data are encouraging to suggest that male patients with RLD are in fact leptin-responsive as they demonstrate salutary metabolic effects as well as histopathological improvement in liver with open-label leptin therapy. We now propose to explore RLD in NASH in a broader scale. In Aim 1, we will test the efficacy of recombinant leptin therapy in 40 men with NAFLD/NASH and RLD against placebo whose diets will be controlled with moderate caloric restriction in a double-blind design for 1 year. In Aim 2, we will investigate the time course of change that we have observed over resting energy expenditure (REE). We will also explore mechanisms of change in REE by studying autonomic function, thyroid axis and brown fat mass by performing FDG- PET scanning. If this proposal is completed successfully, results may offer new clinical and molecular insights into leptin action in humans. In Aim 3, we will determine the differences in hepatic gene expression as well as serum metabolomic profiles. Preliminary data are showing interesting leads for a regulatory role for leptin in the hepatic FXR/RXR pathway. We will have the opportunity to investigate this in greater detail in a larger number of patients using a controlled diet and against placebo control. PUBLIC HEALTH RELEVANCE: A growing complication of obesity is fatty liver disease, with least a third of the general population afflicted with this condition. Understanding the link between signals of adiposity (such as leptin) and fatty liver disease may help us improve our approaches to obesity and insulin resistance. If our hypotheses are correct, 20% of people with fatty liver disease (those with relative leptin deficiency) may derive direct clinical benefit from implications of our research.