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

重组人瘦素对非酒精性脂肪肝（NAFLD）的影响

• 批准号: 8039717
• 负责人: HARI S CONJEEVARAM
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-05 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039717
• 关键词: Adipocytes; American; Biopsy; Body Weight; Body mass index; Brown Fat; Caloric Restriction; Cardiovascular Diseases; Cirrhosis; Classification; Clinical; Comorbidity; Complication; Data; Diet; Disease; Dose; Double-Blind Method; Eating; Energy Metabolism; Fasting; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Food; Funding; Future; GNAI2 gene; Gender; Gene Expression; General Population; Heart; Hepatic; Hepatocyte; Histopathology; Hormones; Human; Hypertriglyceridemia; Individual; Inflammation; Injury; Insulin Resistance; Intervention; Lead; Leptin; Leptin deficiency; Link; Lipodystrophy; Liver; Liver Failure; Liver diseases; Magnetic Resonance Imaging; Measurable; Measures; Metabolic; Metabolism; Methods; Molecular; Monitor; National Health and Nutrition Examination Survey; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Measure; Overweight; Participant; Pathway interactions; Patients; Peripheral; Physiological; Pilot Projects; Placebo Control; Placebos; Plasma; Positron-Emission Tomography; Primary carcinoma of the liver cells; Proteins; RXR; Randomized; Recombinants; Regulation; Relative (related person); Research; Rest; Rodent; Role; Safety; Secondary to; Serum; Signal Transduction; Steatohepatitis; Testing; Therapeutic; Thyroid Function Tests; Thyroid Gland; Time; Translational Research; Up-Regulation; Urban Population; Weight; base; clinical effect; cohort; design; efficacy testing; improved; insight; insulin sensitivity; interest; male; men; metabolomics; non-alcoholic fatty liver; non-diabetic; nonalcoholic steatohepatitis; novel; open label; pilot trial; primary outcome; programs; response; tool

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.

说明（申请人提供）：脂肪细胞激素瘦素具有广泛的作用，包括调节体重和胰岛素敏感性。我们发现，瘦素治疗在非HIV脂肪营养不良的情况下逆转胰岛素抵抗、高脂血症和非酒精性脂肪肝（NAFLD）。随后，我们通过证明瘦素水平<BMI和性别匹配的NHANES III队列的第25百分位数，表明40%的非酒精性脂肪性肝炎（NASH，NAFLD的最严重形式）男性患者具有相对瘦素缺乏（RLD）。我们最近完成了一项初步研究，调查了瘦素治疗NASH和RLD的效果。初步数据令人鼓舞地表明，RLD男性患者实际上是瘦素反应，因为他们表现出有益的代谢作用以及开放标签瘦素治疗肝脏的组织病理学改善。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相对于安慰剂的功效，其饮食将在双盲设计中通过适度热量限制控制1年。在目标2中，我们将研究我们在静息能量消耗（REE）上观察到的变化的时间过程。我们也将借由研究植物神经功能、甲状腺轴及正子断层扫描之棕色脂肪团来探讨稀土元素变化的机制。如果这项提议成功完成，结果可能会提供新的临床和分子的见解瘦素在人类中的作用。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谱。初步的数据显示了瘦素在肝脏FXR/RXR通路中的调节作用的有趣线索。我们将有机会在大量使用控制饮食和安慰剂对照的患者中更详细地研究这一点。 公共卫生相关性：肥胖的一个日益严重的并发症是脂肪肝，至少有三分之一的普通人群患有这种疾病。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善肥胖和胰岛素抵抗的方法。如果我们的假设是正确的，20%的脂肪肝患者（相对瘦素缺乏者）可能会从我们的研究中获得直接的临床益处。