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: 8600674
• 负责人: HARI S CONJEEVARAM
• 金额: $ 33.82万
• 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/8600674
• 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; Gene Expression Profiling; 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; public health relevance; 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.

描述（由申请人提供）：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，在非hiv脂肪营养不良的情况下，瘦素治疗可以逆转胰岛素抵抗、高甘油三酯血症和非酒精性脂肪性肝病（NAFLD）。随后，我们发现40%的非酒精性脂肪性肝炎（NASH，最严重的一种NAFLD）男性患者存在相对瘦素缺乏症（RLD），在BMI和性别匹配的NHANES III队列中，瘦素水平< 25个百分点。我们最近完成了一项调查瘦素治疗在NASH和RLD中的作用的初步研究。初步数据令人鼓舞地表明，男性RLD患者实际上对瘦素有反应，因为他们在接受开放标签瘦素治疗后表现出有益的代谢作用和肝脏组织病理学改善。我们现在建议在更大的范围内探索NASH中的RLD。在目的1中，我们将在40名NAFLD/NASH和RLD患者中测试重组瘦素治疗与安慰剂对照的疗效，这些患者的饮食将在1年的双盲设计中进行适度的热量限制。在目标2中，我们将研究我们观察到的静息能量消耗（REE）变化的时间过程。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量来探索REE变化的机制。如果这项提议成功完成，结果可能为瘦素在人类中的作用提供新的临床和分子见解。在目标3中，我们将确定肝脏基因表达以及血清代谢组学谱的差异。初步数据显示瘦素在肝脏FXR/RXR通路中的调节作用。我们将有机会在大量使用控制饮食和对照安慰剂的患者中进行更详细的研究。