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
基本信息
- 批准号:8814209
- 负责人:
- 金额:$ 33.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-05 至 2016-09-30
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAmericanBiopsyBody WeightBody mass indexBrown FatCaloric RestrictionCardiovascular DiseasesCirrhosisClassificationClinicalComorbidityComplicationDataDietDietary InterventionDiseaseDoseDouble-Blind MethodEatingEnergy MetabolismFastingFatty LiverFatty acid glycerol estersFibrosisFoodFundingFutureGNAI2 geneGenderGene ExpressionGene Expression ProfilingGeneral PopulationHealthHeartHepaticHepatocyteHistopathologyHormonesHumanHypertriglyceridemiaIndividualInflammationInjuryInsulin ResistanceLeadLeptinLeptin deficiencyLinkLipodystrophyLiverLiver FailureLiver diseasesMagnetic Resonance ImagingMeasurableMeasuresMetabolicMetabolismMethodsMolecularMonitorNational Health and Nutrition Examination SurveyNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusObesityOutcome MeasureOverweightParticipantPathway interactionsPatientsPeripheralPhysiologicalPilot ProjectsPlacebo ControlPlacebosPlasmaPositron-Emission TomographyPrimary carcinoma of the liver cellsProteinsRXRRandomizedRecombinantsRegulationRelative (related person)ResearchRestRodentRoleSafetySecondary toSerumSignal TransductionSteatohepatitisTestingTherapeuticThyroid Function TestsThyroid GlandTimeTranslational ResearchUp-RegulationUrban PopulationWeightbaseclinical effectcohortdesignefficacy testingimprovedinsightinsulin sensitivityinterestmalemenmetabolomicsnon-alcoholic fatty livernon-diabeticnonalcoholic steatohepatitisnovelopen labelpilot trialprimary outcomeprogramsresponsetool
项目摘要
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。我们发现瘦素治疗非 HIV 脂肪营养不良可逆转胰岛素抵抗、高甘油三酯血症和非酒精性脂肪肝 (NAFLD)。随后,我们通过证明 BMI 和性别匹配的 NHANES III 队列的瘦素水平 < 25%,发现 40% 的非酒精性脂肪性肝炎(NASH,最严重的 NAFLD)男性患者存在相对瘦素缺乏 (RLD)。我们最近完成了一项试点研究,调查瘦素疗法对 NASH 和 RLD 的影响。令人鼓舞的初步数据表明,RLD 男性患者实际上对瘦素有反应,因为他们通过开放标签瘦素治疗表现出有益的代谢作用以及肝脏组织病理学改善。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疗法相对于安慰剂的疗效,这些男性的饮食将在双盲设计中通过适度的热量限制进行为期 1 年的控制。在目标 2 中,我们将研究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,探讨 REE 的变化机制。如果该提案成功完成,结果可能会为人类瘦素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谱的差异。初步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。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The clinical phenotypes of the juvenile idiopathic inflammatory myopathies.
- DOI:10.1097/md.0b013e31827f264d
- 发表时间:2013-01
- 期刊:
- 影响因子:1.6
- 作者:Shah M;Mamyrova G;Targoff IN;Huber AM;Malley JD;Rice MM;Miller FW;Rider LG;with the Childhood Myositis Heterogeneity Collaborative Study Group
- 通讯作者:with the Childhood Myositis Heterogeneity Collaborative Study Group
Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.
- DOI:10.1111/cen.13732
- 发表时间:2018-07
- 期刊:
- 影响因子:3.2
- 作者:Akinci B;Unlu SM;Celik A;Simsir IY;Sen S;Nur B;Keskin FE;Ozgen Saydam B;Kutbay Ozdemir N;Sarer Yurekli B;Ergur BU;Sonmez M;Atik T;Arslan A;Demir T;Altay C;Tunc UA;Arkan T;Gen R;Eren E;Akinci G;Yilmaz AA;Bilen H;Ozen S;Celtik A;Savas Erdeve S;Cetinkaya S;Onay H;Sarioglu S;Oral EA
- 通讯作者:Oral EA
The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies.
- DOI:10.1097/md.0b013e31829d08f9
- 发表时间:2013-07
- 期刊:
- 影响因子:1.6
- 作者:Rider LG;Shah M;Mamyrova G;Huber AM;Rice MM;Targoff IN;Miller FW;Childhood Myositis Heterogeneity Collaborative Study Group
- 通讯作者:Childhood Myositis Heterogeneity Collaborative Study Group
Early illness features associated with mortality in the juvenile idiopathic inflammatory myopathies.
- DOI:10.1002/acr.22212
- 发表时间:2014-05
- 期刊:
- 影响因子:4.7
- 作者:Huber AM;Mamyrova G;Lachenbruch PA;Lee JA;Katz JD;Targoff IN;Miller FW;Rider LG;Childhood Myositis Heterogeneity Collaborative Study Group
- 通讯作者:Childhood Myositis Heterogeneity Collaborative Study Group
Brief Report: Association of Myositis Autoantibodies, Clinical Features, and Environmental Exposures at Illness Onset With Disease Course in Juvenile Myositis.
- DOI:10.1002/art.39466
- 发表时间:2016-03
- 期刊:
- 影响因子:0
- 作者:Habers GE;Huber AM;Mamyrova G;Targoff IN;O'Hanlon TP;Adams S;Pandey JP;Boonacker C;van Brussel M;Miller FW;van Royen-Kerkhof A;Rider LG;Childhood Myositis Heterogeneity Study Group
- 通讯作者:Childhood Myositis Heterogeneity Study Group
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HARI S CONJEEVARAM其他文献
HARI S CONJEEVARAM的其他文献
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{{ truncateString('HARI S CONJEEVARAM', 18)}}的其他基金
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 - 财政年份:2011
- 资助金额:
$ 33.82万 - 项目类别:
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:
8220799 - 财政年份:2011
- 资助金额:
$ 33.82万 - 项目类别:
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:
8448125 - 财政年份:2011
- 资助金额:
$ 33.82万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 33.82万 - 项目类别:
FENOFIBRATE FOR TREATMENT OF NASH: A RANDOM, DOUBLE BLIND, PLACEBO-CTRLD STUDY
非诺贝特治疗纳什:一项随机、双盲、安慰剂对照研究
- 批准号:
7603761 - 财政年份:2007
- 资助金额:
$ 33.82万 - 项目类别:
PIOGLITAZONE IN HEP C: A RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY
吡格列酮治疗丙型肝炎:一项随机、双盲、安慰剂对照研究
- 批准号:
7603782 - 财政年份:2007
- 资助金额:
$ 33.82万 - 项目类别:
Fenofibrate for the treatment of patients with NASH
非诺贝特用于治疗 NASH 患者
- 批准号:
7178464 - 财政年份:2006
- 资助金额:
$ 33.82万 - 项目类别:
Fenofibrate for the treatment of patients with NASH
非诺贝特用于治疗 NASH 患者
- 批准号:
7032512 - 财政年份:2006
- 资助金额:
$ 33.82万 - 项目类别:
PIOGLITAZONE IN HEPATITIS C: A RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUD
吡格列酮治疗丙型肝炎:随机、双盲、安慰剂对照研究
- 批准号:
7376622 - 财政年份:2006
- 资助金额:
$ 33.82万 - 项目类别:
FENOFIBRATE FOR TREATMENT OF NASH: A RANDOM, DOUBLE BLIND, PLACEBO-CTRLD STUDY
非诺贝特治疗纳什:一项随机、双盲、安慰剂对照研究
- 批准号:
7376592 - 财政年份:2006
- 资助金额:
$ 33.82万 - 项目类别:
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