Metabolic Crosstalk During Hepatic Insulin Resistance

肝脏胰岛素抵抗期间的代谢串扰

• 批准号: 9982302
• 负责人: Morris F. White
• 金额: $ 52.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982302
• 关键词: Adipose tissue; Alleles; Attenuated; Brown Fat; Communication; Cyclic AMP-Dependent Protein Kinases; Data; Dependovirus; Development; Diabetes Mellitus; Disease; Dyslipidemias; Expression Profiling; Extrahepatic; FOXO1A gene; Fatty Liver; Female; Follistatin; Funding; Gene Expression; Genes; Genetic; Glucose Intolerance; Goals; Growth; Hepatic; Hepatocyte; Homeostasis; Hyperglycemia; Hyperinsulinism; IRS1 gene; IRS2 gene; Insulin; Insulin Receptor; Insulin Resistance; Life; Link; Lipids; Lipolysis; Liver; Liver Mitochondria; Liver diseases; LoxP-flanked allele; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Peripheral; Permeability; Phosphorylation; Phosphotransferases; Primary carcinoma of the liver cells; Protein Dephosphorylation; Proteins; Publishing; Regulation; Resistance; Role; Signal Pathway; Site; Skeletal Muscle; Tissues; Work; autocrine; base; cardiovascular disorder risk; cyclophilin D; fibroblast growth factor 21; glucose production; glucose tolerance; improved; innovation; insulin receptor substrate 1 protein; insulin sensitivity; insulin signaling; knock-down; liver metabolism; male; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; overexpression; screening; transcription factor

Type 2 diabetes (T2DM) is a life-threatening disease characterized by hepatic and peripheral insulin resistance, which dysregulate inter-tissue metabolic flux and communication to promote hyperglycemia and dyslipidemia. Insulin signaling throughout the body is mediated by the insulin receptor substrate proteins IRS1 and IRS2. Within the liver, insulin regulates gene expression and metabolism largely via the IRS-dependent inhibition of transcription factor FoxO1. This renewal is founded on the striking observation that hepatic insulin resistance in ‘LDKO’ mice—which lack Irs1 and Irs2 in liver—propagates insulin resistance to the skeletal muscle and white and brown adipose tissues (WAT and BAT). Excessive hepatic glucose production (HGP) during diabetes owes, at least in part, to hepatic insulin resistance and activation of gluconeogenic genes by FoxO1. However, HGP is normalized in LDKO-mice upon inactivation/deletion of hepatic FoxO1 (i.e., ‘LTKO’ mice), suggesting that unknown, FoxO1-dependent factors secreted by the liver (‘hepatokines’) act to promote insulin resistance in peripheral tissues. This competitive renewal focuses upon the dysregulated hepatokines in LDKO liver to reveal how peripheral metabolic disease depends upon FoxO1—rather than hepatic insulin signaling per se. This is an innovative departure from the study of a single tissue or pathway that can, moreover, reveal the mechanisms by which hepatic resistance alone gives rise to many of the features of T2DM in mice. Robust preliminary data allow us to focus upon functionally important hepatokines that are elevated or decreased in LDKO liver, but normalized in LTKO liver. In addition to increased cardiovascular disease risk, T2DM is associated with non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) and eventual hepatocellular carcinoma (HCC); we have further established that this progression is attenuated in LTKO mice. Using deletion of floxed hepatokine alleles—or hepatotropic AAV (adeno-associated virus) to knock-down or over-express hepatokine genes—we employ both LDKO and LTKO mice to reveal (and corroborate) the effects of dysregulated FoxO1-dependent hepatokines upon systemic nutrient homeostasis and the progression of liver disease.

2型糖尿病（T2 DM）是一种以肝脏和外周胰岛素抵抗为特征的危及生命的疾病，其失调的组织间代谢通量和通讯促进高血糖和血脂异常。胰岛素受体底物蛋白IRS 1和IRS 2介导全身的胰岛素信号传导。在肝脏内，胰岛素主要通过IRS依赖性抑制转录因子FoxO 1来调节基因表达和代谢。这种更新是建立在一个惊人的观察基础上的，即“LDKO”小鼠的肝脏胰岛素抵抗--肝脏中缺乏Irs 1和Irs 2--将胰岛素抵抗传播到骨骼肌和白色和棕色脂肪组织（WAT和BAT）。糖尿病期间的过度肝葡萄糖生成（HGP）至少部分归因于肝脏胰岛素抵抗和FoxO 1激活的促胰岛素生成基因。然而，在肝FoxO 1失活/缺失后，HGP在LDKO小鼠中正常化（即，“LTKO”小鼠），这表明肝脏分泌的未知FoxO 1依赖性因子（“肝细胞因子”）可促进外周组织的胰岛素抵抗。这种竞争性更新的重点是LDKO肝脏中失调的肝细胞因子，以揭示外周代谢疾病如何依赖于FoxO 1-而不是肝脏胰岛素信号传导本身。这是对单一组织或途径研究的创新性偏离，而且可以揭示肝抵抗单独引起小鼠T2 DM许多特征的机制。稳健的初步数据使我们能够关注在LDKO肝脏中升高或降低但在LTKO肝脏中正常化的功能重要的肝因子。除了心血管疾病风险增加外，T2 DM还与非酒精性脂肪性肝病（NAFLD）相关，NAFLD可进展为非酒精性脂肪性肝炎（NASH）并最终发展为肝细胞癌（HCC）;我们进一步确定了这种进展在LTKO小鼠中减弱。使用删除floxed hepatokine等位基因或嗜肝性AAV（腺相关病毒）敲低或过度表达hepatokine基因，我们采用LDKO和LTKO小鼠揭示（并证实）失调的FoxO 1依赖性hepatokines对全身营养平衡和肝病进展的影响。

项目成果

Irs2 deficiency alters hippocampus-associated behaviors during young adulthood.

• DOI: 10.1016/j.bbrc.2021.04.101
• 发表时间: 2021-06-25
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Tanokashira D;Wang W;Maruyama M;Kuroiwa C;White MF;Taguchi A
• 通讯作者: Taguchi A

Correction for Long et al., "Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways".

Long 等人的修正，“胰岛素受体底物 Irs1 和 Irs2 通过 Akt 和 AMPK 途径协调骨骼肌生长和代谢”。

• DOI: 10.1128/mcb.00232-17
• 发表时间: 2017
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Long,YunChau;Cheng,Zhiyong;Copps,KyleD;White,MorrisF
• 通讯作者: White,MorrisF

Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia.

出版商更正：灭活肝卵泡抑素可缓解高血糖。

• DOI: 10.1038/s41591-018-0129-0
• 发表时间: 2018
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Tao,Rongya;Wang,Caixia;Stöhr,Oliver;Qiu,Wei;Hu,Yue;Miao,Ji;Dong,XCharlie;Leng,Sining;Stefater,Margaret;Stylopoulos,Nicholas;Lin,Lin;Copps,KyleD;White,MorrisF
• 通讯作者: White,MorrisF

Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance.

• DOI: 10.1016/j.molmet.2023.101703
• 发表时间: 2023-05
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Tao, Rongya;Stohr, Oliver;Wang, Caixia;Qiu, Wei;Copps, Kyle D.;White, Morris F.
• 通讯作者: White, Morris F.

The role of hepatokines in NAFLD.

• DOI: 10.1016/j.cmet.2023.01.006
• 发表时间: 2023-02-07
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Stefan, Norbert;Schick, Fritz;Birkenfeld, Andreas L.;Haering, Hans-Ulrich;White, Morris F.
• 通讯作者: White, Morris F.