Metabolic Stress Signaling

代谢应激信号

• 批准号: 10656434
• 负责人: Roger J Davis
• 金额: $ 52.78万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656434
• 关键词: Achievement; B-Lymphocytes; Blood; Development; Energy Metabolism; Functional disorder; Gene Expression; Genomics; Goals; Health; Hepatic; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; Knockout Mice; Knowledge; Liver; MAPK8 gene; Mediating; Mediator; Metabolic; Metabolic stress; Metabolic syndrome; Molecular; Molecular Target; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Physiology; Protein Isoforms; Regulation; Research; Research Support; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic Intervention; Tissues; biological adaptation to stress; design; feeding; fibroblast growth factor 21; improved; insulin regulation; insulin sensitivity; novel therapeutic intervention; obesity development; phosphoproteomics; prevent; programs; response; treatment strategy

Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to b-cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified the cJun NH2-terminal kinase (JNK) signal transduction pathway as a mediator of metabolic stress responses. Feeding a high fat diet (HFD) causes increased JNK activity and promotes both obesity and insulin resistance. Studies using tissue-specific knockout mice demonstrate a central role for JNK in the regulation of energy expenditure and the development of obesity. In contrast, JNK in peripheral tissues can cause insulin resistance without changes in obesity. The mechanism that accounts for JNK-dependent insulin resistance caused by feeding a HFD has not been defined. This research program is focused on the metabolic function of hepatic JNK signaling. During the initial period of research support, we identified the PPARa pathway as a major target of hepatic JNK signaling that contributes to HFD-induced insulin resistance. We demonstrated that JNK activation caused by feeding a HFD potently suppresses PPARa activity. A key target of PPARa -mediated hepatic gene expression is the hepatokine fibroblast growth factor 21 (FGF21). Consequently, disruption of JNK signaling in the liver causes increased hepatic PPARa activity, increased amounts of FGF21 circulating in the blood, and improved glycemia in HFD-fed mice. Disruption of hepatic Fgf21 expression prevents the effects of JNK deficiency to cause improved glycemia. The PPARa/FGF21 axis therefore represents a major target of hepatic JNK signaling that promotes systemic insulin sensitivity. The overall goal of this research program is to identify mechanisms of hepatic JNK signaling that contribute to the regulation of insulin sensitivity. Our analysis establishes a key role for hepatic PPARa. However, the molecular target(s) that mediate the effects of JNK on PPARa have not been established. The identification of molecular mechanism is the focus of this renewal application. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.

人类肥胖是一个严重的世界性健康问题。肥胖的后果之一是 以胰岛素抵抗和高血糖为特征的代谢综合征的发展，可导致 B 细胞功能障碍和 2 型糖尿病。因此，我们了解肥胖发展的生理学和病理生理学非常重要，因为这些知识是设计潜在治疗干预措施的基础。最近的研究已确定 cJun NH2 末端激酶 (JNK) 信号转导途径是代谢应激反应的介质。高脂肪饮食 (HFD) 会导致 JNK 活性增加，并促进肥胖和胰岛素抵抗。使用组织特异性基因敲除小鼠的研究表明，JNK 在调节能量消耗和肥胖发展中发挥着核心作用。相比之下，外周组织中的JNK可引起胰岛素抵抗，而不会改变肥胖状况。由于 HFD 喂养引起的 JNK 依赖性胰岛素抵抗的机制尚未明确。该研究项目的重点是肝脏 JNK 信号传导的代谢功能。在研究支持的最初阶段，我们确定 PPARa 通路是导致 HFD 诱导的胰岛素抵抗的肝脏 JNK 信号传导的主要靶标。我们证明，喂食 HFD 引起的 JNK 激活可有效抑制 PPARa 活性。 PPARα介导的肝基因表达的关键靶标是肝因子成纤维细胞生长因子21（FGF21）。因此，肝脏中 JNK 信号传导的破坏会导致肝脏 PPARa 活性增加，血液中循环的 FGF21 量增加，并改善 HFD 喂养小鼠的血糖。肝脏 Fgf21 表达的破坏可防止 JNK 缺乏导致血糖改善的影响。因此，PPARa/FGF21 轴代表了促进全身胰岛素敏感性的肝脏 JNK 信号传导的主要靶标。该研究项目的总体目标是确定有助于调节胰岛素敏感性的肝脏 JNK 信号传导机制。我们的分析确定了肝脏 PPARa 的关键作用。然而，介导 JNK 对 PPARa 作用的分子靶标尚未确定。分子机制的识别是本次更新应用的重点。该提案目标的实现将增加对肥胖分子反应的理解。我们预计该研究计划的成功完成将导致发现有助于肥胖反应的新机制。这些知识可能为设计治疗代谢综合征和 2 型糖尿病的新治疗策略奠定基础。

项目成果

c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease.

c-Jun N 末端激酶 (JNK) 信号传导有助于多囊肾病的囊性负担。

• DOI: 10.1371/journal.pgen.1009711
• 发表时间: 2021-12
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Smith AO;Jonassen JA;Preval KM;Davis RJ;Pazour GJ
• 通讯作者: Pazour GJ

HER2-driven breast cancer suppression by the JNK signaling pathway.

• DOI: 10.1073/pnas.2218373120
• 发表时间: 2023-01-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Itah, Zeynep;Chaudhry, Shanzah;Ponny, Sithara Raju;Aydemir, Ozkan;Lee, Alexandra;Cavanagh-Kyros, Julie;Tournier, Cathy;Muller, William J.;Davis, Roger J.
• 通讯作者: Davis, Roger J.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

• DOI: 10.7554/elife.59258
• 发表时间: 2020-12-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: Crespo M;Gonzalez-Teran B;Nikolic I;Mora A;Folgueira C;Rodríguez E;Leiva-Vega L;Pintor-Chocano A;Fernández-Chacón M;Ruiz-Garrido I;Cicuéndez B;Tomás-Loba A;A-Gonzalez N;Caballero-Molano A;Beiroa D;Hernández-Cosido L;Torres JL;Kennedy NJ;Davis RJ;Benedito R;Marcos M;Nogueiras R;Hidalgo A;Matesanz N;Leiva M;Sabio G
• 通讯作者: Sabio G

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

• DOI: 10.1016/j.ccell.2017.08.010
• 发表时间: 2017-09-11
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Boege Y;Malehmir M;Healy ME;Bettermann K;Lorentzen A;Vucur M;Ahuja AK;Böhm F;Mertens JC;Shimizu Y;Frick L;Remouchamps C;Mutreja K;Kähne T;Sundaravinayagam D;Wolf MJ;Rehrauer H;Koppe C;Speicher T;Padrissa-Altés S;Maire R;Schattenberg JM;Jeong JS;Liu L;Zwirner S;Boger R;Hüser N;Davis RJ;Müllhaupt B;Moch H;Schulze-Bergkamen H;Clavien PA;Werner S;Borsig L;Luther SA;Jost PJ;Weinlich R;Unger K;Behrens A;Hillert L;Dillon C;Di Virgilio M;Wallach D;Dejardin E;Zender L;Naumann M;Walczak H;Green DR;Lopes M;Lavrik I;Luedde T;Heikenwalder M;Weber A
• 通讯作者: Weber A

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.

• DOI: 10.1073/pnas.2210434119
• 发表时间: 2022-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1