Feed-forward regulation between GPR120 and PPAR gamma - Revision - 1

GPR120 和 PPAR gamma 之间的前馈调节 - 修订版 - 1

• 批准号: 10398464
• 负责人: DAYOUNG OH
• 金额: $ 20.49万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-09 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398464
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Affinity; Agonist; Anti-Inflammatory Agents; Antibodies; Antidiabetic Drugs; Antiinflammatory Effect; Arachidonic Acids; Attenuated; Automobile Driving; Binding; Biochemical; Biological Assay; CDK5 gene; Cell Nucleus; Cells; Chronic; Clinical; Co-Immunoprecipitations; Complex; Consumption; Cytoplasm; Cytosol; Data; Development; Diabetes Mellitus; Dose; Drug Industry; Edema; Fatty Acids; Fatty Liver; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Heart failure; High Fat Diet; Human Genetics; Hyperinsulinism; In Vitro; Incidence; Inflammation; Insulin Resistance; Knock-out; Knockout Mice; Lead; Ligands; MAP3K7IP1 gene; MAPK8 gene; Malignant Neoplasms; Measures; Mediating; Metabolism; Methods; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Obese Mice; Obesity; Obesity Epidemic; Omega-3 Fatty Acids; PPAR gamma; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Pioglitazone; Play; Production; Regimen; Regulation; Reporting; Risk; Role; Serine; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thiazolidinediones; Time; Tissues; Weight Gain; Work; arrestin 2; base; beta-arrestin; bone loss; chromatin immunoprecipitation; design; drug discovery; genetic corepressor; genetic variant; glucose tolerance; glucose transport; improved; in vivo; insulin sensitivity; insulin sensitizing drugs; lipid biosynthesis; lipid metabolism; macrophage; man; novel; novel therapeutics; preservation; prevent; promoter; receptor; rosiglitazone; side effect; small molecule

PROJECT SUMMARY/ABSTRACT Obesity is the dominant cause of insulin resistance in man and it is the obesity epidemic, which is driving the dramatically increased incidence of Type 2 Diabetes (T2D). Adipocyte dysfunction and chronic low-grade tissue inflammation are major causes of insulin resistance. In our recent work, we have reported that G protein-coupled receptor 120 (GPR120) is the functional receptor for omega-3 fatty acids (ω3-FAs) producing robust anti- inflammatory, insulin sensitizing effects, both in vivo and in vitro. Interestingly, human genetic variants in the GPR120 gene had been described which predispose subjects to obesity and diabetes. The amount of ω3-FAs which would have to be consumed to sustain chronic agonism of GPR120 is too high to be practical, and, thus, a high affinity, small molecule GPR120 agonist would be of potential clinical benefit. Accordingly, GPR120 is a widely studied drug discovery target within the pharmaceutical industry. Recently, we have identified a high affinity, selective, small molecule GPR120 agonist (compound A; cpdA), which exerts potent anti-inflammatory effects on macrophages in vitro, and in obese mice in vivo. GPR120 agonist treatment of HFD/obese mice results in anti-inflammatory signaling with improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that GPR120 agonists could emerge as new insulin sensitizing drugs for the treatment of T2D. Thiazolidinediones (TZDs) represent current therapeutic agents for treating insulin resistance. However, these agents (rosiglitazone and pioglitazone) are also associated with unwanted side effects, such as edema, weight gain, possible risk of heart failure, bone loss, and a possible correlation with certain cancers. While the exact mechanisms of TZD-induced insulin sensitization are not fully understood, these agents operate through PPARγ, and this subject has been extensively reviewed. Thus, both TZDs and GPR120 agonists can improve insulin resistance. Importantly, our recent preliminary data have suggested mechanisms whereby TZDs potentiate the effects of ω3-FAs at the same time that ω3-FAs potentiate the effects of TZDs, leading to a positive reinforcing system. In this project, we will explore the basic cellular mechanisms underlying the molecular interactions between PPARγ and GPR120. This concept also leads us to the novel hypothesis that the combination of PPARγ and GPR120 agonist treatment could produce additive or synergistic effects, leading to a greater degree of insulin sensitization than with either drug alone. Furthermore, combination treatment with a TZD plus a GPR120 agonist could lead to the use of much lower doses of TZDs, preserving the overall insulin sensitizing benefit, while mitigating unwanted side effects.

项目总结/摘要 肥胖症是导致人类胰岛素抵抗的主要原因，肥胖症的流行正在推动胰岛素抵抗。 2型糖尿病（T2 D）的发病率显著增加。脂肪细胞功能障碍和慢性低级别组织 炎症是胰岛素抵抗的主要原因。在我们最近的工作中，我们报道了G蛋白偶联 受体120（GPR 120）是ω-3脂肪酸（ω3-FAs）的功能性受体，其产生稳健的抗- 体内和体外的炎症、胰岛素增敏作用。有趣的是，人类基因变异在 GPR 120基因是肥胖和糖尿病的易感基因。ω3-FA的量 其必须被消耗以维持GPR 120的慢性激动作用太高而不实用，因此， 高亲和力的小分子GPR 120激动剂将具有潜在的临床益处。因此，GPR 120是 在制药行业中被广泛研究的药物发现目标。最近，我们发现了一种高 亲和性、选择性、小分子GPR 120激动剂（化合物A; cpdA），其发挥有效的抗炎作用 体外对巨噬细胞的作用和体内对肥胖小鼠的作用。HFD/肥胖小鼠的GPR 120激动剂治疗结果 在抗炎信号传导中具有改善的葡萄糖耐量、降低的高胰岛素血症、增加的胰岛素 敏感性和减少肝脂肪变性。这表明GPR 120激动剂可以作为新的胰岛素出现 用于治疗T2 D的致敏药物。噻唑烷二酮（TZD）代表目前用于治疗 治疗胰岛素抵抗。然而，这些药物（罗格列酮和吡格列酮）也与 不必要的副作用，如水肿、体重增加、可能的心力衰竭风险、骨质流失和可能的 与某些癌症的关系。TZD诱导胰岛素增敏的确切机制尚不完全 据了解，这些药物通过PPARγ发挥作用，这一主题已被广泛综述。因此， TZD和GPR 120激动剂可改善胰岛素抵抗。重要的是，我们最近的初步数据显示， 提出了TZDs在增强ω 3-FAs作用的同时增强ω 3-FAs作用的机制， TZD的影响，导致积极的强化系统。在这个项目中，我们将探索基本的细胞 PPARγ和GPR 120之间相互作用的分子机制。这一概念也使我们 新的假设是，PPARγ和GPR 120激动剂治疗的组合可以产生累加或 协同作用，导致比单独使用任一种药物更大程度的胰岛素增敏。此外，委员会认为， 用TZD加GPR 120激动剂的联合治疗可导致使用低得多的TZD剂量， 保留了整体胰岛素增敏益处，同时减轻了不希望的副作用。

项目成果

Hepatic sialic acid synthesis modulates glucose homeostasis in both liver and skeletal muscle.

• DOI: 10.1016/j.molmet.2023.101812
• 发表时间: 2023-12
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Peng, Jun;Yu, Liming;Huang, Linzhang;Paschoal, Vivian A.;Chu, Haiyan;de Souza, Camila O.;Varre, Joseph V.;Oh, Da Young;Kohler, Jennifer J.;Xiao, Xue;Xu, Lin;Holland, William L.;Shaul, Philip W.;Mineo, Chieko
• 通讯作者: Mineo, Chieko

GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity.

• DOI: 10.1172/jci168992
• 发表时间: 2023-12-15
• 期刊: The Journal of clinical investigation
• 作者: Sun XN;An YA;Paschoal VA;de Souza CO;Wang MY;Vishvanath L;Bueno LM;Cobb AS;Nieto Carrion JA;Ibe ME;Li C;Kidd HA;Chen S;Li W;Gupta RK;Oh DY
• 通讯作者: Oh DY

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity.

• DOI: 10.3389/fendo.2021.715877
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Oliveira de Souza C;Sun X;Oh D
• 通讯作者: Oh D

Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity.

• DOI: 10.1038/s42255-020-00301-7
• 发表时间: 2020-11
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Shan B;Shao M;Zhang Q;Hepler C;Paschoal VA;Barnes SD;Vishvanath L;An YA;Jia L;Malladi VS;Strand DW;Gupta OT;Elmquist JK;Oh D;Gupta RK
• 通讯作者: Gupta RK

GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model.

• DOI: 10.1172/jci160097
• 发表时间: 2022-11-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: de Souza, Camila O.;Paschoal, Vivian A.;Sun, Xuenan;Vishvanath, Lavanya;Zhang, Qianbin;Shao, Mengle;Onodera, Toshiharu;Chen, Shiuhwei;Joffin, Nolwenn;Bueno, Lorena M. A.;Gupta, Rana K.;Oh, Da Young
• 通讯作者: Oh, Da Young