Insulin Signaling and Metabolic Regulation in Adipocytes

脂肪细胞中的胰岛素信号传导和代谢调节

• 批准号: 10194465
• 负责人: MICHAEL P CZECH
• 金额: $ 57.12万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194465
• 关键词: Address; Adipocytes; Adipose tissue; Apolipoprotein E; Atherosclerosis; Attenuated; Beta Cell; Biological; Blood Glucose; Cardiovascular system; Cell Lineage; Cells; Core Facility; Data; Deposition; Disease; Endothelial Cells; Endothelium; Energy Metabolism; Engineering; Enzymes; Fatty Acids; Fatty acid glycerol esters; Financial compensation; Functional disorder; Funding; Future; Gene Expression; Glucose; Grant; Health; Homeostasis; In Vitro; Inflammation; Instruction; Insulin; Insulin Resistance; Insulin Signaling Pathway; KRP protein; Knockout Mice; Laboratories; Lipids; Liver; LoxP-flanked allele; Lymphatic; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Control; Metabolism; Methods; Mink; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Orthologous Gene; Parabiosis; Pathway interactions; Pharmacotherapy; Phenotype; Play; Procedures; Protein Kinase; Proteomics; Regulation; Research; Role; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Small Interfering RNA; Substrate Specificity; Technology; Testing; Tissues; Triglycerides; Wild Type Mouse; Work; adiponectin; comorbidity; design; enhancing factor; experimental study; fatty acid metabolism; glucose tolerance; in vivo; insulin secretion; insulin sensitivity; insulin sensitizing drugs; insulin signaling; islet; lipid metabolism; metabolic phenotype; mouse model; new therapeutic target; response; transcriptome sequencing

This project, which has been funded for over 30 years, addresses fundamental mechanisms of insulin action on adipose metabolism and functions that control whole body metabolic homeostasis in health and disease. Co-morbidities associated with obesity including insulin resistance and type 2 diabetes are thought to result from insufficient deposition and storage of triglyceride within adipose tissue, leading to deleterious effects of fat on liver, skeletal muscle, cardiovascular organs and insulin secreting beta cells. This project previously employed siRNA screens to discover the Ste20 ortholog Map4k4, a protein kinase that acts as a critical signaling node in many tissues related to metabolic homeostasis. In the previous grant period we have carefully assessed the role of Map4k4 in vivo showing that this protein kinase functions in many tissues to suppress systemic insulin sensitivity as well as promote atherosclerosis. Thus, we consistently observed beneficial metabolic phenotypes in six tissue- specific Map4k4 knockout mouse models we produced, demonstrating that Map4k4 exerts powerful biological effects worthy of continued study. Highlights of these studies include: 1. endothelial cell Map4k4 KO lowers blood glucose and attenuates atherosclerosis in ApoE null mice, 2. Inducible whole body Map4k4 KO mice show increased insulin sensitivity, much lower insulin levels and compromised insulin secretion from islets, 3. Map4k4 KO in Myf5 positive cells (but not in Adiponectin positive cells) causes a marked increase in adipocyte insulin sensitivity and Akt activation. This latter finding is consistent with the exciting hypothesis that skeletal muscle secretes one or more factors that enhance insulin sensitivity of adipocytes. Overall, our findings also suggest that two protein kinases very highly similar to Map4k4, Tnik and Mink, may also be active in the same pathways. We have therefore produced triple floxed Tnik/Mink/Map4k4 mice in order to test their potential redundancy with Map4k4 function in adipocytes (lipid metabolism) by crossing with adiponectin-Cre mice and in beta cells (insulin secretion) by crossing with Ins1Cre or Ins1CreER mice (Aim 1). We also propose to rigorously test the exciting hypothesis that Map4k4 KO in Myf5 positive cells induces a circulating factor that enhances adipocyte insulin sensitivity and glucose tolerance by parabiosis studies with the mouse models we have engineered (Aim 2). Finally, in parallel we seek to identify such circulating factors in serum using Somalogic technology and mass spectroscopy in the UMASS Proteomics Core Facility (Aim 3). RELEVANCE (See instructions): Fat tissue plays a key role in regulating energy metabolism, and excess accumulation of fat in obesity is associated with many maladies including type 2 diabetes. We identified components of signaling pathways in fat cells that mediate dysfunction in obesity and have studied an enzyme called Map4k4 that contributes to insulin resistance, atherosclerosis and other diseases associated with metabolic functions. We hope to further characterize Map4k4's functions, as it may be a good target for new drug therapies.

该项目已资助 30 多年，致​​力于解决胰岛素的基本机制 对脂肪代谢的作用以及控制健康和健康的全身代谢稳态的功能 疾病。与肥胖相关的合并症包括胰岛素抵抗和 2 型糖尿病 被认为是由于脂肪组织内甘油三酯沉积和储存不足造成的，导致 脂肪对肝脏、骨骼肌、心血管器官和分泌胰岛素的β细胞产生有害影响。 该项目之前使用 siRNA 筛选来发现 Ste20 直系同源物 Map4k4，一种蛋白质 激酶在许多与代谢稳态相关的组织中充当关键信号传导节点。在 在之前的资助期间，我们仔细评估了 Map4k4 在体内的作用，表明该蛋白 激酶在许多组织中发挥作用，抑制全身胰岛素敏感性并促进 动脉粥样硬化。因此，我们一致地观察到六种组织中有益的代谢表型—— 我们制作的特定Map4k4敲除小鼠模型，证明Map4k4发挥了强大的作用 生物学效应值得继续研究。这些研究的亮点包括： 1. 内皮细胞 Map4k4 KO 降低 ApoE 缺失小鼠的血糖并减轻动脉粥样硬化，2. 诱导整体 身体 Map4k4 KO 小鼠表现出胰岛素敏感性增加、胰岛素水平低得多且受损 胰岛分泌胰岛素，3. Myf5 阳性细胞中的 Map4k4 KO（但脂联素阳性细胞中则不然） 导致脂肪细胞胰岛素敏感性和 Akt 激活显着增加。后一个发现是一致的 令人兴奋的假设是骨骼肌分泌一种或多种增强胰岛素的因子 脂肪细胞的敏感性。总的来说，我们的研究结果还表明，两种蛋白激酶与 Map4k4、Tnik 和 Mink 也可能在相同的途径中活跃。因此我们生产了三重 floxed Tnik/Mink/Map4k4 小鼠，以测试其与 Map4k4 功能的潜在冗余 通过与脂联素-Cre小鼠和β细胞（胰岛素 通过与 Ins1Cre 或 Ins1CreER 小鼠杂交（目标 1）。我们还建议严格测试 令人兴奋的假设是，Myf5 阳性细胞中的 Map4k4 KO 会诱导一种循环因子，从而增强 通过我们拥有的小鼠模型进行联体共生研究的脂肪细胞胰岛素敏感性和葡萄糖耐量 设计（目标 2）。最后，我们同时寻求使用以下方法来识别血清中的此类循环因子： UMASS 蛋白质组学核心设施中的躯体逻辑技术和质谱（目标 3）。 相关性（参见说明）： 脂肪组织在调节能量代谢中起着关键作用，肥胖中脂肪的过量积累是 与包括 2 型糖尿病在内的许多疾病有关。我们确定了信号通路的组成部分 脂肪细胞中介导肥胖症功能障碍的研究人员研究了一种名为 Map4k4 的酶，该酶有助于 胰岛素抵抗、动脉粥样硬化和其他与代谢功能相关的疾病。我们希望 进一步表征 Map4k4 的功能，因为它可能是新药物疗法的良好靶标。

项目成果

Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.

• DOI: 10.1016/j.molmet.2016.09.009
• 发表时间: 2016-12
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: DiStefano MT;Roth Flach RJ;Senol-Cosar O;Danai LV;Virbasius JV;Nicoloro SM;Straubhaar J;Dagdeviren S;Wabitsch M;Gupta OT;Kim JK;Czech MP
• 通讯作者: Czech MP

Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion.

• DOI: 10.1038/ncomms10686
• 发表时间: 2016-02-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Senol-Cosar O;Flach RJ;DiStefano M;Chawla A;Nicoloro S;Straubhaar J;Hardy OT;Noh HL;Kim JK;Wabitsch M;Scherer PE;Czech MP
• 通讯作者: Czech MP

Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases.

• DOI: 10.1016/j.tem.2016.04.006
• 发表时间: 2016-07
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Virbasius JV;Czech MP
• 通讯作者: Czech MP