Metabolic regulation of adipocyte-macrophage crosstalk in obesity

肥胖症中脂肪细胞-巨噬细胞串扰的代谢调节

基本信息

批准号：
8658425
负责人：
Chaodong Wu
金额：
$ 31.43万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-05 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658425
关键词：
2,4-thiazolidinedione 6-Phosphofructo-2-kinase 6-Phosphofructokinase Accounting Adipocytes Adipose tissue Agonist Anti-Inflammatory Agents Anti-inflammatory Biological Assay Bone Marrow Coculture Techniques Development Diet Disease Distal Enzymes Exhibits Fatty Acids Fatty acid glycerol esters Fructose Functional disorder Genes Glycolysis Goals Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Knowledge Link Liver MAPK8 gene Metabolic Mono-S Mus Muscle Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Oxidative Stress PPAR gamma Peroxisome Proliferator-Activated Receptors Pioglitazone Production Regulation Research Role Signal Pathway Testing Thiazolidinediones Tissues Unsaturated Fatty Acids Wild Type Mouse base db/db mouse design evidence base expectation feeding improved in vivo insulin sensitivity insulin sensitizing drugs insulin signaling macrophage novel nutrient metabolism oxidation palmitoleate prevent public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Metabolic regulation of adipocyte-macrophage crosstalk in obesity Summary Obesity-associated adipose tissue inflammation critically contributes to the development of insulin resistance and type 2 diabetes. While much evidence demonstrates the importance of both adipocytes and macrophages in initiating adipose tissue inflammation, little is known about precisely how nutrient metabolism is linked to inflammatory responses in both adipocytes and macrophages. It is also unknown about the mechanisms underlying metabolic regulation of the crosstalk between adipocytes and macrophages. The long-term goal of this research is to dissect adipocyte-macrophage crosstalk so that novel evidence-based approaches can be developed for preventing and/or treating insulin resistance. As an adipose tissue-abundant gene, PFKFB3 encodes for a regulatory enzyme whose product stimulates glycolysis. For this project, the central hypothesis is that PFKFB3 orchestrates appropriate metabolic regulation of adipocyte-macrophage crosstalk to suppress macrophage proinflammatory (M1) activation, stimulate macrophage alternative (M2) activation, and improve adipocyte functions, thereby protecting against obesity-associated adipose tissue inflammation and systemic insulin resistance. This hypothesis is based on the following novel findings: 1) PFKFB3 stimulates adipocyte production of palmitoleate (a mono-unsaturated fatty acid), which in turn blunts macrophage M1 activation; 2) PFKFB3 is involved in PPARgamma stimulation of macrophage M2 activation; and 3) Myeloid cell-specific PFKFB3 disruption exacerbates diet-induced adipose tissue dysfunctions. Thus, the goal of this project is to define the novel role of PFKFB3 in regulating adipocyte-macrophage crosstalk. Accordingly, mice with selective PFKFB3 disruption in adipocytes and/or myeloid cells are generated. For Specific Aim 1, experiments have been designed to test the hypothesis that adipocyte factors generated in response to PFKFB3 action, in particular palmitoleate, suppress macrophage M1 activation and/or stimulate macrophage M2 activation. Moreover, the in vivo effects of adipocyte PFKFB3 disruption on adipose tissue macrophage polarization, adipose tissue inflammation, and systemic insulin sensitivity will be examined. For Specific Aim 2, experiments have been designed to test the hypothesis that PFKFB3 links nutrient metabolism and macrophage polarization. Also, the in vivo effects of PFKFB3 disruption in myeloid cells on adipose tissue inflammation and systemic insulin sensitivity will be examined. For Specific Aim 3, experiments have been designed to test the hypothesis that the PFKFB3 in adipocytes and/or macrophages is needed for actions of PPARgamma activation. Accordingly, the involvement of the PFKFB3 in adipocytes versus macrophages in PPARgamma regulation of adipocyte-macrophage crosstalk, adipose tissue inflammation, and systemic insulin sensitivity will be examined. Together, the proposed research will illustrate a new paradigm on metabolic regulation of adipocyte-macrophage crosstalk, and provide the experimental basis for insulin sensitization by means of selective PFKFB3 activation.

描述（由申请人提供）：肥胖中脂肪细胞-巨噬细胞串扰的代谢调节总结肥胖相关的脂肪组织炎症对胰岛素抵抗和2型糖尿病的发展有重要影响。虽然大量证据表明脂肪细胞和巨噬细胞在引发脂肪组织炎症中的重要性，但人们对营养代谢与脂肪细胞和巨噬细胞炎症反应之间的确切关系知之甚少。脂肪细胞和巨噬细胞之间的串扰代谢调节的潜在机制尚不清楚。这项研究的长期目标是剖析脂肪细胞-巨噬细胞的串扰，以便开发新的循证方法来预防和/或治疗胰岛素抵抗。作为脂肪组织丰富的基因，PFKFB3 编码一种调节酶，其产物刺激糖酵解。对于该项目，中心假设是PFKFB3协调脂肪细胞-巨噬细胞串扰的适当代谢调节，以抑制巨噬细胞促炎症（M1）激活，刺激巨噬细胞替代（M2）激活，并改善脂肪细胞功能，从而防止肥胖相关的脂肪组织炎症和全身性胰岛素抵抗。该假设基于以下新发现：1) PFKFB3 刺激脂肪细胞产生棕榈油酸（一种单不饱和脂肪酸），进而减弱巨噬细胞 M1 的激活； 2）PFKFB3参与PPARγ刺激巨噬细胞M2活化； 3) 骨髓细胞特异性 PFKFB3 破坏会加剧饮食引起的脂肪组织功能障碍。因此，该项目的目标是确定 PFKFB3 在调节脂肪细胞-巨噬细胞串扰中的新作用。因此，产生了脂肪细胞和/或骨髓细胞中选择性PFKFB3破坏的小鼠。对于特定目标 1，设计了实验来测试以下假设：响应 PFKFB3 作用而产生的脂肪细胞因子，特别是棕榈油酸，抑制巨噬细胞 M1 活化和/或刺激巨噬细胞 M2 活化。此外，还将检查脂肪细胞 PFKFB3 破坏对脂肪组织巨噬细胞极化、脂肪组织炎症和全身胰岛素敏感性的体内影响。对于特定目标 2，设计了实验来检验 PFKFB3 将营养代谢和巨噬细胞极化联系起来的假设。此外，还将检查骨髓细胞中 PFKFB3 破坏对脂肪组织炎症和全身胰岛素敏感性的体内影响。对于特定目标 3，设计了实验来检验以下假设：脂肪细胞和/或巨噬细胞中的 PFKFB3 对于 PPARgamma 激活作用是必需的。因此，将检查脂肪细胞与巨噬细胞中的 PFKFB3 在脂肪细胞-巨噬细胞串扰、脂肪组织炎症和全身胰岛素敏感性的 PPARgamma 调节中的参与。总之，拟议的研究将阐明脂肪细胞-巨噬细胞串扰代谢调节的新范式，并为通过选择性 PFKFB3 激活的胰岛素增敏提供实验基础。