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

• 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
• 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

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）：肥胖症中脂肪细胞-巨噬细胞串扰的代谢调节概述肥胖症相关的脂肪组织炎症对胰岛素抵抗和2型糖尿病的发展起关键作用。虽然许多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，但关于营养代谢如何与脂肪细胞和巨噬细胞中的炎症反应相关联的确切信息却知之甚少。脂肪细胞和巨噬细胞之间的相互作用的代谢调节机制也是未知的。这项研究的长期目标是剖析脂肪细胞-巨噬细胞的相互作用，以便开发新的循证方法来预防和/或治疗胰岛素抵抗。PFKFB 3是一个脂肪组织丰富的基因，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PFKFB 3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（M1）活化，刺激巨噬细胞替代（M2）活化，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）PFKFB 3刺激脂肪细胞产生棕榈油酸酯（一种单不饱和脂肪酸），进而减弱巨噬细胞M1活化; 2）PFKFB 3参与巨噬细胞M2活化的PPARgamma刺激; 3）髓样细胞特异性PFKFB 3破坏加剧饮食诱导的脂肪组织功能障碍。因此，该项目的目标是定义PFKFB 3在调节脂肪细胞-巨噬细胞串扰中的新作用。因此，产生了在脂肪细胞和/或骨髓细胞中具有选择性PFKFB 3破坏的小鼠。对于特定目的1，设计了实验以检验以下假设：响应于PFKFB 3作用而产生的脂肪细胞因子，特别是棕榈酸酯，抑制巨噬细胞M1活化和/或刺激巨噬细胞M2活化。此外，将检查脂肪细胞PFKFB 3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PFKFB 3将营养代谢和巨噬细胞极化联系起来的假设。此外，将检查骨髓细胞中PFKFB 3破坏对脂肪组织炎症和全身胰岛素敏感性的体内作用。对于特定目的3，设计了实验以检验脂肪细胞和/或巨噬细胞中的PFKFB 3是PPARgamma活化作用所需的假设。因此，将检查脂肪细胞与巨噬细胞中的PFKFB 3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，并通过选择性PFKFB 3激活为胰岛素增敏提供实验基础。