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: 8840939
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840939
• 关键词: 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; Health; 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; 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; 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(申请人提供)：肥胖中脂肪细胞-巨噬细胞串扰的代谢调节概述肥胖相关的脂肪组织炎症对胰岛素抵抗和2型糖尿病的发展起着至关重要的作用。虽然许多证据表明脂肪细胞和巨噬细胞在启动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的炎症反应相关联的确切情况还知之甚少。脂肪细胞和巨噬细胞之间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。作为一种富含脂肪组织的基因，PFKFB3编码一种调节酶，其产物刺激糖酵解。对于这个项目，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，以抑制巨噬细胞前炎症(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。这一假说基于以下新发现：1)PFKFB3刺激脂肪细胞产生棕榈油酸(一种单一不饱和脂肪酸)，进而钝化巨噬细胞M1的激活；2)PFKFB3参与PPAR伽马刺激巨噬细胞M2的激活；以及3)髓系细胞特异性的PFKFB3干扰加剧饮食诱导的脂肪组织功能障碍。因此，本项目的目标是确定PFKFB3在调节脂肪细胞-巨噬细胞串扰中的新作用。因此，产生了选择性破坏脂肪细胞和/或髓系细胞的PFKFB3的小鼠。为了达到特定的目的1，已经设计了实验来检验这样的假设，即脂肪细胞因子响应PFKFB3的作用，特别是棕榈油酸酯，抑制巨噬细胞M1的激活和/或刺激巨噬细胞M2的激活。此外，还将检测脂肪细胞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。对于特定的目的2，已经设计了实验来检验PFKFB3将营养代谢和巨噬细胞极化联系在一起的假设。此外，还将检测破坏髓系细胞中的PFKFB3对脂肪组织炎症和全身性胰岛素敏感性的体内影响。对于特定的目的3，已经设计了实验来验证这样的假设，即脂肪细胞和/或巨噬细胞中的PFKFB3是PPAR伽马激活所必需的。因此，将研究脂肪细胞和巨噬细胞中的PFKFB3参与PPAR对脂肪细胞-巨噬细胞串扰、脂肪组织炎症和全身性胰岛素敏感性的调节。总之，这项研究将阐明脂肪细胞-巨噬细胞串扰代谢调节的新范式，并为选择性激活PFKFB3进行胰岛素增敏提供实验基础。