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: 8506084
• 负责人: Chaodong Wu
• 金额: $ 31.47万
• 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/8506084
• 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; 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.

概述：肥胖中脂肪细胞-巨噬细胞串扰的代谢调节肥胖相关的脂肪组织炎症对胰岛素抵抗和2型糖尿病的发展至关重要。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，但对于脂肪细胞和巨噬细胞的营养代谢如何与炎症反应相关联，我们知之甚少。脂肪细胞和巨噬细胞之间相互作用的代谢调节机制也不清楚。本研究的长期目标是解剖脂肪细胞-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。作为一个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。本项目的中心假设是，PFKFB3协调脂肪细胞-巨噬细胞串扰的适当代谢调节，抑制巨噬细胞促炎（M1）激活，刺激巨噬细胞替代（M2）激活，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。这一假设基于以下新发现：1)PFKFB3刺激脂肪细胞产生棕榈油酸酯（一种单不饱和脂肪酸），从而减弱巨噬细胞M1的激活；2) PFKFB3参与ppγ刺激巨噬细胞M2活化；3)骨髓细胞特异性PFKFB3破坏加剧了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，产生了脂肪细胞和/或髓细胞中选择性PFKFB3破坏的小鼠。对于Specific Aim 1，我们设计了实验来验证以下假设，即在PFKFB3作用下产生的脂肪细胞因子，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，我们还将研究脂肪细胞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Specific Aim 2，我们设计了实验来验证PFKFB3与营养代谢和巨噬细胞极化有关的假设。此外，还将研究骨髓细胞中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Specific Aim 3，我们设计了实验来验证脂肪细胞和/或巨噬细胞中的PFKFB3是pppargamma激活所必需的假设。因此，我们将研究脂肪细胞与巨噬细胞中PFKFB3在ppγ调节脂肪细胞-巨噬细胞串声、脂肪组织炎症和全身胰岛素敏感性中的作用。总之，本研究将阐明脂肪细胞-巨噬细胞串扰代谢调控的新范式，并为通过选择性激活PFKFB3实现胰岛素增敏提供实验依据。