High fat diet-induced adrenergic dysfunction and resolution of adipose inflammation

高脂肪饮食引起的肾上腺素能功能障碍和脂肪炎症的解决

• 批准号: 10580596
• 负责人: Ernesto Hector Pena Calderin
• 金额: $ 3.46万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580596
• 关键词: Academia; Adipocytes; Adipose tissue; Adrenal Glands; Adrenergic Agents; Adrenergic Receptor; Anabolism; Animals; Arachidonate 5-Lipoxygenase; Arterial Fatty Streak; CD59 Antigen; Catecholamines; Cells; Cessation of life; Chronic; Chronic Disease; Consumption; Crowns; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Enzymes; Exercise; Functional disorder; Glucose; Goals; High Fat Diet; Immune; Immunohistochemistry; Immunosuppression; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Insulin Receptor; Insulin Resistance; Interruption; Knowledge; LTB4R gene; Laboratories; Learning; Leukotriene B4; Lipoxins; Macrophage; Macrophage Activation; Measures; Mediating; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathway interactions; Phenotype; Physical activity; Polyunsaturated Fatty Acids; Process; Production; Prostaglandin-Endoperoxide Synthase; RNA Interference; Research Personnel; Resistance development; Resolution; Signal Pathway; Signal Transduction; Sorting; Structure; Techniques; Testing; Therapeutic; Tissue Expansion; Tissues; Weight; Work; cardiorespiratory fitness; cytokine; diet and exercise; feeding; glucose uptake; improved; inflammatory marker; insight; insulin sensitivity; lipid mediator; lipidomics; magnetic beads; obesity development; physical inactivity; premature; prevent; receptor expression; response; sedentary; skills; systemic inflammatory response; wound healing

Excess nutrient consumption promotes systemic and tissue-specific inflammatory responses, inhibiting insulin receptor signaling pathways and prevents glucose uptake. Although specific molecular and cellular mechanisms that lead to the development of insulin resistance remain unclear, chronic inflammation is central to obesity- induced T2D. Diet-induced adipose tissue (AT) expansion with infiltration of classically activated macrophages and production of pro-inflammatory cytokines perpetuates chronic inflammation and insulin resistance. Therapeutic approaches that directly interrupt innate immune responses are problematic however as they could lead to immunosuppression and thus have limited therapeutic applicability. We have shown that persistent inflammation in diabetes and obesity is due to a deficiency in the processes that normally resolve inflammation. Nonetheless, mechanisms by which obesity induces perturbations in pro-resolving pathways and promote the development of unmitigated chronic inflammation remains undefined. Physical inactivity contributes to increased adiposity, markers of inflammation, chronic disease, and premature death, while physical activity protects against the development of obesity and chronic inflammation independent of reductions in weight. Cellular mechanisms by which physical activity protects against chronic inflammation, however, remain largely unknown. Recent work has shown that resolution of inflammation is mediated in part by enzymatic (15-,12-, 5-lipoxygenase, and cyclooxygenases) conversion of polyunsaturated fatty acids into specialized proresolving lipid mediators (SPMs; e.g., resolvins, lipoxins, maresins, and protectins) that act to quell inflammatory signaling. Importantly, our lab and others have also shown that obese-diabetic mice treated with SPMs display elevated alternatively activated macrophages with reduced AT inflammation, improved insulin sensitivity, and enhanced wound healing capacity. Additionally, our lab has shown that high fat diet-induced insulin resistance develops due to elevated pro- inflammatory lipid mediator leukotriene B4 (LTB4) production and that BLT-1 (LTB4 receptor) deficient mice are protected against diet-induced insulin resistance— a paradigm that also persists in atherosclerotic lesions. These findings suggest that imbalanced production of pro-inflammatory and proresolving lipid mediators contribute to obesity-induced insulin resistance. Our preliminary data show that exercise increases AT SPM biosynthesis and is inhibited by short duration high fat diet (HFD) feeding. We also find that HFD inhibits exercise-induced alternatively activated adipose tissue macrophages (ATM) levels. Interestingly, adrenal gland expression of biosynthetic enzymes and catecholamine levels—which our lab has previously shown to stimulate SPM biosynthesis in macrophages—are reduced following HFD feeding. Thus, we hypothesize that HFD-induced adrenergic dysfunction inhibits the proresolving response to exercise in AT. In pursuit of the scientific questions herein, I will hone my basic laboratory skills, learn advanced techniques, develop professional skills and network, all of which will propel me towards achieving my goal of becoming an independent investigator in academia.

过量的营养消耗促进全身性和组织特异性炎症反应，抑制胰岛素 受体信号通路并阻止葡萄糖摄取。虽然特定的分子和细胞机制 导致胰岛素抵抗发展的因素仍不清楚，慢性炎症是肥胖的核心- 诱发T2 D。饮食诱导的脂肪组织（AT）扩张伴经典活化巨噬细胞浸润 并且促炎细胞因子的产生使慢性炎症和胰岛素抗性持续存在。 然而，直接中断先天免疫应答的治疗方法是有问题的，因为它们可能 导致免疫抑制，因此具有有限治疗适用性。我们已经证明， 糖尿病和肥胖症中的炎症是由于通常解决炎症的过程中的缺陷。 尽管如此，肥胖诱导促消退途径紊乱并促进胰岛素抵抗的机制仍然存在。 未减轻的慢性炎症的发展仍然不确定。缺乏身体活动有助于增加 肥胖，炎症标志物，慢性疾病和过早死亡，而体力活动可以防止 肥胖和慢性炎症的发展与体重的减轻无关。细胞机制 然而，身体活动如何保护免受慢性炎症的影响仍然是未知的。最近的工作 已经表明炎症的消退部分是由酶促（15-，12-，5-脂氧合酶，和 环加氧酶）将多不饱和脂肪酸转化为专门的促分解脂质介体（SPM）; 例如，在一个实施例中，消退素、脂氧素、maresins和protectins），其起到抑制炎症信号传导的作用。重要的是，我们的实验室 和其他人也表明，用SPM治疗的肥胖糖尿病小鼠显示出升高的交替激活， 在一些实施方案中，本发明的组合物具有减少的AT炎症、改善的胰岛素敏感性和增强的伤口愈合能力。 此外，我们的实验室已经表明，高脂肪饮食诱导的胰岛素抵抗的发展，由于升高的前- 炎性脂质介质白三烯B4（LTB 4）产生和BLT-1（LTB 4受体）缺陷小鼠， 防止饮食诱导的胰岛素抵抗-这一范例在动脉粥样硬化病变中也持续存在。这些 研究结果表明，促炎和促分解脂质介质的不平衡产生有助于 肥胖引起的胰岛素抵抗我们的初步数据表明，运动增加AT SPM的生物合成， 被短期高脂饮食（HFD）喂养抑制。我们还发现，HFD抑制运动诱导的 或者激活的脂肪组织巨噬细胞（ATM）水平。有趣的是， 生物合成酶和儿茶酚胺水平-我们的实验室以前已经证明，刺激SPM 在HFD饲喂后，巨噬细胞中的生物合成减少。因此，我们假设HFD诱导的 肾上腺素能功能障碍抑制AT对运动的前消退反应。为了追寻科学问题 在这里，我将磨练我基本实验技能，学习先进的技术，发展专业技能和网络， 所有这些都将推动我实现成为学术界独立调查员的目标。