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

基本信息

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
项目类别：
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

项目摘要

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.

过量的营养会促进全身和组织特异性炎症反应，抑制胰岛素消耗受体信号通路并阻止葡萄糖摄取，尽管有特定的分子和细胞机制。导致胰岛素抵抗发展的原因尚不清楚，慢性炎症是肥胖的核心- 饮食诱导的 T2D 脂肪组织 (AT) 扩张以及经典激活的巨噬细胞的浸润。促炎细胞因子的产生使慢性炎症和胰岛素抵抗持续存在。然而，直接中断先天免疫反应的治疗方法是有问题的，因为它们可能导致免疫抑制，因此其治疗适用性有限。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造成的。然而，肥胖引起促解决途径扰动并促进未缓解的慢性炎症的发展仍不清楚，缺乏身体活动会导致炎症增加。肥胖、炎症、慢性疾病和过早死亡的标志，而体育活动可以预防肥胖和慢性炎症的发展与体重减轻无关。然而，身体活动如何预防慢性炎症，目前仍不清楚。研究表明，炎症的消退部分是由酶（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溶解脂质介质（SPM；例如，消解素、脂氧素、maresins 和保护素），它们可以平息炎症信号传导。和其他人还表明，用 SPM 治疗的肥胖糖尿病小鼠显示出较高的替代激活巨噬细胞具有减少 AT 炎症、提高胰岛素敏感性和增强伤口愈合能力的作用。此外，我们的实验室已经表明，高脂肪饮食引起的胰岛素抵抗是由于促胰岛素升高而产生的。炎症脂质介质白三烯 B4 (LTB4) 的产生以及 BLT-1（LTB4 受体）缺陷的小鼠防止饮食引起的胰岛素抵抗——这种模式在动脉粥样硬化病变中也持续存在。研究结果表明，促炎和促消退介质脂质的产生不平衡会导致我们的初步数据表明，运动会增加 AT SPM 的生物合成和肥胖引起的胰岛素抵抗。短期高脂肪饮食 (HFD) 喂养会抑制我们还发现 HFD 会抑制运动引起的。替代激活的脂肪组织巨噬细胞（ATM）水平。生物合成酶和儿茶酚胺水平——我们的实验室之前已证明它们可以刺激 SPM HFD 喂养后巨噬细胞的生物合成减少，因此，我们研究了 HFD 诱导的情况。肾上腺素能功能障碍抑制 AT 运动的促缓解反应。在此，我将磨练我的基本实验室技能，学习先进技术，发展专业技能和人际网络，所有这些都将推动我实现成为学术界独立调查员的目标。