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

过量的营养摄入促进全身和组织特异性炎症反应，抑制胰岛素 受体信号通路和阻止葡萄糖摄取。尽管特定的分子和细胞机制 导致胰岛素抵抗的原因尚不清楚，慢性炎症是肥胖的核心- 诱导的T2D。饮食诱导的脂肪组织(AT)扩张与经典激活的巨噬细胞的渗透 促炎细胞因子的产生会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，从而限制了治疗的适用性。我们已经证明了坚持不懈 糖尿病和肥胖症的炎症是由于正常情况下消除炎症的过程中的缺陷。 尽管如此，肥胖在促进解决途径中诱导扰动的机制并促进 未缓解的慢性炎症的发展仍不明确。缺乏体力活动有助于增加 肥胖、炎症、慢性病和过早死亡的标志，而体力活动可以预防 肥胖和慢性炎症的发展与体重减轻无关。细胞机制 然而，体育活动通过什么来预防慢性炎症，在很大程度上还不清楚。近期工作 已表明炎症的消退部分是由酶(15-，12-，5-脂氧合酶，和 环氧合酶)将多不饱和脂肪酸转化为专门化的前分解脂类介体(SPM； 例如，分解素、脂氧素、松脂素和保护素)，其作用于平息炎症信号。重要的是，我们的实验室 其他研究也表明，用SPM治疗的肥胖-糖尿病小鼠表现为升高或激活。 巨噬细胞减少AT炎症，改善胰岛素敏感性，并增强伤口愈合能力。 此外，我们的实验室已经证明，高脂饮食诱导的胰岛素抵抗是由于体内胰岛素原水平升高所致。 炎性脂质介质白三烯B4(LTB4)的产生和BLT-1(LTB4受体)缺陷小鼠 防止饮食诱导的胰岛素抵抗--这一范例也在动脉粥样硬化病变中持续存在。这些 研究结果表明，促炎和促溶解脂质介质的不平衡生产有助于 肥胖导致的胰岛素抵抗。我们的初步数据显示，锻炼增加了SPM的生物合成和 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 交替激活的脂肪组织巨噬细胞(ATM)水平。有趣的是，肾上腺表达的 生物合成酶和儿茶酚胺水平-我们的实验室以前已经证明它们可以刺激SPM 巨噬细胞的生物合成--在喂食HFD后减少。因此，我们假设HFD诱导的 肾上腺素能功能障碍抑制AT对运动的前解反应。追寻科学问题 在这里，我将磨练我的实验室基本技能，学习先进技术，发展专业技能和人脉， 所有这些都将推动我实现成为学术界独立研究员的目标。

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.