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The contribution of arachidonate 15-lipoxygenase in tissue macrophages to adipose tissue remodeling

机译：组织巨噬细胞中花生四烯酸15-脂氧合酶对脂肪组织重塑的贡献

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摘要

Cellular plasticity in adipose tissue involves adipocyte death, its clearance, and de novo adipogenesis, enabling homeostatic turnover and adaptation to metabolic challenges; however, mechanisms regulating these serial events are not fully understood. The present study investigated the roles of arachidonate 15-lipoxygenase (Alox15) in the clearance of dying adipocytes by adipose tissue macrophages. First, upregulation of Alox15 expression and apoptotic adipocyte death in gonadal white adipose tissue (gWAT) were characterized during adipose tissue remodeling induced by β 3-adrenergic receptor stimulation. Next, an in vitro reconstruction of adipose tissue macrophages and apoptotic adipocytes recapitulated adipocyte clearance by macrophages and demonstrated that macrophages co-cultured with apoptotic adipocytes increased the expression of efferocytosis-related genes. Genetic deletion and pharmacological inhibition of Alox15 diminished the levels of adipocyte clearance by macrophages in a co-culture system. Gene expression profiling of macrophages isolated from gWAT of Alox15 knockout (KO) mice demonstrated distinct phenotypes, especially downregulation of genes involved in lipid uptake and metabolism compared to wild-type mice. Finally, in vivo β 3-adrenergic stimulation in Alox15 KO mice failed to recruit crown-like structures, a macrophage network clearing dying adipocytes in gWAT. Consequently, in Alox15 KO mice, proliferation/differentiation of adipocyte progenitors and β 3-adrenergic remodeling of gWAT were impaired compared to wild-type control mice. Collectively, our data established a pivotal role of Alox15 in the resolution of adipocyte death and in adipose tissue remodeling.
机译：脂肪组织中的细胞可塑性涉及脂肪细胞的死亡，其清除和从头开始的脂肪形成，从而实现体内稳态转换和适应代谢挑战。但是，调节这些串行事件的机制尚未完全了解。本研究调查了花生四烯酸15-脂加氧酶（Alox15）在脂肪组织巨噬细胞清除垂死的脂肪细胞中的作用。首先，在由β3-肾上腺素受体刺激引起的脂肪组织重塑期间，表征了性腺白色脂肪组织（gWAT）中Alox15表达的上调和凋亡性脂肪细胞死亡。接下来，对脂肪组织巨噬细胞和凋亡性脂肪细胞的体外重建通过巨噬细胞概括了脂肪细胞的清除，并证明与凋亡性脂肪细胞共培养的巨噬细胞增加了与胞吐作用相关基因的表达。 Alox15的遗传删除和药理抑制作用减少了共培养系统中巨噬细胞对脂肪细胞清除的水平。从Alox15基因敲除（KO）小鼠的gWAT分离出的巨噬细胞的基因表达谱显示出明显的表型，特别是与野生型小鼠相比，脂质吸收和代谢相关基因的下调。最后，Alox15 KO小鼠体内的β3-肾上腺素刺激未能募集冠状结构，这是一种清除gWAT中垂死的脂肪细胞的巨噬细胞网络。因此，与野生型对照小鼠相比，在Alox15 KO小鼠中，脂肪细胞祖细胞的增殖/分化和gWAT的β3-肾上腺素重塑受到损害。总的来说，我们的数据确立了Alox15在解决脂肪细胞死亡和脂肪组织重塑中的关键作用。

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