The role of ADAM17, its substrates, and its natural inhibitor has been well studied in the context of inflammation, including metabolic inflammation, with mixed results. Previous studies examining global Adam17 knockdown models and ADAM17 inhibition using overexpression of endogenous ADAM17 inhibitors have shown improved metabolic health and decreased metabolic inflammation. However, there have been no studies examining the role of adipocyte ADAM17 using in vivo models. In this study, we developed an adipocyte-specific Adam17 knockout model using Adipoq-Cre-expressing mice crossed with Adam17-floxed mice. Using this model, we show that loss of adipocyte ADAM17 plays no evident role in baseline metabolic responses. Surprisingly, in a state of metabolic stress using high-fat diet (HFD), we observed that adipocyte ADAM17 had little effect overall on the metabolic phenotype as well as inflammatory cell populations. Using whole-body metabolic phenotyping, we show that loss of ADAM17 has no effect on energy utilization both at a baseline state as well as following HFD. However, lastly, using high-parameter flow cytometry, we show that loss of adipocyte ADAM17 alters macrophage and eosinophil populations following HFD. Overall, the studies presented here give more insight into the role of ADAM17 in metabolic responses and metabolic inflammation, specifically in adipocytes.

中文翻译：

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脂肪细胞 ADAM17 在代谢性炎症中发挥有限作用。


ADAM17、其底物及其天然抑制剂的作用已在炎症（包括代谢性炎症）背景下得到了深入研究，结果好坏参半。先前的研究使用内源性 ADAM17 抑制剂的过度表达来检查全球 Adam17 敲除模型和 ADAM17 抑制，结果表明代谢健康状况得到改善，代谢炎症减少。然而，还没有研究使用体内模型检验脂肪细胞 ADAM17 的作用。在这项研究中，我们使用表达 Adipoq-Cre 的小鼠与 Adam17 floxed 小鼠杂交，开发了脂肪细胞特异性 Adam17 敲除模型。使用该模型，我们表明脂肪细胞 ADAM17 的损失在基线代谢反应中没有明显作用。令人惊讶的是，在使用高脂肪饮食（HFD）的代谢应激状态下，我们观察到脂肪细胞 ADAM17 对代谢表型以及炎症细胞群总体影响很小。通过全身代谢表型分析，我们发现 ADAM17 的缺失对基线状态以及 HFD 后的能量利用没有影响。然而，最后，使用高参数流式细胞术，我们发现脂肪细胞 ADAM17 的丢失会改变 HFD 后的巨噬细胞和嗜酸性粒细胞群体。总体而言，本文提出的研究更深入地了解了 ADAM17 在代谢反应和代谢炎症（特别是在脂肪细胞中）中的作用。