钙调蛋白激酶CAMKIIδ调控巨噬细胞活化介导的肥胖和胰岛素抵抗的分子机制研究

Macrophage activation is not only regulated by the microenvironment, but also by fine-tuning at the molecular level. Related research has always been the focus and hotspot of innate immune. We found that CAMKIIδ knockout mice are more prone to obesity and insulin resistance, more macrophages and crown-like structure. After knockdown of CAMKIIδ, expression of inflammatory cytokines IL-6, TNF-α, iNOS and IL-12p40 increased in the classical activation of macrophages. We hypothesized that CAMKIIδ inhibits the expression of classically activated inflammatory genes, thereby inhibiting obesity and insulin resistance. We constructed Camk2dflox/flox Lysm Cre+/+ conditional knockout mice to verified the role of CAMKIIδ in vivo, and screened for target genes of CAMKIIδ. Then, we constructed target gene knockout mice target genes to verify in vivo. Taken together, the objective of our project is to illuminate the molecular mechanism of CAMKIIδin regulating macrophage activation, obesity and metabolism, which is expected to provide new ideas and targets for obesity intervention.

巨噬细胞活化不仅受到所处微环境的调控，也受到分子水平的精细调节。在小鼠肥胖模型中，发现CAMKIIδ全身性敲除小鼠更易于发生肥胖和胰岛素抵抗，且脂肪组织巨噬细胞和皇冠状结构变多。CAMKIIδ敲低后，导致巨噬细胞IL-6、TNF-α、iNOS和IL-12p40表达上升。我们猜测：CAMKIIδ抑制巨噬细胞经典活化促炎基因的表达，进而抑制肥胖及胰岛素抵抗。继而构建了Camk2d flox/flox Lysm Cre+/+条件性敲除小鼠，以阐明CAMKIIδ特异性缺失在小鼠肥胖中的作用和筛选CAMKIIδ的靶基因。研究结果有望为肥胖干预提供新思路新靶点。

近年来，肥胖和胰岛素抵抗等代谢性疾病发病越来越严重。研究表明，脂肪组织巨噬细胞（ATM）在与肥胖相关的代谢疾病中起着重要作用。 对巨噬细胞进行干预对于治疗肥胖和胰岛素抵抗具有巨大的潜力。然而，对脂肪组织中巨噬细胞活化的机制仍有待研究。我们发现多功能丝氨酸/苏氨酸蛋白激酶CaMKIIδ的表达在肥胖小鼠脂肪组织的基质血管组分 (SVF)中显着降低。CaMKIIδ的全身和骨髓敲除导致高脂肪饮食 (HFD) 诱导的小鼠表现出严重的肥胖和胰岛素抵抗。 此外，单细胞RNA测序分析表明，CaMKIIδ缺失引起巨噬细胞促炎激活以及巨噬细胞与其他免疫细胞之间的特异性相互作用。研究发现，CaMKIIδ通过磷酸化 Ser378以降低其转录活性来促进Egr1的降解，从而导致ATM的活化和代谢性炎症。同样，Egr1敲低抑制巨噬细胞的激活。总之，研究揭示了CaMKIIδ/Egr1轴可能是脂肪组织炎症和肥胖相关代谢疾病的潜在治疗靶点。

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