AIMS/HYPOTHESIS Absent in melanoma 2 (AIM2) is a cytosolic sensor for double-stranded DNA and a tumour suppressor. Binding of double-stranded DNA to AIM2 forms the AIM2 inflammasome, leading to activation of caspase-1 and production of IL-1β and IL-18. Although inflammasome-independent effects of AIM2 have been reported, its role in energy metabolism is unknown. We aimed to evaluate the effect of AIM2 in energy metabolism and glucose homeostasis. METHODS Male and female whole body Aim2 knockout (Aim2-/-) mice were used in the current study. Body weight, food intake, body composition, energy expenditure, fasting blood glucose levels, GTT and body temperature were measured at indicated time points. RNA sequencing was carried out on gonadal white adipose tissue (gWAT) in 14-month-old female mice. mRNA and protein levels in tissues were analysed by quantitative real-time PCR and immunoblot. Immune cell infiltration in gWAT was examined by flow cytometry. Stromal vascular fractions isolated from gWAT were used to investigate adipocyte differentiation. RESULTS Male and female Aim2-/- mice were obese compared with wild-type controls from 7 weeks of age until 51 weeks of age, with increased adiposity in both subcutaneous and visceral fat depots. While there were no differences in food intake, Aim2-/- mice demonstrated decreased energy expenditure and impaired brown adipose tissue function compared with wild-type controls. Fasting glucose and insulin levels were elevated, and Aim2-/- mice were glucose intolerant on intraperitoneal GTT. RNA sequencing revealed marked upregulation of the IFN-inducible gene Ifi202b, which encodes protein 202 (p202) and elevated inflammatory signalling in gWAT of Aim2-/- mice. Increased infiltration of total and Ly6Clow monocytes was noted at 8 weeks of age in gWAT, before the onset of obesity and insulin resistance. Ifi202b knockdown blocked adipogenesis in stromal vascular fractions and reduced inflammation in bone marrow-derived macrophages, demonstrating a key role of p202 in mediating the increased adipogenesis and inflammation in Aim2-/- mice. CONCLUSIONS/INTERPRETATION These results demonstrate a fundamental role for AIM2 in energy metabolism, inflammation and insulin resistance. Our studies establish a novel link between the innate immunity proteins, AIM2 and p202, and metabolism.

中文翻译：

---

AIM2缺乏会诱发白色脂肪组织中的炎症和脂肪生成，从而导致肥胖和胰岛素抵抗。

目的/假设黑素瘤2（AIM2）中不存在的是双链DNA和肿瘤抑制因子的胞质传感器。双链DNA与AIM2的结合形成AIM2炎性小体，导致caspase-1的活化以及IL-1β和IL-18的产生。尽管已经报道了AIM2的独立于炎性体的作用，但其在能量代谢中的作用尚不清楚。我们旨在评估AIM2在能量代谢和葡萄糖稳态中的作用。方法在本研究中使用雄性和雌性全身Aim2基因敲除（Aim2-/-）小鼠。在指定的时间点测量体重，食物摄入量，身体成分，能量消耗，空腹血糖水平，GTT和体温。在14个月大的雌性小鼠的性腺白色脂肪组织（gWAT）上进行RNA测序。通过定量实时PCR和免疫印迹分析组织中的mRNA和蛋白质水平。通过流式细胞术检查了gWAT中的免疫细胞浸润。从gWAT中分离出的基质血管级分用于研究脂肪细胞的分化。结果从7周龄到51周龄，雄性和雌性Aim2-/-小鼠与野生型对照组相比均较肥胖，皮下和内脏脂肪库的脂肪增加。尽管进食量没有差异，但与野生型对照组相比，Aim2-/-小鼠表现出的能量消耗减少和褐色脂肪组织功能受损。空腹血糖和胰岛素水平升高，并且Aim2-/-小鼠腹膜内GTT对葡萄糖不耐受。RNA测序显示IFN诱导型基因Ifi202b明显上调，它在Aim2-/-小鼠的gWAT中编码蛋白质202（p202）和炎性信号转导。在肥胖和胰岛素抵抗发作之前，在8周龄时，在gWAT中发现了总单核细胞和Ly6Clow单核细胞的浸润增加。Ifi202b基因敲低阻止了基质血管部分的脂肪形成，并减少了骨髓来源的巨噬细胞的炎症，证明了p202在介导Aim2-/-小鼠脂肪形成和炎症增加中起关键作用。结论/解释这些结果证明了AIM2在能量代谢，炎症和胰岛素抵抗中的基本作用。我们的研究在先天免疫蛋白AIM2和p202与代谢之间建立了新的联系。在肥胖和胰岛素抵抗发作之前，在8周龄时，在gWAT中发现了总单核细胞和Ly6Clow单核细胞的浸润增加。Ifi202b敲低可阻断基质血管部分的脂肪形成，并减少骨髓源性巨噬细胞的炎症，证明p202在介导Aim2-/-小鼠脂肪形成和炎症增加中起关键作用。结论/解释这些结果证明了AIM2在能量代谢，炎症和胰岛素抵抗中的基本作用。我们的研究在先天免疫蛋白AIM2和p202与代谢之间建立了新的联系。在肥胖和胰岛素抵抗发作之前，在8周龄时，在gWAT中发现了总单核细胞和Ly6Clow单核细胞的浸润增加。Ifi202b基因敲低阻止了基质血管部分的脂肪形成，并减少了骨髓来源的巨噬细胞的炎症，证明了p202在介导Aim2-/-小鼠脂肪形成和炎症增加中起关键作用。结论/解释这些结果证明了AIM2在能量代谢，炎症和胰岛素抵抗中的基本作用。我们的研究在先天免疫蛋白AIM2和p202与代谢之间建立了新的联系。证明了p202在介导Aim2-/-小鼠脂肪形成和炎症增加中的关键作用。结论/解释这些结果证明了AIM2在能量代谢，炎症和胰岛素抵抗中的基本作用。我们的研究在先天免疫蛋白AIM2和p202与代谢之间建立了新的联系。证明了p202在介导Aim2-/-小鼠脂肪形成和炎症增加中的关键作用。结论/解释这些结果证明了AIM2在能量代谢，炎症和胰岛素抵抗中的基本作用。我们的研究在先天免疫蛋白AIM2和p202与代谢之间建立了新的联系。