Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Metabolism. 2023 Dec;149:155706. doi: 10.1016/j.metabol.2023.155706. Epub 2023 Oct 13.
Dysregulation of angiotensin II type 1 receptor-associated protein (ATRAP) expression in cardiovascular, kidney, and adipose tissues is involved in the pathology of hypertension, cardiac hypertrophy, atherosclerosis, kidney injury, and metabolic disorders. Furthermore, ATRAP is highly expressed in bone marrow-derived immune cells; however, the functional role of immune cell ATRAP in obesity-related pathology remains unclear. Thus, we sought to identify the pathophysiological significance of immune cell ATRAP in the development of visceral obesity and obesity-related metabolic disorders using a mouse model of diet-induced obesity.
Initially, we examined the effect of high-fat diet (HFD)-induced obesity on the expression of immune cell ATRAP in wild-type mice. Subsequently, we conducted bone marrow transplantation to generate two types of chimeric mice: bone marrow wild-type chimeric (BM-WT) and bone marrow ATRAP knockout chimeric (BM-KO) mice. These chimeric mice were provided an HFD to induce visceral obesity, and then the effects of immune cell ATRAP deficiency on physiological parameters and adipose tissue in the chimeric mice were investigated.
In wild-type mice, body weight increase by HFD was associated with increased expression of immune cell ATRAP. In the bone marrow transplantation experiments, BM-KO mice exhibited amelioration of HFD-induced weight gain and visceral fat expansion with small adipocytes compared BM-WT mice. In addition, BM-KO mice on the HFD showed significant improvements in white adipose tissue metabolism, inflammation, glucose tolerance, and insulin resistance, compared with BM-WT mice on the HFD. Detailed analysis of white adipose tissue revealed significant suppression of HFD-induced activation of transforming growth factor-beta signaling, a key contributor to visceral obesity, via amelioration of CD206 macrophage accumulation in the adipose tissue of BM-KO mice. This finding suggests a relevant mechanism for the anti-obesity phenotype in BM-KO mice on the HFD. Finally, transcriptome analysis of monocytes indicated the possibility of genetic changes, such as the enhancement of interferon-γ response at the monocyte level, affecting macrophage differentiation in BM-KO mice.
Collectively, our results indicate that ATRAP in bone marrow-derived immune cells plays a role in the pathogenesis of visceral obesity. The regulation of ATRAP expression in immune cells may be a key factor against visceral adipose obesity with metabolic disorders.
血管紧张素 II 型 1 型受体相关蛋白 (ATRAP) 在心血管、肾脏和脂肪组织中的表达失调与高血压、心脏肥大、动脉粥样硬化、肾脏损伤和代谢紊乱的病理学有关。此外，ATRAP 在骨髓来源的免疫细胞中高度表达；然而，免疫细胞 ATRAP 在肥胖相关病理学中的功能作用尚不清楚。因此，我们使用饮食诱导肥胖的小鼠模型，试图确定免疫细胞 ATRAP 在内脏肥胖和肥胖相关代谢紊乱发展中的病理生理意义。
首先，我们检查了高脂肪饮食（HFD）诱导肥胖对野生型小鼠免疫细胞 ATRAP 表达的影响。随后，我们进行了骨髓移植，生成了两种嵌合小鼠：骨髓野生型嵌合（BM-WT）和骨髓 ATRAP 敲除嵌合（BM-KO）小鼠。这些嵌合小鼠接受 HFD 以诱导内脏肥胖，然后研究免疫细胞 ATRAP 缺失对嵌合小鼠生理参数和脂肪组织的影响。
在野生型小鼠中，HFD 引起的体重增加与免疫细胞 ATRAP 的表达增加有关。在骨髓移植实验中，与 BM-WT 小鼠相比，BM-KO 小鼠在 HFD 诱导下体重增加和内脏脂肪扩张得到改善，脂肪细胞较小。此外，与 HFD 喂养的 BM-WT 小鼠相比，HFD 喂养的 BM-KO 小鼠的白色脂肪组织代谢、炎症、葡萄糖耐量和胰岛素抵抗显著改善。对白色脂肪组织的详细分析表明，通过改善 BM-KO 小鼠脂肪组织中 CD206 巨噬细胞的积累，HFD 诱导的转化生长因子-β信号转导的激活得到显著抑制，这是内脏肥胖的关键贡献者。这一发现为 HFD 喂养的 BM-KO 小鼠的抗肥胖表型提供了一个相关机制。最后，单核细胞的转录组分析表明，在单核细胞水平增强干扰素-γ反应等遗传变化可能影响 BM-KO 小鼠的巨噬细胞分化。
综上所述，我们的结果表明，骨髓来源的免疫细胞中的 ATRAP 在内脏肥胖发病机制中起作用。免疫细胞中 ATRAP 表达的调节可能是对抗代谢紊乱内脏脂肪肥胖的关键因素。
