Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Int J Obes (Lond). 2022 Oct;46(10):1759-1769. doi: 10.1038/s41366-022-01175-3. Epub 2022 Jul 6.
Obesity, a metabolic syndrome, is known to be related to inflammation, especially adipose tissue inflammation. Cellular interactions within the expanded white adipose tissue (WAT) in obesity contribute to inflammation and studies have suggested that inflammation is triggered by inflamed adipocytes that recruit M1 macrophages into WAT. What causes accumulation of unhealthy adipocytes is an important topic of investigation. This study aims to understand the action of Cellular Retinoic Acid Binding Protein 1 (CRABP1) in WAT inflammation.
Eight weeks-old wild type (WT) and Crabp1 knockout (CKO) mice were fed with a normal diet (ND) or high-fat diet (HFD) for 8 weeks. Body weight and food intake were monitored. WATs and serum were collected for cellular and molecular analyses to determine affected signaling pathways. In cell culture studies, primary adipocyte differentiation and bone marrow-derived macrophages (BMDM) were used to examine adipocytes' effects, mediated by CRABP1, in macrophage polarization. The 3T3L1-adipocyte was used to validate relevant signaling pathways.
CKO mice developed an obese phenotype, more severely under high-fat diet (HFD) feeding. Further, CKO's WAT exhibited a more severe inflammatory state as compared to wild type (WT) WAT, with a significantly expanded M1-like macrophage population. However, this was not caused by intrinsic defects of CKO macrophages. Rather, CKO adipocytes produced a significantly reduced level of adiponectin and had significantly lowered mitochondrial DNA content. CKO adipocyte-conditioned medium, compared to WT control, inhibited M2-like (CD206) macrophage polarization. Mechanistically, defects in CKO adipocytes involved the ERK1/2 signaling pathway that could be modulated by CRABP1.
This study shows that CRABP1 plays a protective role against HFD-induced WAT inflammation through, in part, its regulation of adiponectin production and mitochondrial homeostasis in adipocytes, thereby modulating macrophage polarization in WAT to control its inflammatory potential.
肥胖是一种代谢综合征，已知与炎症有关，尤其是脂肪组织炎症。肥胖时扩大的白色脂肪组织（WAT）内的细胞相互作用导致炎症，研究表明炎症是由发炎的脂肪细胞引发的，这些脂肪细胞将 M1 巨噬细胞招募到 WAT 中。导致不健康脂肪细胞堆积的原因是一个重要的研究课题。本研究旨在了解细胞视黄醇结合蛋白 1（CRABP1）在 WAT 炎症中的作用。
8 周龄野生型（WT）和 Crabp1 敲除（CKO）小鼠分别用正常饮食（ND）或高脂肪饮食（HFD）喂养 8 周。监测体重和食物摄入量。收集 WAT 和血清进行细胞和分子分析，以确定受影响的信号通路。在细胞培养研究中，使用原代脂肪细胞分化和骨髓来源的巨噬细胞（BMDM）来研究脂肪细胞通过 CRABP1 对巨噬细胞极化的影响。使用 3T3L1 脂肪细胞来验证相关信号通路。
CKO 小鼠表现出肥胖表型，在高脂肪饮食（HFD）喂养下更为严重。此外，与野生型（WT）WAT 相比，CKO 的 WAT 表现出更严重的炎症状态，M1 样巨噬细胞群体显著扩大。然而，这不是由于 CKO 巨噬细胞的内在缺陷引起的。相反，CKO 脂肪细胞产生的脂联素水平显著降低，线粒体 DNA 含量显著降低。与 WT 对照相比，CKO 脂肪细胞条件培养基抑制了 M2 样（CD206）巨噬细胞极化。从机制上讲，CKO 脂肪细胞的缺陷涉及 ERK1/2 信号通路，该通路可通过 CRABP1 进行调节。
本研究表明，CRABP1 通过部分调节脂肪细胞中的脂联素产生和线粒体动态平衡，在防止 HFD 诱导的 WAT 炎症中发挥保护作用，从而调节 WAT 中的巨噬细胞极化，控制其炎症潜力。
