Division of Endocrinology Mayo Clinic, Rochester, Minnesota.
Endocrinology. 2020 Oct 1;161(10). doi: 10.1210/endocr/bqaa160.
Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.
内脏脂肪组织（VAT）的致病性与增大的成熟脂肪细胞的代谢应激以及招募新脂肪细胞的能力有限有关。与皮下脂肪组织（SAT）相比，VAT 前体细胞的一个主要区别特征是高表达锌金属蛋白酶、妊娠相关血浆蛋白-A（PAPP-A）。在这项研究中，我们使用了两种不同的方法来研究在高脂肪饮食（HFD）喂养 15 周的小鼠中，PAPP-A 抑制对不同脂肪沉积的影响。在雌性成年小鼠中，条件性敲低 PAPP-A 基因表达导致 VAT（肠系膜和心包沉积）中的脂肪细胞大小显著减少 30%至 40%，与对照小鼠相比。SAT（腹股沟）或腹腔内性腺周脂肪没有影响。肝脂质也显著减少，而心脏和骨骼肌脂质没有影响。当使用药理学方法时，我们发现了类似的效果。每周向雄性和雌性野生型小鼠注射特异性免疫中和单克隆抗体（mAb-PA 1/41）或同种型对照，在 HFD 喂养 15 周。只有在用 mAb-PA 1/41 治疗时，VAT 中的脂肪细胞大小才显著减小（30%-50%）。在这种模型中，在用 mAb-PA 1/41 治疗的小鼠的肠系膜脂肪中，细胞数量显著增加，表明这个 VAT 沉积中存在增生，同时伴随着肥大减少。基因表达数据表明，在用 mAb-PA 1/41 治疗的小鼠的肠系膜脂肪中，F4/80（巨噬细胞标记物）和白细胞介素-6（促炎细胞因子）显著减少，而脂联素（具有有益代谢作用的抗炎脂肪因子）显著增加，与腹股沟脂肪相比。此外，在用 mAb-PA 1/41 治疗时，肝脂质含量显著降低。因此，使用两种不同的模型系统，我们提供了 PAPP-A 抑制是预防内脏肥胖及其代谢后果（如脂肪肝）的潜在治疗靶点的原理证明。
