Löffler D, Landgraf K, Rockstroh D, Schwartze J T, Dunzendorfer H, Kiess W, Körner A
Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
Int J Obes (Lond). 2017 Jan;41(1):112-119. doi: 10.1038/ijo.2016.180. Epub 2016 Oct 17.
Meteorin-like (METRNL) is a recently described circulating protein shown to be highly expressed in white adipose tissue and to beneficially affect energy metabolism in mice.
We systematically evaluated the role of METRNL for human adipogenesis and its association with obesity, browning and hyperinsulinemia in children. In addition, we assessed the functional relevance of METRNL for human adipogenesis.
METRNL expression decreased during human adipocyte differentiation in vitro. Coherently, METRNL expression was lower in isolated adipocytes compared with stromal vascular fraction (SVF) cells in human samples. Withdrawal of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone from adipogenic media partially preserved the METRNL downregulation during adipogenesis. METRNL expression was higher in adipocytes of obese compared with lean children and correlated with adipocyte size, whereas in SVF METRNL expression correlated with proliferation capacity. Concordantly, overexpression of METRNL inhibited human adipocyte differentiation as shown by decreased lipogenesis and lower expression of PPARγ and markers of adipogenesis, whereas experimental downregulation promoted adipogenesis. Proliferation, in contrast, was advanced by METRNL overexpression. These interactions with adipose tissue dynamics may contribute to the clinically observed body mass index-independent association of METRNL expression with hyperinsulinemia and adipose tissue inflammation in human samples. METRNL was not associated with UCP1 expression or induction of browning in white adipocytes.
Taken together, the downregulation of METRNL during adipogenesis and functional induction of increased proliferation in SVF cells with concomitant inhibition of adipocyte differentiation may result in hypertrophic AT accumulation. This may also explain our observations of increased METRNL expression in adipocytes but not SVF cells in obese children compared with lean children and the subsequent hyperinsulinemia.
类 Meteorin（METRNL）是一种最近被描述的循环蛋白，在白色脂肪组织中高表达，对小鼠能量代谢有有益影响。
我们系统评估了 METRNL 在人类脂肪生成中的作用及其与儿童肥胖、脂肪褐变和高胰岛素血症的关联。此外，我们评估了 METRNL 对人类脂肪生成的功能相关性。
在体外人类脂肪细胞分化过程中，METRNL 表达降低。同样，在人类样本中，与基质血管成分（SVF）细胞相比，分离出的脂肪细胞中 METRNL 表达较低。从成脂培养基中撤除过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮可部分保留脂肪生成过程中 METRNL 的下调。肥胖儿童的脂肪细胞中 METRNL 表达高于瘦儿童，且与脂肪细胞大小相关，而在 SVF 中，METRNL 表达与增殖能力相关。一致地，METRNL 过表达抑制人类脂肪细胞分化，表现为脂肪生成减少以及 PPARγ 和脂肪生成标志物表达降低，而实验性下调则促进脂肪生成。相比之下，METRNL 过表达促进增殖。这些与脂肪组织动态变化的相互作用可能导致临床上观察到的 METRNL 表达与人类样本中的高胰岛素血症和脂肪组织炎症之间与体重指数无关的关联。METRNL 与白色脂肪细胞中解偶联蛋白 1（UCP1）表达或脂肪褐变诱导无关。
综上所述，脂肪生成过程中 METRNL 的下调以及 SVF 细胞中增殖增加的功能诱导与脂肪细胞分化的抑制可能导致肥大性脂肪组织积累。这也可能解释了我们观察到的肥胖儿童与瘦儿童相比，肥胖儿童脂肪细胞中而非 SVF 细胞中 METRNL 表达增加以及随后的高胰岛素血症。
