Diabetes and Obesity Research Group (L.J.M., T.J.R., E.J.P., K.K.), University of Exeter Medical School, Exeter EX2 5DW, United Kingdom; Department of Molecular and Clinical Medicine (K.S., L.M.C.), The Sahlgrenska Academy at University of Gothenburg 413 45, Sweden; Department of Medical and Health Sciences (N.F., F.N.), Faculty of Health Sciences, Linkoping University, Linkoping 58185, Sweden; K.G Jebsen Centre for Diabetes Research (S.N.D., G.M.), Department of Clinical Science, University of Bergen 5021 Norway; National Institute for Health Research Exeter Clinical Research Facility (B.K.), University of Exeter Medical School, United Kingdom; and Department of Obstetrics and Gynaecology (N.H.L.), Royal Devon and Exeter National Health Service Foundation Trust, United Kingdom.
Endocrinology. 2015 Jan;156(1):134-46. doi: 10.1210/en.2014-1042.
Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability, and contributes to metabolic dysfunction. Collagen type VI, α3 (COL6A3) encodes 1 subunit of a fibrotic extracellular matrix protein highly expressed in rodent AT. Knockout of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic ob/ob mice. However, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterization of COL6A3 in human AT showed 5-fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous AT (SCAT) than omental AT. In both depots, COL6A3 expression appeared to be lowered in obesity, whereas diet- and surgery-induced weight loss increased COL6A3 expression in SCAT. Leptin treatment caused a dose-dependent decrease in COL6A3 expression, although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents, because COL6A3 does not appear to be the predominant collagen in adipose, muscle, or liver. Our findings oppose those initially seen in rodent studies and, most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signaling pathway in human AT and suggests an additional mechanism by which leptin can regulate extracellular matrix composition and, with it, AT expandability.
脂肪组织（AT）纤维化会增加 AT 的刚性，降低其可扩展性，并导致代谢功能障碍。胶原 VI 型，α3（COL6A3）编码在啮齿动物 AT 中高度表达的纤维细胞外基质蛋白的 1 个亚基。在肥胖、糖尿病 ob/ob 小鼠的 AT 中敲除胶原 VI 会导致代谢健康状况显著改善。然而，尚不清楚这种胶原蛋白在人类 AT 中是否具有相同的代谢意义。因此，我们旨在对 COL6A3 与人类 AT 和肥胖的关系进行全面评估。COL6A3 在人类 AT 中的特征表明，与脂肪细胞表达相比，基质血管部分的表达高 5 倍，与网膜 AT 相比，皮下 AT（SCAT）的表达明显更高。在这两个储存库中，COL6A3 的表达似乎在肥胖中降低，而饮食和手术引起的体重减轻会增加 SCAT 中的 COL6A3 表达。瘦素处理会导致 COL6A3 表达呈剂量依赖性下降，尽管胰岛素或葡萄糖处理没有效果，并且在糖尿病患者中没有观察到差异。此外，我们发现人类的胶原表达谱与啮齿动物有很大的不同，因为 COL6A3 似乎不是脂肪、肌肉或肝脏中主要的胶原。我们的发现与最初在啮齿动物研究中看到的结果相反，最重要的是，证明了瘦素对 COL6A3 的直接调节。这凸显了人 AT 中旁分泌瘦素信号通路的重要性，并表明瘦素可以调节细胞外基质组成及其 AT 可扩展性的另一种机制。
