Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA.
J Clin Invest. 2009 Mar;119(3):531-9. doi: 10.1172/JCI37273. Epub 2009 Feb 2.
Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.
抵抗素是一种脂肪因子，可导致小鼠胰岛素抵抗。然而，在人类中，关于抵抗素与代谢疾病之间联系的研究结果存在争议。更复杂的是，人类抵抗素主要由巨噬细胞而不是脂肪细胞产生。为了解决这个重要问题，我们生成了缺乏脂肪细胞衍生的小鼠抵抗素但以类似于人类的方式产生人抵抗素的小鼠，即巨噬细胞（人源化抵抗素小鼠）。当给予高脂肪饮食时，人源化抵抗素小鼠迅速发展出加速的白色脂肪组织（WAT）炎症，导致脂肪分解增加和血清游离脂肪酸增加。随着时间的推移，这些小鼠在肌肉中积累了包括二酰基甘油在内的脂质。我们发现这导致 Pkcq 途径活性增加，导致 Irs-1 的丝氨酸磷酸化增加和胰岛素抵抗。因此，尽管抵抗素的产生部位在物种间存在差异，但人类抵抗素可加剧 WAT 炎症并导致胰岛素抵抗。
