Petersen Pia S, Lei Xia, Wolf Risa M, Rodriguez Susana, Tan Stefanie Y, Little Hannah C, Schweitzer Michael A, Magnuson Thomas H, Steele Kimberley E, Wong G William
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Am J Physiol Endocrinol Metab. 2017 Apr 1;312(4):E309-E325. doi: 10.1152/ajpendo.00344.2016. Epub 2017 Feb 21.
Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.
慢性低度炎症和细胞应激是肥胖相关代谢功能障碍的重要促成因素。在此，我们发现了C1q/TNF相关蛋白7（CTRP7）的免疫代谢作用，CTRP7是C1q家族的一种分泌蛋白，其功能此前未知。在肥胖人群中，循环CTRP7水平显著升高，且与体重指数、血糖、胰岛素、胰岛素抵抗指数、糖化血红蛋白和甘油三酯水平呈正相关。在肥胖人群中，肝脏中CTRP7的表达也显著上调，且与糖异生基因呈正相关。在小鼠中，禁食和再喂食以及饮食诱导的肥胖会使CTRP7在各种组织中的表达受到不同程度的调节。我们使用基因功能缺失小鼠模型来确定CTRP7对代谢稳态的需求。当喂食对照低脂饮食时，缺乏CTRP7的雄性或雌性小鼠与野生型同窝小鼠没有区别。然而，在食用高脂饮食的肥胖雄性小鼠中，CTRP7缺乏减轻了胰岛素抵抗并增强了葡萄糖耐量，这些作用与体重、代谢率和身体活动水平无关。CTRP7缺陷小鼠葡萄糖代谢的改善与脂肪组织炎症减轻以及肝纤维化、细胞氧化和内质网应激减少有关。这些结果揭示了CTRP7水平升高与葡萄糖代谢受损之间的联系，而葡萄糖代谢受损常与肥胖相关。抑制CTRP7的作用可能在肥胖和糖尿病情况下带来有益的代谢结果。
