CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress
CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress
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DOI：
10.1152/ajpendo.00344.2016
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发表时间：
2017-04-01
影响因子：
5.1
通讯作者：
Wong, G. William
中科院分区：
文献类型：
--
作者：
Petersen, Pia S.;Lei, Xia;Wong, G. William
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因素。在这里，我们揭示了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，具有以前未知的功能。在肥胖人群中，循环CTRP7水平显著升高，并与体重指数、葡萄糖、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。肥胖人群肝脏中CTRP7的表达也显著上调，且与糖异生基因呈正相关。在小鼠中，Ctrp7的表达通过禁食和再喂养以及饮食诱导的肥胖在不同组织中受到差异调节。采用基因功能缺失小鼠模型来确定代谢稳态对CTRP7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幼崽无法区分。然而，在摄入高脂肪饮食的肥胖雄性小鼠中，CTRP7缺乏会减弱胰岛素抵抗和增强葡萄糖耐量，这些影响与体重、代谢率和身体活动水平无关。ctrp7缺陷小鼠的糖代谢改善与脂肪组织炎症减少、肝纤维化、细胞氧化和内质网应激减少有关。这些结果提供了CTRP7水平升高与葡萄糖代谢受损之间的联系，葡萄糖代谢受损通常与肥胖有关。在肥胖和糖尿病的情况下，抑制CTRP7的作用可能会带来有益的代谢结果。
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 CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 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.