C1q/TNF-related Protein-12 (CTRP12), a Novel Adipokine That Improves Insulin Sensitivity and Glycemic Control in Mouse Models of Obesity and Diabetes
C1q/TNF-related Protein-12 (CTRP12), a Novel Adipokine That Improves Insulin Sensitivity and Glycemic Control in Mouse Models of Obesity and Diabetes
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DOI：
10.1074/jbc.m111.303651
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发表时间：
2012-03-23
影响因子：
4.8
通讯作者：
Wong, G. William
中科院分区：
文献类型：
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作者：
Wei, Zhikui;Peterson, Jonathan M.;Wong, G. William
尽管胰岛素抵抗和2型糖尿病普遍存在，但其潜在机制仍不完全清楚。许多分泌的内分泌因子及其介导的组织间相互作用在2型糖尿病中失调。在这里，我们描述了CTRP12，一种具有抗糖尿病作用的新型脂肪因子。在肥胖小鼠模型中，CTRP12的mRNA和循环水平降低，但在抗糖尿病药物罗格列酮的作用下，其在脂肪细胞中的表达升高。重组蛋白给药使循环中CTRP12水平适度升高，足以降低野生型、瘦素缺乏型和饮食诱导型肥胖小鼠的血糖。通过腺病毒介导的血清CTRP12表达短期升高可改善肥胖和糖尿病小鼠的葡萄糖耐量和胰岛素敏感性，使高血糖和高胰岛素血症正常化，并降低餐后胰岛素抵抗。CTRP12改善胰岛素敏感性部分是通过增强肝脏和脂肪组织中的胰岛素信号传导。此外，CTRP12也以与胰岛素无关的方式起作用；在培养的肝细胞和脂肪细胞中，CTRP12直接激活PI3K-Akt信号通路，分别抑制糖异生和促进葡萄糖摄取。综上所述，这些数据表明CTRP12是一种新的代谢调节剂，通过胰岛素依赖和独立的机制将脂肪组织与全身葡萄糖稳态联系起来。
Despite the prevalence of insulin resistance and type 2 diabetes mellitus, their underlying mechanisms remain incompletely understood. Many secreted endocrine factors and the intertissue cross-talk they mediate are known to be dysregulated in type 2 diabetes mellitus. Here, we describe CTRP12, a novel adipokine with anti-diabetic actions. The mRNA and circulating levels of CTRP12 were decreased in a mouse model of obesity, but its expression in adipocytes was increased by the anti-diabetic drug rosiglitazone. A modest rise in circulating levels of CTRP12 by recombinant protein administration was sufficient to lower blood glucose in wild-type, leptin-deficient ob/ob, and diet-induced obese mice. A short term elevation of serum CTRP12 by adenovirus-mediated expression improved glucose tolerance and insulin sensitivity, normalized hyperglycemia and hyperinsulinemia, and lowered postprandial insulin resistance in obese and diabetic mice. CTRP12 improves insulin sensitivity in part by enhancing insulin signaling in the liver and adipose tissue. Further, CTRP12 also acts in an insulin-independent manner; in cultured hepatocytes and adipocytes, CTRP12 directly activated the PI3K-Akt signaling pathway to suppress gluconeogenesis and promote glucose uptake, respectively. Collectively, these data establish CTRP12 as a novel metabolic regulator linking adipose tissue to whole body glucose homeostasis through insulin-dependent and independent mechanisms.