Harmancey Romain, Senard Jean-Michel, Rouet Philippe, Pathak Atul, Smih Fatima
I2MR INSERM U858, Laboratoire de Pharmacologie, Faculté de Médecine, Universite Paul Sabatier, Institut Louis Bugnard IFR31, 37 allées Jules Guesde, 31000 Toulouse, France.
Diabetes. 2007 Mar;56(3):553-63. doi: 10.2337/db06-0857.
We generated preadipocyte cell lines impaired in adrenomedullin production through integration of an adrenomedullin small interfering RNA expression vector. The reduction of adrenomedullin synthesis strongly accelerated adipose differentiation. These results were bolstered when overexpression of active adrenomedullin peptide led to delayed differentiation. Therefore, we propose that adrenomedullin is an antiadipogenic factor. Moreover, we checked whether insulin, a proadipogenic factor, regulates expression of adrenomedullin. We observed that insulin had an inhibitory effect on adrenomedullin expression in isolated human adipocyte cells. This response was dose dependent and was reversed by resistin, a new anti-insulin agent. We quantified circulating adrenomedullin in healthy obese patients and observed a threefold increase of adrenomedullin compared with lean patients. Furthermore, adrenomedullin plasma levels are negatively correlated to plasma insulin levels in these obese patients. The insulin inhibitory response was also observed in vivo in Sprague-Dawley rats but not in the insulin-resistant Zucker rat, suggesting that adrenomedullin expression is upregulated in insulin-resistant adipose cells. Using adrenomedullin promoter-luciferase reporter gene constructs, we have shown that the adrenomedullin response to insulin is mediated by insulin-responsive elements. These findings provide new insight into fat mass development and the relationship between obesity and elevated circulating adrenomedullin levels in diabetic patients.
我们通过整合肾上腺髓质素小干扰RNA表达载体，构建了肾上腺髓质素生成受损的前脂肪细胞系。肾上腺髓质素合成的减少强烈加速了脂肪分化。当活性肾上腺髓质素肽的过表达导致分化延迟时，这些结果得到了进一步支持。因此，我们提出肾上腺髓质素是一种抗脂肪生成因子。此外，我们检测了促脂肪生成因子胰岛素是否调节肾上腺髓质素的表达。我们观察到胰岛素对分离的人脂肪细胞中肾上腺髓质素的表达具有抑制作用。这种反应呈剂量依赖性，并且被一种新的抗胰岛素剂抵抗素所逆转。我们对健康肥胖患者的循环肾上腺髓质素进行了定量分析，发现与瘦患者相比，肥胖患者的肾上腺髓质素增加了两倍。此外，在这些肥胖患者中，肾上腺髓质素血浆水平与血浆胰岛素水平呈负相关。在Sprague-Dawley大鼠体内也观察到了胰岛素的抑制反应，但在胰岛素抵抗的Zucker大鼠中未观察到，这表明肾上腺髓质素的表达在胰岛素抵抗的脂肪细胞中上调。使用肾上腺髓质素启动子-荧光素酶报告基因构建体，我们表明肾上腺髓质素对胰岛素的反应是由胰岛素反应元件介导的。这些发现为脂肪量的发展以及糖尿病患者肥胖与循环肾上腺髓质素水平升高之间的关系提供了新的见解。
