Zemel M B, Kim J H, Woychik R P, Michaud E J, Kadwell S H, Patel I R, Wilkison W O
Department of Nutrition, University of Tennessee, Knoxville 37996-1900, USA.
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4733-7. doi: 10.1073/pnas.92.11.4733.
Several dominant mutations at the agouti locus in the mouse cause a syndrome of marked obesity, hyperinsulinemia, and insulin resistance. Although it is known that the agouti gene is expressed in an ectopic manner in these mutants, the precise mechanism by which the agouti gene product mediates these effects is unclear. Since intracellular Ca2+ is believed to play a role in mediating insulin action and dysregulation of Ca2+ flux is observed in diabetic animals and humans, we examined the status of intracellular Ca2+ in mice carrying the dominant agouti allele, viable yellow (Avy). We show here that in mice carrying this mutation, the intracellular free calcium concentration ([Ca2+]i) is elevated in skeletal muscle, and the degree of elevation is closely correlated with the degree to which the mutant traits are expressed in individual animals. Moreover, we demonstrate that the agouti gene product is capable of inducing increased [Ca2+]i in cultured and freshly isolated skeletal muscle myocytes from wild-type mice. Based on these findings, we present a model in which we propose that the agouti polypeptide promotes insulin resistance in mutant animals through its ability to increase [Ca2+]i.
小鼠刺鼠基因座上的几个显性突变会导致明显肥胖、高胰岛素血症和胰岛素抵抗综合征。尽管已知刺鼠基因在这些突变体中以异位方式表达，但刺鼠基因产物介导这些效应的确切机制尚不清楚。由于细胞内Ca2+被认为在介导胰岛素作用中起作用，并且在糖尿病动物和人类中观察到Ca2+通量失调，我们研究了携带显性刺鼠等位基因——存活黄色（Avy）的小鼠细胞内Ca2+的状态。我们在此表明，在携带这种突变的小鼠中，骨骼肌中的细胞内游离钙浓度（[Ca2+]i）升高，并且升高程度与单个动物中突变性状的表达程度密切相关。此外，我们证明刺鼠基因产物能够在来自野生型小鼠的培养和新鲜分离的骨骼肌肌细胞中诱导[Ca2+]i增加。基于这些发现，我们提出了一个模型，其中我们认为刺鼠多肽通过其增加[Ca2+]i的能力在突变动物中促进胰岛素抵抗。
