Mynatt R L, Miltenberger R J, Klebig M L, Zemel M B, Wilkinson J E, Wilkinson W O, Woychik R P
Biology Division, Oak Ridge National Laboratory, TN 37831-8080, USA.
Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):919-22. doi: 10.1073/pnas.94.3.919.
The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.
刺豚鼠基因产物是一种分泌蛋白，以旁分泌方式作用于哺乳动物的毛色调节。小鼠刺豚鼠基因座上的几个显性突变导致刺豚鼠异位、普遍表达，从而引发与成年期肥胖和非胰岛素依赖型糖尿病类似的病症。人类刺豚鼠蛋白与小鼠刺豚鼠蛋白的同源性为85%；然而，与小鼠刺豚鼠基因不同，人类刺豚鼠通常在脂肪组织中表达。为了探究刺豚鼠在人类脂肪组织中的表达是否具有生理相关性，研究人员构建了在脂肪组织中表达刺豚鼠的转基因小鼠。与大多数人类相似，这些小鼠不会肥胖或患糖尿病。然而，我们发现，每日注射胰岛素会显著增加脂肪组织中表达刺豚鼠的转基因品系的体重增加，但对非转基因小鼠却没有这种影响。这些结果表明，胰岛素会引发肥胖，且脂肪组织中刺豚鼠的表达会增强这种作用。因此，研究刺豚鼠在小鼠肥胖和非胰岛素依赖型糖尿病中的作用，对于理解人类肥胖的病理生理学具有重要意义。
