Hochgeschwender Ute, Costa Jessica L, Reed Peggy, Bui Stephanie, Brennan Miles B
Oklahoma Medical Research Foundation, , Oklahoma City, Oklahoma 73104.
Endocrinology. 2003 Dec;144(12):5194-202. doi: 10.1210/en.2003-1008. Epub 2003 Sep 11.
Prolonged obesity frequently leads to insulin resistance and, eventually, to diabetes. This relationship reflects the integration of fat stores and carbohydrate metabolism and the coordination of central nervous system functions, e.g. appetite, and peripheral metabolism. Recent work suggests that the melanocortin system is involved in this integration; specifically, central administration of melanocyte-stimulating hormone (MSH) decreases, whereas lack of central MSH signaling increases, peripheral insulin resistance. Here we asked whether MSH acting in the periphery has a complementary role in insulin resistance. We tested this in a mouse model where the proopiomelanocortin (POMC) gene encoding all of the melanocortins has been genetically deleted. The homozygous POMC-null mouse lacks central as well as peripheral MSH signaling; in addition, it lacks adrenal glands and thus is devoid of corticosterone and epinephrine. Here we report that homozygous POMC mutants have normal serum levels of insulin, normal fasting levels of glucose, and normal clearance of glucose in glucose tolerance tests. Thus, insulin production and sensitivity and glucose uptake in peripheral tissues are functioning normally. However, we found a striking inability of the homozygous POMC mutants to recover from insulin-induced hypoglycemia. This defect was in the glucagon-mediated counterregulatory response. Both peripheral administration of an MSH analog and supplementation with corticosterone alleviated the hypoglycemia after insulin challenge, but did not make the obese POMC mutant mice diabetic. We conclude that, similar to the regulation of body weight homeostasis, the regulation of glucose homeostasis requires the integration of both central and peripheral melanocortin signaling systems.
长期肥胖常常会导致胰岛素抵抗，最终引发糖尿病。这种关系反映了脂肪储存与碳水化合物代谢的整合以及中枢神经系统功能（如食欲）与外周代谢的协调。最近的研究表明，黑皮质素系统参与了这种整合；具体而言，中枢给予促黑素细胞激素（MSH）会降低外周胰岛素抵抗，而缺乏中枢MSH信号则会增加外周胰岛素抵抗。在这里，我们探讨了外周作用的MSH在胰岛素抵抗中是否具有互补作用。我们在一个编码所有黑皮质素的阿黑皮素原（POMC）基因已被基因敲除的小鼠模型中对此进行了测试。纯合POMC基因缺失小鼠缺乏中枢和外周MSH信号；此外，它没有肾上腺，因此缺乏皮质酮和肾上腺素。我们在此报告，纯合POMC突变体的胰岛素血清水平正常、空腹血糖水平正常，并且在葡萄糖耐量试验中葡萄糖清除正常。因此，外周组织中的胰岛素产生、敏感性和葡萄糖摄取功能正常。然而，我们发现纯合POMC突变体从胰岛素诱导的低血糖中恢复的能力明显受损。这种缺陷在于胰高血糖素介导的反调节反应。外周给予MSH类似物和补充皮质酮均可减轻胰岛素激发后的低血糖，但并未使肥胖的POMC突变小鼠患糖尿病。我们得出结论，与体重稳态的调节类似，葡萄糖稳态的调节需要中枢和外周黑皮质素信号系统的整合。
