Rajala Michael W, Qi Yong, Patel Hiral R, Takahashi Nobuhiko, Banerjee Ronadip, Pajvani Utpal B, Sinha Madhur K, Gingerich Ronald L, Scherer Philipp E, Ahima Rexford S
Department of Cell Biology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Diabetes. 2004 Jul;53(7):1671-9. doi: 10.2337/diabetes.53.7.1671.
Resistin was originally reported as an adipose tissue-specific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance. More recently, we have shown that ablation of the resistin gene in mice decreased fasting glucose through impairment of gluconeogenesis, while resistin treatment in these knockout mice increased hepatic glucose production. However, the link between resistin and glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased, resistin mRNA expression in obese and diabetic mice. To better understand the regulation of resistin, we developed a sensitive and specific RIA resistin that could accurately measure serum resistin levels in several mouse models. We show that while resistin mRNA is indeed suppressed in obese mice, the circulating resistin level is significantly elevated and positively correlated with insulin, glucose, and lipids. Both resistin mRNA expression and protein levels in Lep(ob/ob) mice are suppressed by leptin treatment in parallel with reductions in glucose and insulin. In wild-type mice, serum resistin increases after nocturnal feeding, concordant with rising levels of insulin. Resistin mRNA and protein levels decline in parallel with glucose and insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether resistin is causally related to insulin and glucose. Adipose resistin expression and serum resistin increased in response to hyperinsulinemia and further in response to hyperglycemia. Taken together, these findings suggest that the nutritional regulation of resistin and changes in resistin gene expression and circulating levels in obesity are mediated, at least in part, through insulin and glucose.
抵抗素最初被报道为一种脂肪组织特异性激素，它在肥胖与糖尿病之间建立了联系。肥胖小鼠体内抵抗素蛋白水平升高，而胰岛素增敏剂噻唑烷二酮可使其降低。对抵抗素进行免疫中和可改善饮食诱导的肥胖小鼠的胰岛素敏感性，而给予外源性抵抗素则会诱导胰岛素抵抗。最近，我们发现敲除小鼠的抵抗素基因会通过损害糖异生作用降低空腹血糖，而在这些基因敲除小鼠中给予抵抗素则会增加肝脏葡萄糖生成。然而，肥胖和糖尿病小鼠中抵抗素mRNA表达降低而非升高的研究对抵抗素与葡萄糖稳态之间的联系提出了质疑。为了更好地理解抵抗素的调节机制，我们开发了一种灵敏且特异的抵抗素放射免疫分析法（RIA），它能够准确测量多种小鼠模型中的血清抵抗素水平。我们发现，虽然肥胖小鼠体内抵抗素mRNA确实受到抑制，但循环中的抵抗素水平却显著升高，且与胰岛素、葡萄糖和脂质呈正相关。瘦素治疗可使肥胖（ob/ob）小鼠的抵抗素mRNA表达和蛋白水平同时受到抑制，同时血糖和胰岛素水平也会降低。在野生型小鼠中，夜间进食后血清抵抗素会增加，这与胰岛素水平的升高相一致。禁食期间，抵抗素mRNA和蛋白水平会随葡萄糖和胰岛素水平的下降而平行下降，重新进食后则会恢复。我们进行了钳夹实验以确定抵抗素是否与胰岛素和葡萄糖存在因果关系。脂肪组织中的抵抗素表达和血清抵抗素会因高胰岛素血症而增加，在高血糖时进一步增加。综上所述，这些发现表明，抵抗素的营养调节以及肥胖状态下抵抗素基因表达和循环水平的变化至少部分是通过胰岛素和葡萄糖介导的。
