Hazel Mark, Cooksey Robert C, Jones Deborah, Parker Glendon, Neidigh John L, Witherbee Bryan, Gulve Eric A, McClain Donald A
Department of Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
Endocrinology. 2004 May;145(5):2118-28. doi: 10.1210/en.2003-0812. Epub 2003 Dec 18.
Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and beta-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-D-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNF alpha and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor gamma decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.
先前研究表明，转基因小鼠肌肉和脂肪组织中己糖胺合成限速酶（谷氨酰胺：果糖-6-磷酸酰胺转移酶）的过表达会导致胰岛素抵抗和高瘦素血症。来自转基因小鼠的离体肌肉在体外并无胰岛素抵抗，这表明肌肉胰岛素抵抗可能由脂肪组织中的可溶性因子介导。为剖析肌肉和脂肪对己糖胺诱导的胰岛素抵抗的相对作用，我们使谷氨酰胺：果糖-6-磷酸酰胺转移酶在aP2启动子控制下在脂肪中特异性过表达2.5倍。转基因小鼠的空腹血糖、胰岛素和甘油三酯未发生变化；瘦素和β-羟基丁酸水平分别升高了91%和29%。禁食的转基因小鼠在体内有轻度葡萄糖不耐受和骨骼肌胰岛素抵抗。在禁食的转基因小鼠中，高胰岛素血症时的葡萄糖处置率在雌性中降低了27%，在雄性中降低了10%。雌性转基因小鼠肌肉对2-脱氧-D-葡萄糖的摄取减少了45%，雄性减少了21%。禁食的转基因小鼠血清脂联素也较低，雌性降低了37%，雄性降低了22%。禁食的转基因小鼠脂肪组织中肿瘤坏死因子α和抵抗素mRNA水平未改变；瘦素mRNA水平升高，过氧化物酶体增殖物激活受体γ降低。为进一步探究脂联素与胰岛素敏感性之间的关系，我们检测了禁食24小时后再喂食6小时的小鼠。再喂食野生型小鼠会导致血清脂联素降低和瘦素升高。然而，在转基因小鼠中，再喂食对这些激素的调节作用在脂联素方面丧失，在瘦素方面减弱。再喂食的转基因雌性和雄性小鼠在再喂食状态下不再表现出血清脂联素降低，并且由于胰岛素和葡萄糖水平降低或未改变，它们不再有胰岛素抵抗。我们得出结论，脂肪中己糖胺水平升高，模拟了过多的营养输送，足以导致骨骼肌胰岛素抵抗。血清脂联素的变化与转基因动物的胰岛素抵抗相关。
