Einstein Francine H, Fishman Sigal, Bauman Jeffery, Thompson Reid F, Huffman Derek M, Atzmon Gil, Barzilai Nir, Muzumdar Radhika H
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
FASEB J. 2008 Oct;22(10):3450-7. doi: 10.1096/fj.08-109041. Epub 2008 Jun 19.
Calorie restriction improves life span whereas nutrient excess leads to obesity and unfavorable metabolic consequences, supporting the role for a cellular "nutrient sensor" in aging. Hexosamine biosynthetic pathway (HBP) is a candidate nutrient-sensing pathway. We hypothesized that altered nutrient sensing (by HBP) with age may provide a link among aging, nutrient flux, and insulin resistance. Using a hyperinsulinemic clamp in young rats, we show that experimental activation of HBP, through the systemic infusion of glucosamine, induced severe insulin resistance (36% decline in peripheral insulin action; P<0.05), increased adipose tissue gene expression of fat-derived peptides (PAI-1 by 4-fold, angiotensinogen 3-fold, leptin 2-fold, resistin 4-fold, and adiponectin 4-fold; P<0.01 compared with young saline-infused), and enhanced glycosylation of transcription factors, thus mimicking a physiological and biological phenotype of aging. We further demonstrate a greater activation of nutrient-sensing HBP with age in both old ad libitum-fed and calorie-restricted rats. Interestingly, old calorie-restricted animals rapidly develop insulin resistance when exposed to glucosamine, despite their "young" phenotype. These results suggest that altered nutrient sensing by HBP with age may be the link among nutrients, insulin resistance, and age-related diabetes.
热量限制可延长寿命，而营养过剩则会导致肥胖和不良的代谢后果，这支持了细胞“营养传感器”在衰老过程中的作用。己糖胺生物合成途径（HBP）是一种候选的营养感应途径。我们假设，随着年龄增长，（由HBP介导的）营养感应改变可能在衰老、营养通量和胰岛素抵抗之间建立联系。通过对年轻大鼠进行高胰岛素钳夹实验，我们发现，通过全身输注氨基葡萄糖来实验性激活HBP，会诱导严重的胰岛素抵抗（外周胰岛素作用下降36%；P<0.05），增加脂肪组织中脂肪衍生肽的基因表达（纤溶酶原激活物抑制剂-1增加4倍，血管紧张素原增加3倍，瘦素增加2倍，抵抗素增加4倍，脂联素增加4倍；与输注生理盐水的年轻大鼠相比，P<0.01），并增强转录因子的糖基化，从而模拟衰老的生理和生物学表型。我们进一步证明，在自由进食的老年大鼠和热量限制的老年大鼠中，随着年龄增长，营养感应HBP的激活程度更高。有趣的是，尽管老年热量限制动物具有“年轻”的表型，但当暴露于氨基葡萄糖时，它们会迅速出现胰岛素抵抗。这些结果表明，随着年龄增长，HBP介导的营养感应改变可能是营养、胰岛素抵抗和年龄相关性糖尿病之间的联系。
