Hales C N, Ozanne S E
Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
J Physiol. 2003 Feb 15;547(Pt 1):5-10. doi: 10.1113/jphysiol.2002.024406. Epub 2002 Aug 2.
Many epidemiological studies have now shown a strongly increased risk of developing type 2 diabetes and the metabolic syndrome in adults who as neonates showed signs of poor early (fetal and early postnatal) growth. The thrifty phenotype hypothesis was proposed to provide a conceptual and experimentally testable basis of these relationships. We have used protein restriction of rat dams, as a means to test this hypothesis. In vivo and in vitro studies of the growth-restricted offspring of such pregnancies have provided findings showing remarkable parallels with the human conditions. Permanent changes in the expression of regulatory proteins in liver, muscle and adipose tissue provide at least part of the explanation of the changes observed and offer potential markers for testing in the human context. These studies have also raised the question as to whether 'catch up' growth following early growth retardation may add to the risks posed by this early handicap. Male rats growth-retarded during fetal life and cross-fostered shortly after birth to normal lactating dams reach normal body and organ weights by weaning but have a reduced longevity. This finding raises the possibility that catch up growth, whilst potentially beneficial in the short term, may be detrimental to long-term survival. Human epidemiological studies may point in the same direction. Work by others on other models of early growth restriction have produced similar, although more limited, data. These findings raise the interesting possibility that the response to fetal stress, be it nutritional or other, may evoke a somewhat restricted and uniform pattern of adaptive response.
许多流行病学研究现已表明，在新生儿期出现早期（胎儿期和出生后早期）生长不良迹象的成年人患2型糖尿病和代谢综合征的风险大幅增加。节俭表型假说是为这些关系提供一个概念性且可通过实验检验的基础而提出的。我们通过对大鼠母鼠进行蛋白质限制来检验这一假说。对这类妊娠所生生长受限后代的体内和体外研究结果显示，与人类情况有显著相似之处。肝脏、肌肉和脂肪组织中调节蛋白表达的永久性变化至少部分解释了所观察到的变化，并为在人类环境中进行检测提供了潜在标志物。这些研究还提出了一个问题，即早期生长迟缓后的“追赶”生长是否会增加这种早期缺陷所带来的风险。在胎儿期生长迟缓且出生后不久寄养到正常哺乳母鼠的雄性大鼠，到断奶时体重和器官重量达到正常，但寿命缩短。这一发现增加了一种可能性，即追赶生长虽然在短期内可能有益，但可能对长期生存有害。人类流行病学研究可能也指向同一方向。其他人在其他早期生长受限模型上的研究也得出了类似但更有限的数据。这些发现引发了一个有趣的可能性，即对胎儿应激（无论是营养性还是其他方面的）的反应可能会引发一种有点受限且统一的适应性反应模式。
