Nyirenda Moffat J, Carter Roderick, Tang Justin I, de Vries Annick, Schlumbohm Christina, Hillier Stephen G, Streit Frank, Oellerich Michael, Armstrong Victor W, Fuchs Eberhard, Seckl Jonathan R
Endocrinology Unit, Queen's Medical Research Institute, University of Edinburgh, U.K.
Diabetes. 2009 Dec;58(12):2873-9. doi: 10.2337/db09-0873. Epub 2009 Aug 31.
Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11beta-HSD1 dysregulation are unknown. Here, we tested whether 11beta-HSD1 expression, like the metabolic syndrome, is "programmed" by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.
We used a "fetal programming" paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11beta-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.
Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11beta-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous-but not visceral-fat. The increase in 11beta-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.
These data suggest that long-term upregulation of 11beta-HSD1 in metabolically active tissues may follow prenatal "stress" hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.
近期针对人类肥胖及动物肥胖模型的研究表明，11β-羟类固醇脱氢酶1型（11β-HSD1）在脂肪组织中的活性增强，这会放大局部组织的糖皮质激素浓度。11β-HSD1失调的原因尚不清楚。在此，我们在普通狨猴这一非人灵长类动物模型中测试了11β-HSD1的表达是否像代谢综合征一样，由产前环境事件“编程”。
我们采用了一种“胎儿编程”范式，即孕期短暂暴露于糖皮质激素会导致后代出现代谢综合征。怀孕的狨猴在妊娠早期或晚期口服合成糖皮质激素地塞米松1周，或给予赋形剂。在后代4个月和24个月大时检测组织中11β-HSD1和糖皮质激素受体mRNA的表达。
仅在妊娠晚期给予产前地塞米松，会导致肝脏、胰腺和皮下脂肪（而非内脏脂肪）中11β-HSD1 mRNA表达和活性早期且持续升高。11β-HSD1的增加发生在动物出现肥胖或代谢综合征明显特征之前。与啮齿动物不同，子宫内暴露于地塞米松并未改变狨猴代谢组织中糖皮质激素受体的表达。
这些数据表明，代谢活跃组织中11β-HSD1的长期上调可能是产前“应激”激素暴露所致，并提示了成人肥胖和代谢综合征胎儿起源的一种新机制。
