Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center, University of California- Los Angeles, Los Angeles, CA 90095-1752, USA.
Endocrinology. 2013 Jan;154(1):102-13. doi: 10.1210/en.2012-1640. Epub 2012 Nov 26.
Enhanced de novo lipogenesis (DNL), an adult hepatic adaption, is seen with high carbohydrate or low-fat diets. We hypothesized that ad libitum intake after prenatal calorie restriction will result in adult-onset glucose intolerance and enhanced DNL with modified lipid metabolic gene expression profile. Stable isotopes were used in 15-month-old adult male rat offspring exposed to prenatal (IUGR), pre- and postnatal (IPGR), or postnatal (PNGR) caloric restriction vs. controls (CON). IUGR vs. CON were heavier with hepatomegaly but unchanged visceral white adipose tissue (WAT), glucose intolerant with reduced glucose-stimulated insulin secretion (GSIS), pancreatic β-cell mass, and total glucose clearance rate but unsuppressed hepatic glucose production. Liver glucose transporter (Glut) 1 and DNL increased with decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase but increased WAT fatty acid transport protein-1 and peroxisomal proliferator-activated receptor-γ, resistin, and visfatin gene expression. In contrast, PNGR and IPGR were lighter, had reduced visceral WAT, and were glucose tolerant with unchanged hepatic glucose production but with increased GSIS, β-cell mass, glucose clearance rate, and WAT insulin receptor. Hepatic Glut1 and DNL were also increased in lean IPGR and PNGR with increased hepatic ACC, phosphorylated ACC, and pAMPK and reduced WAT fatty acid transport protein-1, peroxisomal proliferator-activated receptor-γ, and ACCα. We conclude the following: 1) the heavy, glucose-intolerant and insulin-resistant IUGR adult phenotype is ameliorated by postnatal caloric restriction; 2) increased DNL paralleling hepatic Glut1 is a biomarker of exposure to early caloric restriction rather than the adult metabolic status; 3) hepatic lipid enzyme expression reflects GSIS rather than DNL; and 4) WAT gene expression reflects an obesogenic vs. lean phenotype.
增强的从头脂肪生成（DNL）是一种适应成人肝脏的现象，发生在高碳水化合物或低脂肪饮食中。我们假设在产前热量限制后自由摄入会导致成人发病的葡萄糖不耐受和增强的 DNL，并伴有脂质代谢基因表达谱的改变。稳定同位素用于研究暴露于产前（IUGR）、产前和产后（IPGR）或产后（PNGR）热量限制的 15 个月大的成年雄性大鼠后代，与对照组（CON）相比。与 CON 相比，IUGR 体重更重，肝脏肿大，但内脏白色脂肪组织（WAT）不变，葡萄糖耐量降低，葡萄糖刺激胰岛素分泌（GSIS）减少，胰岛β细胞质量和总葡萄糖清除率降低，但肝葡萄糖生成未受抑制。肝脏葡萄糖转运蛋白（Glut）1 和 DNL 增加，而肝乙酰辅酶 A 羧化酶（ACC）和脂肪酸合成酶减少，但 WAT 脂肪酸转运蛋白-1 和过氧化物酶体增殖物激活受体-γ、抵抗素和内脂素基因表达增加。相比之下，PNGR 和 IPGR 体重较轻，内脏 WAT 减少，葡萄糖耐量正常，肝葡萄糖生成不变，但 GSIS、β细胞质量、葡萄糖清除率和 WAT 胰岛素受体增加。IPGR 和 PNGR 中也增加了 lean，肝 ACC、磷酸化 ACC、pAMPK 增加，WAT 脂肪酸转运蛋白-1、过氧化物酶体增殖物激活受体-γ和 ACCα减少，同时也增加了肝脏 Glut1 和 DNL。我们得出以下结论：1）产后热量限制改善了体重较重、葡萄糖不耐受和胰岛素抵抗的 IUGR 成年表型；2）增加的 DNL 与肝脏 Glut1 平行，是暴露于早期热量限制的生物标志物，而不是成人代谢状态；3）肝脂质酶表达反映 GSIS 而不是 DNL；4）WAT 基因表达反映肥胖表型与 lean 表型。
