School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, NSW, 2007, Australia,
Diabetologia. 2014 Mar;57(3):614-22. doi: 10.1007/s00125-013-3132-5. Epub 2013 Dec 14.
AIMS/HYPOTHESIS: Maternal obesity leads to increased adiposity, hyperlipidaemia and glucose intolerance in offspring. The analogue of glucagon-like peptide-1, exendin-4 (Ex-4), has been shown to induce weight loss in both adolescence and adulthood. We hypothesised that, in rats, daily injection of Ex-4 would reduce body fat and improve metabolic disorders in offspring from obese dams, especially those consuming a high-fat diet (HFD).
Female Sprague Dawley rats were fed chow or an HFD for 5 weeks before mating, and throughout gestation and lactation. At postnatal day 20, male pups from HFD-fed mothers were weaned onto chow or HFD and those from chow-fed mothers were fed chow. Within each dietary group, half of the pups were injected with Ex-4 (15 μg/kg/day i.p.) for 6 weeks, while the other half received saline.
Maternal obesity alone or combined with postweaning HFD consumption led to increased adiposity, hyperinsulinaemia, hyperlipidaemia, inflammation and impaired regulation of hypothalamic appetite regulators by glucose in offspring, while glucose intolerance was only observed in HFD-fed rats from obese dams. Ex-4 injection significantly reduced adiposity, hyperlipidaemia and insulin resistance in HFD-fed rats from obese dams. It also restored glucose tolerance and the lipid-lowering effect of blood glucose. However, Ex-4 did not change hypothalamic appetite regulation or the response of appetite regulators to hyperglycaemia. Liver and adipose inflammatory cytokine expression was significantly reduced by Ex-4.
CONCLUSIONS/INTERPRETATION: Ex-4 reversed the detrimental impact of maternal obesity on lipid and glucose metabolism in offspring regardless of diet, supporting its potential application in reducing metabolic disorders in high-risk populations.
目的/假设：母体肥胖会导致后代脂肪增加、血脂异常和葡萄糖耐量受损。胰高血糖素样肽-1类似物 exendin-4（Ex-4）已被证明可在青春期和成年期引起体重减轻。我们假设，在大鼠中，每天注射 Ex-4 将减少肥胖母鼠后代的体脂肪，并改善其代谢紊乱，尤其是那些摄入高脂肪饮食（HFD）的后代。
雌性 Sprague Dawley 大鼠在交配前、妊娠和哺乳期均喂食标准饮食或 HFD 5 周。在产后第 20 天，来自 HFD 喂养母亲的雄性幼崽断奶为标准饮食或 HFD，而来自标准饮食喂养母亲的幼崽则继续喂食标准饮食。在每个饮食组中，一半的幼崽接受 Ex-4（15 μg/kg/天腹腔注射）治疗 6 周，而另一半则接受生理盐水注射。
母体肥胖本身或与断奶后 HFD 摄入相结合会导致后代脂肪增加、高胰岛素血症、血脂异常、炎症和下丘脑食欲调节剂对葡萄糖的调节受损，而葡萄糖耐量仅在肥胖母鼠喂养 HFD 的幼崽中观察到。Ex-4 注射显著降低了肥胖母鼠喂养 HFD 的后代的体脂肪、血脂异常和胰岛素抵抗。它还恢复了葡萄糖耐量和血糖降低血脂的作用。然而，Ex-4 并未改变下丘脑食欲调节或食欲调节剂对高血糖的反应。Ex-4 显著降低了肝脏和脂肪组织中炎性细胞因子的表达。
结论/解释：Ex-4 逆转了母体肥胖对后代脂质和葡萄糖代谢的不利影响，无论饮食如何，这支持了其在降低高危人群代谢紊乱中的潜在应用。
