School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
J Neuroendocrinol. 2019 Aug;31(8):e12757. doi: 10.1111/jne.12757. Epub 2019 Jul 15.
The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippocampal microglia that are hyper-responsive to an immune challenge in adulthood. However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippocampus. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity.
生命早期的环境对大脑发育的编程很重要，此时的代谢紊乱会产生持久的影响。之前，我们已经表明，新生大鼠在生命的前 3 周过度喂养会维持肥胖到成年。新生期过度喂养还会导致下丘脑和海马体的小胶质细胞被预先激活，使其在成年后对免疫挑战更加敏感。然而，这种小胶质细胞的预激活是否导致肥胖表型，以及是否有可能逆转肥胖或小胶质细胞的预激活尚不清楚。在本研究中，我们假设在青少年期（出生后第 21-42 天）用米诺环素进行干预可以使小胶质细胞的预激活和肥胖正常化。为了在新生 Wistar 大鼠中诱导肥胖，我们操纵了它们的哺乳窝仔数，产生了 12 只（对照组）或 4 只（新生期过度喂养）的窝仔。断奶后，我们每隔一天腹腔注射米诺环素 3 周，并在脂多糖免疫挑战后 24 小时检查身体成分和小胶质细胞谱。如前所述，新生期过度喂养导致体重持续增加。然而，米诺环素未能逆转这种效果。米诺环素确实逆转了与进食相关的下丘脑区域的小胶质细胞预激活，对海马体中的促炎细胞因子和小胶质细胞数量及形态的影响最小。因此，新生期过度喂养对小胶质细胞预激活的编程效应可以通过生命后期的米诺环素得到改善。然而，新生期过度喂养后持续存在的肥胖可能不是由下丘脑炎症和小胶质细胞活性的变化引起的。
