Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Spain.
J Neuroendocrinol. 2011 Apr;23(4):365-70. doi: 10.1111/j.1365-2826.2011.02113.x.
Much attention has been drawn to the possible involvement of hypothalamic inflammation in the pathogenesis of metabolic disorders, especially in response to a high-fat diet. Microglia, the macrophages of the central nervous system, can be activated by proinflammatory signals resulting in the local production of specific interleukins and cytokines, which in turn could exacerbate the pathogenic process. Because obesity itself is considered to be a state of chronic inflammation, we evaluated whether being overweight results in microglial activation in the hypothalamus of rats on a normal diet. Accordingly, we used a model of neonatal overnutrition that entailed adjustment of litter size at birth (small litters: four pups/dam versus normal litters: 12 pups/dam) and resulted in a 15% increase in bodyweight and increased circulating leptin levels at postnatal day 60. Rats that were overnourished during neonatal life had an increased number of activated microglia in specific hypothalamic areas such as the ventromedial hypothalamus, which is an important site for metabolic control. However, this effect was not confined to the hypothalamus because significant microglial activation was also observed in the cerebellar white matter. There was no change in circulating tumour necrosis factor (TNF) α levels or TNFα mRNA levels in either the hypothalamus or cerebellum. Interleukin (IL)6 protein levels were higher in both the hypothalamus and cerebellum, with no change in IL6 mRNA levels. Because circulating IL6 levels were elevated, this rise in central IL6 could be a result of increased uptake. Thus, activation of microglia occurs in adult rats exposed to neonatal overnutrition and a moderate increase in weight gain on a normal diet, possibly representing a secondary response to systemic inflammation. Moreover, this activation could result in local changes in specific hypothalamic nuclei that in turn further deregulate metabolic homeostasis.
人们已经关注到下丘脑炎症可能与代谢紊乱的发病机制有关，尤其是在高脂肪饮食的刺激下。小胶质细胞是中枢神经系统的巨噬细胞，能被促炎信号激活，从而导致特定白细胞介素和细胞因子的局部产生，进而可能加重致病过程。由于肥胖本身被认为是一种慢性炎症状态，我们评估了超重是否会导致正常饮食的大鼠下丘脑小胶质细胞的激活。因此，我们使用了一种新生期营养过剩的模型，包括在出生时调整窝仔数（小窝仔：4 只/母鼠与正常窝仔：12 只/母鼠），导致体重增加 15%，并在出生后 60 天增加循环瘦素水平。在新生儿期营养过剩的大鼠，在特定的下丘脑区域（如腹内侧下丘脑）有更多的激活小胶质细胞，而腹内侧下丘脑是代谢控制的重要部位。然而，这种效应并不局限于下丘脑，因为小脑白质也观察到明显的小胶质细胞激活。在下丘脑或小脑，循环肿瘤坏死因子 (TNF)α 水平或 TNFα mRNA 水平均无变化。下丘脑和小脑的白细胞介素 (IL)6 蛋白水平均升高，但 IL6 mRNA 水平不变。由于循环 IL6 水平升高，中央 IL6 的增加可能是摄取增加的结果。因此，在接触新生期营养过剩和正常饮食下体重适度增加的成年大鼠中，小胶质细胞会被激活，这可能代表对全身炎症的继发反应。此外，这种激活可能导致特定下丘脑核团的局部变化，进而进一步破坏代谢稳态。
