Fragile X mental retardation protein (FMRP), strongly associated with fragile X syndrome, plays important roles by regulating gene expression via interacting with other RNA binding proteins in the brain. However, the role of FMRP in hypothalamus, a central part responsible for metabolic control, is poorly known. Our study shows that FMRP is primarily located in the hypothalamic arcuate nucleus (ARC). Using proteomic analysis, we identified 56 up-regulated and 22 down-regulated proteins in the hypothalamus of Map1b KO mice, with microtubule-associated protein 1 B (MAP1B) being the most outstanding increased protein (more than 10 folds). Immunofluorescent assays showed that MAP1B significantly increased in the Map1b-KO ARC, in which the number of agouti-related peptide (AgRP)-staining neurons significantly reduced, but not altered for pro-opiomelanocortin (POMC) neurons. We further showed an age-dependent reduces in food intake and body weight of the KO mice, along with the decreases of MAP1B and AgRP at the same time points. In hypothalamic GT1-7 cells, the AgRP expression decreased upon knockdown of FMRP or overexpression of MAP1B, and increased in response to overexpression of FMRP or knockdown of MAP1B. Co-knockdown or co-overexpression of FMRP and MAP1B led to a reverse expression of AgRP compared to overexpression of knockdown of FMRP alone, demonstrating that MAP1B is essential for the regulatory effect of FMRP on AgRP expression. Taken together, these data suggest that FMRP-deficiency-induced increase of hypothalamic MAP1B and decrease of AgRP might be associated with reduces in food intake and body weight.

脆性 X 智力障碍蛋白 (FMRP) 与脆性 X 综合征密切相关，通过与大脑中其他 RNA 结合蛋白相互作用调节基因表达，从而发挥重要作用。然而，FMRP 在下丘脑（负责代谢控制的中心部分）中的作用鲜为人知。我们的研究表明 FMRP 主要位于下丘脑弓状核 (ARC)。使用蛋白质组学分析，我们在Map1b KO 小鼠的下丘脑中鉴定了 56 个上调和 22 个下调的蛋白质，其中微管相关蛋白 1 B (MAP1B) 是最显着的增加蛋白质（超过 10 倍）。免疫荧光分析表明，MAP1B 在Map1b 中显着增加-KO ARC，其中刺鼠相关肽 (AgRP) 染色神经元的数量显着减少，但阿片黑素原 (POMC) 神经元没有改变。我们进一步显示 KO 小鼠的食物摄入量和体重随年龄增加而减少，同时 MAP1B 和 AgRP 也随之减少。在下丘脑 GT1-7 细胞中，AgRP 表达在 FMRP 敲低或 MAP1B 过表达时降低，并在 FMRP 过表达或 MAP1B 敲低时增加。与单独敲低 FMRP 的过表达相比，FMRP 和 MAP1B 的共敲除或共过表达导致 AgRP 的反向表达，这表明 MAP1B 对 FMRP 对 AgRP 表达的调节作用至关重要。综合起来，