Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Nat Metab. 2021 May;3(5):701-713. doi: 10.1038/s42255-021-00382-y. Epub 2021 Apr 15.
Obesity is mainly due to excessive food intake. IRX3 and IRX5 have been suggested as determinants of obesity in connection with the intronic variants of FTO, but how these genes contribute to obesity via changes in food intake remains unclear. Here, we show that mice doubly heterozygous for Irx3 and Irx5 mutations exhibit lower food intake with enhanced hypothalamic leptin response. By lineage tracing and single-cell RNA sequencing using the Ins2-Cre system, we identify a previously unreported radial glia-like neural stem cell population with high Irx3 and Irx5 expression in early postnatal hypothalamus and demonstrate that reduced dosage of Irx3 and Irx5 promotes neurogenesis in postnatal hypothalamus leading to elevated numbers of leptin-sensing arcuate neurons. Furthermore, we find that mice with deletion of Irx3 in these cells also exhibit a similar food intake and hypothalamic phenotype. Our results illustrate that Irx3 and Irx5 play a regulatory role in hypothalamic postnatal neurogenesis and leptin response.
肥胖主要是由于食物摄入过多。IRX3 和 IRX5 已被认为是与 FTO 内含子变异相关的肥胖决定因素，但这些基因如何通过改变食物摄入导致肥胖尚不清楚。在这里，我们表明 Irx3 和 Irx5 突变的双杂合子小鼠表现出较低的食物摄入，同时增强了下丘脑瘦素反应。通过使用 Ins2-Cre 系统进行谱系追踪和单细胞 RNA 测序，我们在早期出生后下丘脑发现了一个以前未报道的放射状胶质样神经干细胞群体，该群体具有高 Irx3 和 Irx5 表达，并证明 Irx3 和 Irx5 的剂量降低促进了出生后下丘脑的神经发生，导致瘦素感应弓状神经元数量增加。此外，我们发现这些细胞中 Irx3 缺失的小鼠也表现出类似的食物摄入和下丘脑表型。我们的结果表明，Irx3 和 Irx5 在下丘脑出生后神经发生和瘦素反应中发挥调节作用。
