Characterizing the Hypothalamic Functions of Irx3 and Irx5 in Energy Balance Regulation
Obesity and overweight have become growing epidemics around the globe. The homeodomain transcription factors IRX3 and IRX5 are important risk factors of human obesity and key regulators of energy balance, acting in connection with the intronic variants of FTO. Irx3 and Irx5 are expressed in the arcuate nucleus and median eminence (ARC-ME), a hypothalamic site known to control energy homeostasis via distinct cell types, yet the identities of Irx3- and Irx5-expressing hypothalamic cells and their roles in regulating energy balance remain poorly characterized. In addition, although accumulating evidence has suggested that postnatal neurogenesis in ARC contributes to energy balance regulation and obesity, little is known about the genetic factors that are involved in this process. Using marker gene staining, lineage tracing and single-cell RNA sequencing analyses, I demonstrate that Irx3 and Irx5 are predominantly expressed in a previously unreported population of radial glia-like cells (RGL) in postnatal mouse hypothalamus, which could be targeted by Ins2-Cre. These RGLs harbor a gene signature highly reminiscent to neural stem cells (NSC) and hold the potential to give rise to other neural cells in postnatal ARC-ME. Through bioinformatics analyses and in vivo labeling experiments, I show that reduced dosage of Irx3 and Irx5 promotes postnatal hypothalamic neurogenesis, leading to elevated numbers of leptin-sensing neurons in postnatal and adult ARC. Next, I investigated the specific functions of Irx3 and Irx5 in Ins2-Cre+ cells by generating mutant mice with conditional deletion of Irx3 or both Irx3 and Irx5 in the Ins2-Cre lineage. These mutants exhibit improved hypothalamic leptin response associated with increased postnatal neurogenesis and higher numbers of leptin-sensing ARC neurons, contributing to their reduced food intake and lean phenotype. Altogether, my thesis work illustrates important roles for Irx3 and Irx5 in the hypothalamic control of energy balance and remodeling of leptin-sensing ARC neurons through postnatal neurogenesis.
Hypothalamus, Iroquois homeobox genes, Leptin, Obesity, Postnatal neurogenesis, Radial glia-like cells
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