Molecular profiling of human iPS-derived hypothalamic neurons provides developmental insights to genetic loci for body weight regulation

Abstract

Background/Objectives

Recent data suggests that common genetic risk for metabolic disorders such as obesity may be human-specific and exert effects through the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures which recapture many features of hypothalamic neurons within the arcuate nucleus. Here we have comprehensively characterized this model across development, benchmarked these neurons to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development.

Methods

The dynamic transcriptome across neuronal maturation was examined using microarray and RNAseq methods at 9 time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and miRNA control of biological processes. The transcriptomes were compared to those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance assessed with Fisher's exact test.

Results

The human neuronal cultures have a transcriptional and physiological profile of NPY/AGRP ARC neurons. The neuronal transcriptomes were highly correlated with adult hypothalamus as compared to any other brain region from the GTEx. Also, roughly 25% of the transcripts showed substantial changes in expression across neuronal development and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants.

Conclusions

We affirmed the utility of this in vitro human model to study development of key hypothalamic neurons involved in energy balance and show that genes at loci associated with body weight regulation may share a pattern of developmental regulation. These data support the need to investigate early development to elucidate human-specific CNS pathophysiology underlying obesity susceptibility.

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