Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation

L. Yao, Y. Liu, Z. Qiu, S. Kumar, J. E. Curran, J. Blangero, Yidong Chen, Donna M Lehman

Research output: Contribution to journalArticle

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Abstract

Recent data suggest that common genetic risks for metabolic disorders such as obesity may be human-specific and exert effects via 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 that recapture many features of hypothalamic neurones within the arcuate nucleus. In the present study, we have comprehensively characterised this model across development, benchmarked these neurones to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development. The dynamic transcriptome across neuronal maturation was examined using microarray and RNA sequencing methods at nine time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and microRNA control of biological processes. The transcriptomes were compared with 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 was assessed with Fisher's exact test. The human neuronal cultures have a transcriptional and physiological profile of neuropeptide Y/agouti-related peptide arcuate nucleus neurones. The neuronal transcriptomes were highly correlated with adult hypothalamus compared to any other brain region from the GTEx. Also, approximately 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. We confirmed the utility of this in vitro human model for studying the development of key hypothalamic neurones 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 the human-specific central nervous system pathophysiology underlying obesity susceptibility.

Original languageEnglish (US)
JournalJournal of Neuroendocrinology
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Induced Pluripotent Stem Cells
Genetic Loci
Body Weight
Neurons
Transcriptome
Biological Phenomena
Arcuate Nucleus of Hypothalamus
Obesity
Genes
Body Mass Index
Central Nervous System
Genotype
Databases
RNA Sequence Analysis
Neuropeptide Y
Brain
Principal Component Analysis
MicroRNAs
Hypothalamus
Cluster Analysis

Keywords

  • adiponectin
  • AgRP
  • GABA
  • leptin
  • neuropeptides
  • NPY

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

Cite this

Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation. / Yao, L.; Liu, Y.; Qiu, Z.; Kumar, S.; Curran, J. E.; Blangero, J.; Chen, Yidong; Lehman, Donna M.

In: Journal of Neuroendocrinology, Vol. 29, No. 2, 01.02.2017.

Research output: Contribution to journalArticle

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