title: Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation.
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.
authors.affiliation: Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, Brownsville, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.affiliation: South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, Brownsville, TX, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, Brownsville, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Epidemiology and Biostatistics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: D M
authors.identifier: 0000-0001-8547-9927
authors.initials: DM
authors.lastname: Lehman
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D001111:Arcuate Nucleus of Hypothalamus / Q000254:growth & development* / Q000378:metabolism*; D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology*; D002478:Cells, Cultured; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D059467:Transcriptome / Q000502:physiology
chemical_list: D054369:Agouti-Related Protein; D009478:Neuropeptide Y
keywords: 
  GABA
  ; 
  NPY
  ; AgRP; adiponectin; leptin; neuropeptides