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Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions.
Kar, Asha; Alvarez, Marcus; Garske, Kristina M; Huang, Huiling; Lee, Seung Hyuk T; Deal, Milena; Das, Sankha Subhra; Koka, Amogha; Jamal, Zoeb; Mohlke, Karen L; Laakso, Markku; Heinonen, Sini; Pietiläinen, Kirsi H; Pajukanta, Päivi.
Afiliación
  • Kar A; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Alvarez M; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Garske KM; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Huang H; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Lee SHT; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA.
  • Deal M; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Das SS; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Koka A; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Jamal Z; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Mohlke KL; Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles (UCLA), Gonda Center, Room 6357B, 695 Charles E. Young Drive South, Los Angeles, CA, 90095-7088, USA.
  • Laakso M; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Heinonen S; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
  • Pietiläinen KH; Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Pajukanta P; Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Genome Med ; 16(1): 19, 2024 01 31.
Article en En | MEDLINE | ID: mdl-38297378
ABSTRACT

BACKGROUND:

Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner.

METHODS:

We integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI).

RESULTS:

We found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level.

CONCLUSIONS:

Overall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Tejido Adiposo / Obesidad Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Genome Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Tejido Adiposo / Obesidad Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Genome Med Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos