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A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.
Nat. Metab. 5, 861-879 (2023)
Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Genome-wide Association; Cardiovascular-disease; Genetic Architecture; Healthy Obese; Sexual-dimorphism; Insulin-receptor; Hip Ratio; Loci; Risk; Differentiation
ISSN (print) / ISBN
2522-5812
e-ISSN
2522-5812
Zeitschrift
Nature metabolism
Quellenangaben
Band: 5,
Heft: 5,
Seiten: 861-879
Verlag
Springer
Verlagsort
London
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes and Obesity (IDO)
Förderungen
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Novo Nordisk Foundation
Next Generation Award from the Broad Institute of MIT and Harvard
Center for Advanced Light Microscopy of the Technical University of Munich School of Life Sciences
University of Hohenheim
Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes' from the Helmholtz Center Munich
German Center for Diabetes Research
Else Kroener-Fresenius-Foundation
Foundation for the National Institutes of Health (NIH)
Center for Computational, Evolutionary and Human Genomics Graduate Fellowship
Novo Nordisk Foundation Challenge
NIH
Federal Ministry of Education and Research
German Research Foundation
Stanford Graduate Fellowship
Novo Nordisk Foundation
Next Generation Award from the Broad Institute of MIT and Harvard
Center for Advanced Light Microscopy of the Technical University of Munich School of Life Sciences
University of Hohenheim
Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes' from the Helmholtz Center Munich
German Center for Diabetes Research
Else Kroener-Fresenius-Foundation
Foundation for the National Institutes of Health (NIH)
Center for Computational, Evolutionary and Human Genomics Graduate Fellowship
Novo Nordisk Foundation Challenge
NIH
Federal Ministry of Education and Research
German Research Foundation
Stanford Graduate Fellowship