ArticleNature metabolism2023
A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.
Article in Nature metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 34 citations in OpenAlex.
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- Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.Nature medicine · 2025Article
- Multi-omics integration reveals Chr1 associated QTL mediating backfat thickness in pigs.Journal of animal science and biotechnology · 2025Article
- Genome-wide interaction study with body mass index identifies CYP7A1 and GIPR as genetic modulators of metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2025Article
- Exercise-regulated lipolysis: Its role and mechanism in health and diseases.Journal of advanced research · 2025Review
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- Transcriptomic characterization of transitioning cell types in the skin of Atlantic salmon.BMC biology · 2025Article
- Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment.The Journal of clinical investigation · 2025Review
- Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation.iScience · 2025Article
- MRI-Based Genetic Studies Reveal Specific Genetic Variants and Disease Risks Associated With Fat Distribution Across Anatomical Sites.Journal of obesity · 2025Article
- Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro.Nature communications · 2024Article
- Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.Nature communications · 2024Article
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Authors and funding
26 authors at 8 institutions in 4 countries.
Funding
Abstract
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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