Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by adipose tissue loss and redistribution and metabolic dysfunction. FPLD2 is caused by pathogenic variants in the LMNA gene, encoding nuclear lamins A/C, structural proteins that control nuclear function and gene expression. However, the mechanisms driving adipocyte loss in FPLD2 remain poorly defined. In this study, we recruited 8 families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nucleus RNA sequencing revealed suppression of lipid metabolism and mitochondrial pathways, alongside increased inflammation. These signatures were mirrored in tamoxifen-inducible adipocyte-specific Lmna-knockout mice, in which lamin A/C-deficient adipocytes shrank and disappeared. Lmna-deficient fibroblasts shared similar gene expression changes, linked to altered chromatin accessibility, underscoring lamin A/C's potential regulatory role in lipid metabolism and inflammatory programs. By directly comparing atrophic and hypertrophic adipose depots in FPLD2, and integrating human, mouse, and in vitro models, this study provides insights into disease progression and potential therapeutic targets.
Authors
- Hadla Hariri (ORCID: https://orcid.org/0009-0006-7965-9941)
- Özge Besci (ORCID: https://orcid.org/0000-0003-3135-9617)
- Akira Nishii (ORCID: https://orcid.org/0000-0002-8981-3264)
- Donatella Gilio (ORCID: https://orcid.org/0000-0001-9609-6286)
- Carey N. Lumeng (ORCID: https://orcid.org/0000-0003-0303-6204)
- Merve Çelik Güler (ORCID: https://orcid.org/0000-0003-1112-7640)
- Rebecca L. Schill (ORCID: https://orcid.org/0000-0001-7123-0418)
- Susanne Mandrup (ORCID: https://orcid.org/0000-0002-0961-5787)
- Bonje Obua (ORCID: https://orcid.org/0000-0002-9814-3645)
- Elif A Oral (ORCID: https://orcid.org/0000-0002-9171-1144)
- Taryn Hetrick
- Jessica N. Maung (ORCID: https://orcid.org/0000-0003-4289-0614)
- María Del Mar Méndez‐Casillas (ORCID: https://orcid.org/0000-0002-9286-7351)
- Kenneth T. Lewis
- Marcus Nygård (ORCID: https://orcid.org/0009-0002-1762-8593)
- Romina M. Uranga (ORCID: https://orcid.org/0000-0002-8113-4646)
- Ormond A. MacDougald (ORCID: https://orcid.org/0000-0001-6907-7960)
- Paul S. Cederna (ORCID: https://orcid.org/0000-0002-6756-7197)
- Ziru Li (ORCID: https://orcid.org/0000-0002-2755-9299)
- Keegan S. Hoose (ORCID: https://orcid.org/0009-0009-5458-0155)
- Isabel D. K. Hermsmeyer (ORCID: https://orcid.org/0000-0002-1232-8252)
- Yang Chen (ORCID: https://orcid.org/0000-0001-9406-8273)
- Ping Zhang (ORCID: https://orcid.org/0000-0001-9163-6191)
- Hiroyuki Mori (ORCID: https://orcid.org/0000-0003-0503-3277)
- Ana Aparecida Adeodato de Souza (ORCID: https://orcid.org/0000-0002-6560-648X)
- ANABELA DILL GOMES (ORCID: https://orcid.org/0009-0007-4666-715X)
- Maria Foss de Freitas
- Rolf Adler
- Brian Desrosiers
Institutions
- University of Southern Denmark (DK)
- University of Michigan (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1172/jci198387
- Citations
- 1
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Institutes of Health
- Michigan Diabetes Research Center, University of Michigan