Lamin A/C regulates lipid metabolism and inflammation: insights from models of familial partial lipodystrophy 2

Jessica N. Maung; Rebecca L. Schill; Akira Nishii; Maria Foss de Freitas; Bonje N. Obua; Marcus Nygård; Maria D. Mendez-Casillas; Isabel D.K. Hermsmeyer; Donatella Gilio; Ozge Besci; Yang Chen; Brian Desrosiers; Rose E. Adler; Anabela D. Gomes; Merve Celik Guler; Hiroyuki Mori; Romina M. Uranga; Ziru Li; Hadla Hariri; Liping Zhang; Anderson de Paula Souza; Keegan S. Hoose; Kenneth T. Lewis; Taryn A. Hetrick; Paul Cederna; Carey N. Lumeng; Susanne Mandrup; Elif A. Oral; Ormond A. MacDougald

doi:10.1172/JCI198387

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Hariri, H. in: PubMed | Google Scholar

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Zhang, L. in: PubMed | Google Scholar

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Hetrick, T. in: PubMed | Google Scholar

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Mandrup, S. in: PubMed | Google Scholar |

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Oral, E. in: PubMed | Google Scholar |

¹Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States of America

²Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

³Cell and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, United States of America

⁴Center for Functional Genomics and Tissue Plasticity, Department of Biochem, University of Southern Denmark, Odense, Denmark

⁵Department of Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI198387.
Copyright © 2025, Maung et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published November 11, 2025 - Version history

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 eight families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nuclei 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 new insights into disease progression and potential therapeutic targets.

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Lamin A/C regulates lipid metabolism and inflammation: insights from models of familial partial lipodystrophy 2

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