Altered lipid metabolism and inflammatory programs associate with adipocyte loss in 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
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
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Research Article Clinical Research Metabolism

Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2

Abstract

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

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

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Figure 8

Lmna-KO MEFs and adipocytes have shared patterns of altered gene expression, correlated with changes in chromatin accessibility.

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Lmna-KO MEFs and adipocytes have shared patterns of altered gene expres...
(A) Schematic of dataset integration between LmnaiADKO pmWAT RNA-Seq and Lmna-KO MEF microarray (39, 40) and assay for transposase-accessible chromatin sequencing (ATAC-Seq). Overlapping changed genes in RNA-Seq of LmnaiADKO WAT (iADKO), Lmna-KO MEF microarray (MEF), and Lmna-KO MEF ATAC-Seq (ATAC) were identified, and GSEA was run to identify changes in (B) lipid metabolism Gene Ontology (GO) terms with their corresponding (C) overlapping leading-edge genes, along with (D) inflammatory GO terms with (E) corresponding overlapping leading-edge genes. (F) Distribution of chromatin features represented by percentage of overall chromatin composition compared between Lmna control (CTRL) and KO MEF ATAC-Seq. (G) Enriched motifs in Lmna-KO MEFs, stratified into 4 bins based on microarray gene expression changes, from most downregulated to most upregulated. (H and I) ATAC-Seq signal tracks and visualization of significantly enriched regions and their predicted target genes. Red lines represent enhancers with a positive fold-change upon Lmna KO, and blue lines represent negative.