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 3

Single nucleus RNA-Seq identifies changes in cell proportions and subclustering analyses between subcutaneous abdomen and upper neck adipose tissue in unaffected patients.

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Single nucleus RNA-Seq identifies changes in cell proportions and subclu...
(A) Uniform manifold approximation and projection (UMAP) of abdomen and upper neck biopsies across all patient groups (A, B, and C). ASPC, adipose stem and progenitor cells; LEC, lymphatic endothelial cells. (B) Marker genes for each cell population. (C) Permutation tests to identify changes in cell proportions in the upper neck relative to the abdominal biopsies from control patients (group C); changes were statistically significant if the log2FC was less or greater than 0.32 and the FDR was less than 0.05. (D) Adipocyte subclusters and corresponding GSEA pathways. (E) Adipocyte subcluster changes between the upper neck and abdomen in control patients. (F) ASPC subclusters with GSEA pathways. EMT, epithelial-mesenchymal transition. (G) ASPC subcluster changes in the upper neck relative to abdomen. (H) Macrophage subclusters with GSEA pathways. (I) Subcluster changes in macrophages in upper neck relative to abdomen. (J) T cell subclusters with GSEA pathways. (K) Subcluster changes in T cells in upper neck relative to abdomen.