Insights on Adipose Loss in Familial Partial Lipodystrophy

Familial partial lipodystrophy type 2 (FPLD2), also known as Dunnigan disease, has long puzzled clinicians. A comprehensive translational study published in The Journal of Clinical Investigation provides new mechanistic insight into how pathogenic LMNA variants drive adipocyte failure and identifies converging defects in lipid metabolism, mitochondrial function, and inflammatory signaling as central features of disease.

FPLD2 is caused by missense mutations in LMNA, the gene encoding nuclear lamins A and C. Although the clinical phenotype has been well described, the mechanisms leading to adipocyte loss have remained unclear. To address this gap, investigators recruited eight families with confirmed LMNA variants and performed detailed phenotyping alongside histologic, bulk RNA sequencing, and single-nucleus RNA sequencing analyses of subcutaneous adipose tissue biopsies.

Even in individuals with early or “developing” FPLD2, total and regional fat mass was reduced compared with unaffected relatives. However, overt metabolic dysfunction—elevated HbA1c, hypertriglyceridemia, and increased fibroblast growth factor 21—was primarily observed in those with established disease. Circulating leptin and adiponectin levels were diminished, consistent with loss of functional adipose tissue.

At the tissue level, histology revealed preserved adipocyte size across depots and disease stages, despite increased fibrosis in abdominal fat. The molecular data, however, told a different story. Bulk RNA sequencing of adipose tissue from affected participants demonstrated coordinated downregulation of fatty acid metabolism, oxidative phosphorylation, and mitochondrial pathways, alongside upregulation of inflammatory and extracellular matrix programs. These transcriptomic signatures were reinforced by single-nucleus RNA sequencing, which showed that adipocytes themselves exhibited impaired lipid metabolic gene expression and heightened inflammatory signaling. Notably, pro-inflammatory adipocyte states were enriched in dorsocervical fat, a depot that paradoxically expands in FPLD2.

To determine whether these changes were causally linked to lamin A/C loss, the investigators turned to a tamoxifen-inducible, adipocyte-specific Lmna knockout mouse model. Within two weeks of gene deletion—before overt adipocyte shrinkage—white adipose tissue already exhibited suppression of lipogenic genes and mitochondrial proteins, along with increased immune-related pathways. Over time, lamin-deficient adipocytes became misshapen, shrank, and ultimately disappeared from tissue, confirming a cell-autonomous requirement for lamin A/C in adipocyte maintenance.

Functionally, Lmna-deficient adipocytes demonstrated reduced expression of key lipogenic enzymes such as SCD1 and diminished oxidative phosphorylation capacity, with impaired baseline and maximal respiration. Ultrastructural analyses revealed abnormal mitochondrial cristae organization, reinforcing the link between nuclear architecture and mitochondrial integrity.

Importantly, inflammatory activation appeared to originate within adipocytes themselves rather than from infiltrating immune cells. Isolated lamin-deficient adipocytes upregulated Il6, Il1b, and Tnfa expression, even in the absence of increased macrophage infiltration. Integration with publicly available chromatin accessibility datasets further suggested that lamin A/C loss alters enhancer accessibility near lipid metabolism and inflammatory genes, implicating disrupted chromatin organization as a unifying mechanism.

Together, these findings position FPLD2 not simply as a disorder of fat redistribution, but as a disease of adipocyte instability driven by nuclear structural dysfunction. By linking lamin A/C deficiency to impaired lipogenesis, mitochondrial failure, and intrinsic inflammatory signaling, the study offers a coherent framework for understanding adipocyte loss in FPLD2—and potentially in broader laminopathies. Therapeutically, pathways regulating lipid synthesis, mitochondrial homeostasis, and chromatin remodeling may represent promising targets for intervention in this rare but metabolically consequential condition.