Lamin A/C Loss Silences Fat Metabolism and Fuels Inflammation in Rare Lipodystrophy

Adipose tissue is an essential metabolic and endocrine organ, and losing it is harmful. In lipodystrophy syndromes, loss of safe lipid storage leads to insulin resistance, fatty liver and cardiovascular risk. Familial partial lipodystrophy type 2 (FPLD2, Dunnigan's disease) is the most common form. It is caused by missense variants in LMNA, which encodes the nuclear lamins A/C, and it produces selective subcutaneous fat loss from the limbs and trunk with fat redistribution to the face, neck and sometimes viscera. Why adipocytes are lost remains poorly understood, partly because human tissue is scarce and earlier mouse models relied on overexpression or on the aP2 promoter, which is also active in macrophages.

The team enrolled 8 families with confirmed LMNA variants (5 distinct disease-causing variants by whole-genome sequencing) into the LEAD-ABC study. The 16 participants were grouped as controls (C), carriers with developing disease (A), and patients with overt FPLD2 (B). They underwent body composition imaging, metabolic testing, and subcutaneous fat biopsies from the abdomen (an atrophic depot) and the dorsocervical upper neck (an expanding depot), which allows within-person comparison. Samples were examined histologically and by bulk and single-nucleus RNA sequencing. The authors also built a tamoxifen-inducible adipocyte-specific Lmna-knockout mouse (LmnaiADKO) to follow adipocyte loss in adults, and analyzed chromatin accessibility in Lmna-knockout fibroblasts.

Both developing and developed FPLD2 groups had lower total body fat and leg fat than controls, and the developing group already showed reduced trunk fat. Developed FPLD2 was linked to higher HbA1c, triglycerides, NEFA and OGTT glucose AUC, along with lower leptin and adiponectin and higher FGF21 and GDF15. HOMA-IR, fasting insulin and ADIPO-IR did not differ significantly, and MRI showed no significant liver fat. In biopsies, abdominal fat appeared more fibrotic, though quantification was limited by sampling variability. Adipocyte size was unchanged in both depots, so surviving adipocytes looked morphologically similar across disease states. Bulk RNA-seq, with developing and developed groups combined because of sample size, showed upregulated inflammation, intermediate filament and muscle-related pathways and downregulated mitochondrial, translational and fatty acid metabolism pathways. Per the abstract, single-nucleus data and the inducible knockout mouse mirrored these signatures, with lamin A/C-deficient adipocytes shrinking and disappearing. Lmna-deficient fibroblasts showed similar expression changes linked to altered chromatin accessibility of lipid and immune regulatory genes.

Together, the findings suggest that lamin A/C loss or dysfunction suppresses lipid handling and mitochondrial programs while activating inflammatory ones, which may contribute to adipocyte degeneration. A conserved signature across human tissue, mouse and cell models raises the possibility that these pathways could be therapeutic targets. Comparing atrophic and hypertrophic depots within the same patients is a distinctive strength.

Several caveats apply. FPLD2 is rare, so the cohort is small and heterogeneous in genotype and disease stage. Groups had to be pooled for transcriptomics. Fibrosis findings were qualitative. The mouse model deletes Lmna entirely rather than reproducing a patient missense variant. The results are associative and do not establish which changes are causal. The available text was truncated partway through the results, so some analyses are described only from the abstract and introduction.