PROJECT SUMMARY/ABSTRACT
Lipodystrophies are rare diseases, characterized by a striking loss, redistribution, and dysfunction of adipose
tissue, and accompanied by metabolic dysfunction. Familial partial lipodystrophy 2 (FPLD2) is the most
common type of lipodystrophy, caused by mutations in LMNA, which encodes the nuclear lamina proteins
lamin A/C. Lamin A/C is crucial for nuclear function and controls gene expression, but its role in adipocyte
maintenance and function is incompletely understood. Our lab created a constitutive adipocyte specific Lmna
knockout mouse model (LmnaADKO) to better characterize the roles of Lmna in adipocytes. LmnaADKO mice
develop adipose tissues that are subsequently lost starting at 4 weeks of age; LmnaADKO mice have hepatic
steatosis and reduced circulating leptin concentrations, closely recapitulating FPLD2. Analyses of LmnaADKO
mice suggest that lamin A/C is required for adipocyte maintenance, substantially advancing our mechanistic
understanding, since previous studies did not reveal how loss of Lmna function leads to lipodystrophy.
To study mechanisms of how knockout of Lmna in adipocytes leads to subsequent loss of adipocytes, we
generated mice in which Lmna can be inducibly knocked out with administration of tamoxifen (LmnaiADKO). This
approach allows us to use adult mice, which have more adipose tissue, and to temporally synchronize
adipocyte loss. In preliminary experiments, we have tested multiple mechanisms in vivo that could contribute to
loss of adipocytes in LmnaiADKO mice. Altered adipogenesis seems unlikely, considering that functional white
adipose tissue (WAT) develops in LmnaADKO mice and patients with FPLD2. We also did not observe signs of
increased lipolytic capacity or increased acute cell death in WAT lacking Lmna in adipocytes. However, we did
observe that adipocytes lacking Lmna are visibly smaller and misshapen compared to controls, suggesting
adipocytes are losing their lipid stores, and are unable to maintain viability. Bulk RNA-seq and proteomics from
LmnaiADKO WAT revealed downregulation of lipogenic pathways, and upregulation of inflammatory genes. We
hypothesize that lamin A/C is required to maintain mature adipocyte characteristics, and that absence of
functional lamin A/C leads to adipocyte loss through reduced lipogenic gene expression, driven by altered
interactions between Lmna and chromatin. My project will test this hypothesis by (1) evaluating changes in
lipogenic and mitochondrial genes in Lmna knockout adipocytes and performing DamID and FISH to study
changes in chromatin-lamina interactions that may underlie changes in gene expression and (2) assessing
decreased de novo lipogenesis in LmnaiADKO mice, in addition to restoring lipogenic gene expression to Lmna
KO adipocytes to prevent WAT loss. Ultimately, these studies will reveal underlying molecular mechanisms of
FPLD2, uncovering novel therapeutic targets for lipodystrophy patients while bolstering our understanding of
fundamental adipocyte biology.