Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans

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Abstract Lipodystrophy is a disorder characterized by adipose tissue loss and redistribution, with associated metabolic complications including diabetes. The most common form of monogenic lipodystrophy is familial partial lipodystrophy type 2 (FPLD2), which is caused by a mutation in the LMNA gene, encoding nuclear lamins A and C. The mechanisms for how adipose tissues are lost, after developing normally through adolescence are unknown. To address this shortfall, we selectively deleted LMNA in adipocytes (LMNAADKO) of mice. We observed a striking loss of white adipose tissue in adult LMNAADKO mice, along with increased fat deposition in the liver, elevated blood glucose levels in both fasting and fed states, increased circulating insulin levels compared to the LMNAfl/fl controls. Analyses of young mice revealed development of white adipose tissue in LMNAADKO mice, which is progressively lost coincident with puberty. These phenotypes closely mirror those observed in human FPLD2 patients. Importantly, we also have access to a highly motivated LMNA R482Q patient population, who are not yet exhibiting signs of lipodystrophy. Analyses of their WAT will provide an unprecedented opportunity to advance our understanding of this disease and its progression. We propose experiments in tissue from these patients to pinpoint the earliest defects in WAT cellularity, including specific alterations in adipocyte gene expression. To test our hypotheses, we propose the following specific aims: SA1) determine in LMNAADKO mice whether loss of adipose tissues with lamin A/C deficiency is due to impaired adipogenesis or is the result of increased adipocyte turnover, SA2) ascertain in LMNAADKO mice whether loss of adipocytes occurs through intrinsic or extrinsic cellular mechanisms, and SA3) evaluate in young FPLD2 patients, who are not yet showing overt signs of lipodystrophy, the effects of LMNA mutation on morphology, gene expression, signaling pathways and cellular composition of adipose tissue depots.