FPLD2 Supplementary Methods with Ref.pdf (6.9 MB)
Download fileAdipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2
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posted on 2021-07-02, 21:30 authored by Callie A.S. Corsa, Carolyn M. Walsh, Devika P. Bagchi, Maria C. Foss Freitas, Ziru Li, Julie Hardij, Katrina Granger, Hiroyuki Mori, Rebecca L. Schill, Kenneth T. Lewis, Jessica N. Maung, Ruth D. Azaria, Amy E. Rothberg, Elif A. Oral, Ormond A. MacDougaldMechanisms by which autosomal recessive
mutations in Lmna cause familial
partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate
function of lamin A/C in adipose tissues, we created mice with an
adipocyte-specific loss of Lmna (LmnaADKO). Although LmnaADKO mice develop and
maintain adipose tissues in early postnatal life, they show a striking and
progressive loss of white and brown adipose tissues as they approach sexual
maturity. LmnaADKO mice exhibit
a surprisingly mild metabolic dysfunction on a chow diet, but on a high fat
diet they share many characteristics of FPLD2 including hyperglycemia, hepatic
steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin
and leptin. Whereas LmnaADKO
mice have reduced regulated and
constitutive bone marrow adipose tissue with a concomitant increase in cortical
bone, FPLD2 patients have reduced bone mass and bone mineral density compared to
controls. In cell culture models of Lmna
deficiency, mesenchymal
precursors undergo adipogenesis
without impairment, whereas fully-differentiated adipocytes have increased
lipolytic responses to adrenergic stimuli. LmnaADKO mice faithfully reproduce many characteristics of
FPLD2 and thus provide a unique animal model to investigate mechanisms
underlying Lmna-dependent loss of
adipose tissues.