American Diabetes Association
FPLD2 Supplementary Methods with Ref.pdf (6.9 MB)

Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2

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Version 2 2021-07-02, 21:30
Version 1 2021-06-05, 00:29
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. MacDougald
Mechanisms 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.


This work was supported by funds from the National Institute of Health to CASC (T32 DK101357), DPB (T32 HD007505 and T32 GM007863), CMW (T32 DK071212), RLS (T32 DK101357 and F32 DK123887), KTL (T32 DK071212 and F32 DK122654), EO (R01 DK125513) and OAM (R24 DK092759, R01 DK125513, R01 DK121759). This work was also supported by postdoctoral fellowships from the American Diabetes Association to CASC (1-18-PDF-064) and ZL (1-18-PDF-087) and from the Michigan Life Sciences Fellows program to CMW. This research was supported by the Michigan Mouse Metabolic Phenotyping Center (U2C DK110768), the Microscopy, Imaging, and Cellular Physiology Core (P30 DK020572), the Adipose Tissue Core of the MNORC (P30 DK089503), and the University of Michigan Advanced Genomics Core. Histological analyses were supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (P30 AR069620).