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

Abstract

Mechanisms by which autosomal recessive mutations in <i>Lmna</i> 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 <i>Lmna</i> (<i>Lmna</i><sup>ADKO</sup>). Although <i>Lmna</i><sup>ADKO</sup> 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. <i>Lmna</i><sup>ADKO</sup> 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 <i>Lmna</i><sup>ADKO</sup> 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 <i>Lmna</i> deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully-differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. <i>Lmna</i><sup>ADKO</sup> mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying <i>Lmna</i>-dependent loss of adipose tissues.

Caveolin‐2 in association with nuclear lamina controls adipocyte hypertrophy

“…As a component of the nuclear lamina, lamin A/C is important for maintaining the nuclear envelope functions, and its loss or mutation causes metabolic dysfunction of adipocyte. 15,16 Lelliot et al showed that lamin A/C expression was increased with ex vivo differentiation of human adipocyte cells. 17 Miranda et al reported that lamin A/C mRNA expression was elevated in subcutaneous adipose tissue of obese and type 2 diabetes mellitus patients.…”

“…As a component of the nuclear lamina, lamin A/C is important for maintaining the nuclear envelope functions, and its loss or mutation causes metabolic dysfunction of adipocyte 15,16 . Lelliot et al showed that lamin A/C expression was increased with ex vivo differentiation of human adipocyte cells 17 .…”

Constitutive bone marrow adipocytes suppress local bone formation

“…Other approaches used to explore the relationship between adipocytes and bone have included depletion of these cells using mice expressing diphtheria toxin A (DTA) (9), or DT receptor (DTR) (10) in all adipocytes, or adipocyte-specific deletion of genes related to adipocyte differentiation and lipid formation, such as Pparg (11), Kindlin-2 (12), Cebp and other bZIP family members (13), and Lmna (14). These studies suggest that loss of adipocytes, including BMAds, is associated with significant increases of bone mass; however, interpretation of these data is complicated since white, beige, brown and bone marrow adipocytes are all depleted by Adipoq-or Fapb4-Cre in these animal models.…”