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

Abstract

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, 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 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 with 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.

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

“…Previously, the role of BMAds in the marrow niche was deduced through indirect inferences from associations of skeletal and hematopoietic phenotypes with bone marrow adipose tissue volume. This has been exemplified by a number of BMAT depletion models which showed high bone mass, including A-ZIP ( Naveiras et al, 2009 ), Adipoq -driven DTA ( Zou et al, 2019 ), and Adipoq -driven loss of Pparg ( Wang et al, 2013 ), Lmna ( Corsa et al, 2021 ), or Bscl2 ( Mcilroy et al, 2018 ); however these lipodystrophic mice also lacked white and brown adipose depots and thus exhibit global metabolic dysfunction, including fatty liver, hyperlipidemia and insulin resistance. Moreover, Adipoq -driven Cre used in those studies also causes recombination in bone marrow stromal cells ( Mukohira et al, 2019 ).…”

“…adipsin, RANK ligand, and stem cell factor; Aaron et al, 2021 ; Li et al, 2018 ). Removal of these stimuli in mouse models of lipodystrophy, which lack BMAT, results in increased bone mass ( Corsa et al, 2021 ; Zou et al, 2020 ; Zou et al, 2019 ). However, use of these models to investigate direct effects of BMAT depletion is confounded by concurrent loss of white and brown adipose depots, which also regulate bone mass through myriad mechanisms, including secretion of adipokines ( Riddle and Clemens, 2017 ; Zou et al, 2019 ).…”

Emerging roles of circular RNAs in osteoporosis

“…10 The modulation processes of bone metabolism are associated with several factors such as mechanical stimulation, epigenetic regulation and hormones. [11][12][13][14][15] The major therapies of osteoporosis are drug therapy and surgery, while the curative effect remains unsatisfactory. [16][17][18] Thus, it is crucial to find new biomarkers for the indention and therapy of osteoporosis.Circular RNAs (circRNAs) are formed by reverse splicing of splice accepter at 5′ end splice donor at the 3′ end in the pre-mRNA.…”

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

“…To date, investigation of the physiological functions of BMAT have been hampered by the lack of a BMAd-specific mouse model. Although a number of BMAT depletion models show high bone mass, including A-ZIP (Naveiras et al, 2009), Adipoq -driven DTA (Zou et al, 2019), and Adipoq -driven loss of Pparγ (Wang, Mullican, DiSpirito, Peed, & Lazar, 2013), Lmna (Corsa et al, 2021), or Bscl2 (McIlroy et al, 2018), these lipodystrophic mice also lack white and brown adipose depots and thus exhibit global metabolic dysfunction, including fatty liver, hyperlipidemia and insulin resistance. Of note, Adipoq -driven Cre used in those studies also causes recombination in bone marrow stromal cells (Mukohira et al, 2019).…”

“…stem cell factor). Removal of these stimuli in mouse models of lipodystrophy, which lack BMAT, results in increased bone mass (Corsa et al, 2021; Zou et al, 2020; Zou et al, 2019). However, use of these models to investigate the direct effects of BMAT depletion is confounded by concurrent loss of white and brown adipose depots, which also regulate bone mass through myriad mechanisms, including secretion of adipokines (Riddle & Clemens, 2017; Zou et al, 2019).…”