Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction
Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by <i>LMNA</i> mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocort...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/22/2586 |
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| author | Elisa Schena Elisabetta Mattioli Chiara Peres Laura Zanotti Paolo Morselli Patricia Iozzo Maria Angela Guzzardi Chiara Bernardini Monica Forni Salvatore Nesci Massimiliano Caprio Carolina Cecchetti Uberto Pagotto Elena Gabusi Luca Cattini Gina Lisignoli William Blalock Alessandra Gambineri Giovanna Lattanzi |
| author_facet | Elisa Schena Elisabetta Mattioli Chiara Peres Laura Zanotti Paolo Morselli Patricia Iozzo Maria Angela Guzzardi Chiara Bernardini Monica Forni Salvatore Nesci Massimiliano Caprio Carolina Cecchetti Uberto Pagotto Elena Gabusi Luca Cattini Gina Lisignoli William Blalock Alessandra Gambineri Giovanna Lattanzi |
| author_sort | Elisa Schena |
| collection | DOAJ |
| description | Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by <i>LMNA</i> mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient’s neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies. |
| first_indexed | 2024-03-09T16:57:04Z |
| format | Article |
| id | doaj.art-ce99735e236c4a80ae4251f9d5cb37de |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T16:57:04Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ce99735e236c4a80ae4251f9d5cb37de2023-11-24T14:35:09ZengMDPI AGCells2073-44092023-11-011222258610.3390/cells12222586Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte DysfunctionElisa Schena0Elisabetta Mattioli1Chiara Peres2Laura Zanotti3Paolo Morselli4Patricia Iozzo5Maria Angela Guzzardi6Chiara Bernardini7Monica Forni8Salvatore Nesci9Massimiliano Caprio10Carolina Cecchetti11Uberto Pagotto12Elena Gabusi13Luca Cattini14Gina Lisignoli15William Blalock16Alessandra Gambineri17Giovanna Lattanzi18Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyUnit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyUnit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyUnit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyPlastic Surgery Unit, Department of Specialised, Experimental and Diagnostic Medicine, Alma Mater Studiorum University of Bologna, S. Orsola-Malpighi Hospital, 40126 Bologna, ItalyCNR—National Research Council of Italy, Institute of Clinical Physiology, 56124 Pisa, ItalyCNR—National Research Council of Italy, Institute of Clinical Physiology, 56124 Pisa, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, ItalyDepartment of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, ItalyLaboratory of Cardiovascular Endocrinology, IRCCS San Raffaele, 00163 Rome, ItalyUnit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyUnit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalySC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalySC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalySC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyUnit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyUnit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, ItalyUnit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyType-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by <i>LMNA</i> mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient’s neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.https://www.mdpi.com/2073-4409/12/22/2586type 2 familial partial lipodystrophy (FPLD2)mineralocorticoid receptor (MR)spironolactonelamin A/Cprelamin Aadipose tissue |
| spellingShingle | Elisa Schena Elisabetta Mattioli Chiara Peres Laura Zanotti Paolo Morselli Patricia Iozzo Maria Angela Guzzardi Chiara Bernardini Monica Forni Salvatore Nesci Massimiliano Caprio Carolina Cecchetti Uberto Pagotto Elena Gabusi Luca Cattini Gina Lisignoli William Blalock Alessandra Gambineri Giovanna Lattanzi Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction Cells type 2 familial partial lipodystrophy (FPLD2) mineralocorticoid receptor (MR) spironolactone lamin A/C prelamin A adipose tissue |
| title | Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction |
| title_full | Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction |
| title_fullStr | Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction |
| title_full_unstemmed | Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction |
| title_short | Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction |
| title_sort | mineralocorticoid receptor antagonism prevents type 2 familial partial lipodystrophy brown adipocyte dysfunction |
| topic | type 2 familial partial lipodystrophy (FPLD2) mineralocorticoid receptor (MR) spironolactone lamin A/C prelamin A adipose tissue |
| url | https://www.mdpi.com/2073-4409/12/22/2586 |
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