Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction

Author:

Schena Elisa12ORCID,Mattioli Elisabetta12,Peres Chiara12ORCID,Zanotti Laura34,Morselli Paolo5,Iozzo Patricia6ORCID,Guzzardi Maria Angela6,Bernardini Chiara7ORCID,Forni Monica4ORCID,Nesci Salvatore7ORCID,Caprio Massimiliano89ORCID,Cecchetti Carolina34,Pagotto Uberto34ORCID,Gabusi Elena10,Cattini Luca10,Lisignoli Gina10ORCID,Blalock William12ORCID,Gambineri Alessandra34,Lattanzi Giovanna12ORCID

Affiliation:

1. Unit of Bologna, CNR—National Research Council of Italy, Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, Italy

2. IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

3. Unit of Gynecology and Obstetrics, Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy

4. Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy

5. Plastic Surgery Unit, Department of Specialised, Experimental and Diagnostic Medicine, Alma Mater Studiorum University of Bologna, S. Orsola-Malpighi Hospital, 40126 Bologna, Italy

6. CNR—National Research Council of Italy, Institute of Clinical Physiology, 56124 Pisa, Italy

7. Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia, Italy

8. Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele, 00163 Rome, Italy

9. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy

10. SC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

Abstract

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA 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.

Funder

AIPROSAB

Italian MUR PRIN

IRCCS San Raffaele Institutional

Publisher

MDPI AG

Subject

General Medicine

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