Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Camilla Pellegrini, Marta Columbaro, Elisa Schena, Sabino Prencipe, Davide Andrenacci, Patricia Iozzo, Maria Angela Guzzardi, Cristina Capanni, Elisabetta Mattioli, Manuela Loi, David Araujo-Vilar, Stefano Squarzoni, Saverio Cinti, Paolo Morselli, Assuero Giorgetti, Laura Zanotti, Alessandra Gambineri, Giovanna Lattanzi

Research output: Contribution to journalArticle

Abstract

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalExperimental and Molecular Medicine
Volume51
Issue number8
DOIs
Publication statusPublished - Aug 2 2019

    Fingerprint

Cite this

Pellegrini, C., Columbaro, M., Schena, E., Prencipe, S., Andrenacci, D., Iozzo, P., Angela Guzzardi, M., Capanni, C., Mattioli, E., Loi, M., Araujo-Vilar, D., Squarzoni, S., Cinti, S., Morselli, P., Giorgetti, A., Zanotti, L., Gambineri, A., & Lattanzi, G. (2019). Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning. Experimental and Molecular Medicine, 51(8), 1-17. https://doi.org/10.1038/s12276-019-0289-0