Journal Article

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

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

2019

Overview

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. Fat tissue disorders: Dysfunctional fat cell differentiation An abnormal distribution of fatty tissues associated with certain tissue disorders is driven by disrupted fat cell differentiation. Type 2 familial partial lipodystrophy (FPLD2) is a genetic condition that results in fat being lost from the limbs and accumulating in the face and neck. Giovanna Lattanzi at the National Research Council of Italy in Bologna and co-workers found that fat cell (adipocyte) precursors did not clearly differentiate into either of the two main fatty tissue types, brown or white, in FPLD2 patients. White adipocyte precursors exhibited impaired lipid formation and abnormal levels of brown tissue markers. Conversely, brown adipocyte precursors showed high lipid levels and increased autophagy, a natural process involving degradation and recycling of cellular components. The neck is normally where brown fat accumulates, but FPLD2 patients had adipocytes there displaying white fat characteristics.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/106 / 13/109 / 14 / 14/19 / 14/28 / 38 / 38/77 / 59 / 631/80/304 / 631/80/386/1700 / 631/80/39/2346 / 692/163/2743/2037 / 692/308/575 / 82 / 82/29 / 96 / Adipocytes / Adipocytes - pathology / Adipocytes - physiology / Adipocytes, Brown - physiology / Adipogenesis / Adipogenesis - physiology / Adipose tissue (brown) / Adipose Tissue, Brown - metabolism / Adipose Tissue, Brown - physiology / Adult / Autophagy / Autophagy - physiology / Biomedical and Life Sciences / Biomedicine / Cell Differentiation / Cell Transdifferentiation - physiology / Cells, Cultured / Female / Gene regulation / Humans / Lipodystrophy / Lipodystrophy, Familial Partial - metabolism / Lipodystrophy, Familial Partial - pathology / Lipodystrophy, Familial Partial - physiopathology / Medical Biochemistry / Middle Aged / Molecular Medicine / Neck / Phagocytosis / Phenotypes / Preadipocytes / Stem Cells / Young Adult / 생화학