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

doi:10.1038/s12276-019-0289-0

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.

Highlights

Lipodystrophic syndromes are rare heterogeneous genetic diseases associated with LMNA, PPARG, BSCL2, or other gene mutations or acquired diseases induced by the use of some human immunodeficiency virus (HIV) protease inhibitors[1,2]
Activation and block of autophagy in laminopathic adipocyte precursors Autophagy in brown adipocyte precursors Compared with control adipose tissue from the trunk, markers of brown adipose tissue (BAT), including uncoupling protein 1 (UCP1), type II deiodinase (DIO2), and PR domain containing 16 (PRDM16), were upregulated in control and FPLD2 adipose tissue from the neck area (Fig. 1a)
PRDM16 was highly increased in FPLD2 preadipocytes, whereas very low levels of PRDM16 and UCP1 were detected in FPLD2 adipocytes with respect to reference control cells (Fig. 1b)

Summary

Introduction

Lipodystrophic syndromes are rare heterogeneous genetic diseases associated with LMNA, PPARG, BSCL2, or other gene mutations or acquired diseases induced by the use of some human immunodeficiency virus (HIV) protease inhibitors[1,2]. These diseases are characterized by generalized or partial fat dystrophy associated with metabolic complications comprising severe insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease[2,3,4]. FPLD2 clinical features include anomalous fat distribution (loss of peripheral subcutaneous fat and abnormal accumulation of fat in the neck and face), severe metabolic alterations with insulin resistance, generalized dyslipidemia, and early cardiovascular complications[3]

Methods

Results

Conclusion