Among the mechanisms that regulate pre-adipocyte commitment towards the brown or white adipose tissue lineage is the differential activation of autophagic processes. We identified deregulation of autophagy in both Type-2 Familial Partial Lipodystrophy (FPLD2) pre-adipocytes and experimental models obtained by drug-induced accumulation of prelamin A in adipocyte precursors. FPLD2 is a genetic disorder associated with LMNA mutations and characterized, at the molecular level, by prelamin A accumulation. Anomalous fat distribution is the main clinical feature of the disease. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Early activation of autophagy and subsequent block were observed in laminopathic brown and white adipocyte precursors. Precocious activation of autophagy at the onset of white adipogenesis impaired formation of large lipid droplets and was associated with PPAR? 2 downregulation and upregulation of the brown adipose tissue marker UCP-1. Conversely, activation of autophagy before the onset of brown adipogenesis, shifted the differentiation process towards the white pathway, causing downregulation of PPAR? 1 ultimately eliciting brite adipocytes. In agreement with these in vitro results, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and suggest that modulation of autophagic signaling may represent a tool to counteract pathogenetic processes.
Modulation of brown adipose tissue differentiation in FPLD2
Giovanna Lattanzi
2016
Abstract
Among the mechanisms that regulate pre-adipocyte commitment towards the brown or white adipose tissue lineage is the differential activation of autophagic processes. We identified deregulation of autophagy in both Type-2 Familial Partial Lipodystrophy (FPLD2) pre-adipocytes and experimental models obtained by drug-induced accumulation of prelamin A in adipocyte precursors. FPLD2 is a genetic disorder associated with LMNA mutations and characterized, at the molecular level, by prelamin A accumulation. Anomalous fat distribution is the main clinical feature of the disease. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Early activation of autophagy and subsequent block were observed in laminopathic brown and white adipocyte precursors. Precocious activation of autophagy at the onset of white adipogenesis impaired formation of large lipid droplets and was associated with PPAR? 2 downregulation and upregulation of the brown adipose tissue marker UCP-1. Conversely, activation of autophagy before the onset of brown adipogenesis, shifted the differentiation process towards the white pathway, causing downregulation of PPAR? 1 ultimately eliciting brite adipocytes. In agreement with these in vitro results, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and suggest that modulation of autophagic signaling may represent a tool to counteract pathogenetic processes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
