👤 Ioannis Charalampopoulos

Nerve Growth Factor (NGF) affects sympathetic neurons' development and survival. NGF is also found in non-neural cell lineages that are implicated in immune-endocrine interactions associated with metabolic diseases. Although NGF is expressed in white adipose tissue (WAT), little is known about the regulation of its expression and role in adipocytes. To determine whether NGF and its receptors are expressed in human adipocytes and demonstrate their role in adipocyte metabolic and inflammatory phenotypes. The expression of NGF and its receptors TrkA and p75NTR and their effects on metabolic and inflammatory responses were examined in freshly isolated adipocytes from human abdominal WAT and mouse 3T3L1 cells. TrkA and p75NTR were expressed in both human and mouse adipocytes and pre-adipocytes. NGF was secreted by human white adipocytes and their exogenous exposure to NGF increased mitochondrial mass and activity, PPAR-gamma, CEBPA and adiponectin levels. Additionally, NGF increased lipolysis in human WAT explants and suppressed lipids accumulation, LPL and pro-inflammatory mediators IL-6 and IL-8 in human white adipocytes. The pro-inflammatory factor LPS down-regulated the levels of NGF receptors in human white adipocytes. NGF also affected mitochondrial activity in both human and mouse pre-adipocytes and TrkA appeared to mediate, at least partially, the effects of NGF on adipocytes. Our data suggests that NGF is produced locally within the adipose tissue where it up-regulates mitochondrial function while it suppresses the pro-inflammatory phenotype of human and mouse adipocytes. Show less

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75(NTR)), but the mechanism of receptor activation has remained elusive. Here, we show that p75(NTR) forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys(257) in its transmembrane domain. Mutation of Cys(257) abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75(NTR)/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75(NTR). FRET experiments revealed a close association of p75(NTR) intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys(257) did not alter the oligomeric state of p75(NTR), the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75(NTR) by a mechanism involving rearrangement of disulphide-linked receptor subunits. Show less