Fibroblast Growth Factor-21 (FGF-21) enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons.

The Fibroblast Growth factor 21 (FGF-21) is a member of the FGFs family and forms a subfamily with FGF-19 and FGF-23. These three unique FGFs are able to function in an endocrine manner. FGF-21 plays important roles in metabolic regulations including, glucose homeostasis, energy expenditure, and lipid metabolism; it is widely express in metabolic tissues such as liver, adipose tissue, muscle, and pancreas. Thus FGF-21 has been largely studied due to its physiological functions, but very little is known yet about the expression of FGF-21 in the brain, and its possible actions in the Central Nervous System (CNS). FGF-21 exerts also its functions through the involvement of other factors, modulating the expression of specific proteins, that activate downstream pathways in response to certain stimuli. One of the main target of FGF-21 is the Peroxisome proliferator-activated receptor co-activator protein-1α (PGC-1α), a transcriptional co-activator that is increased in several tissues by FGF-21. PGC-1α is a major regulator of mitochondrial functions, biogenesis, and antioxidant response and it was suggested as a therapeutic target in Parkinson’s Disease (PD). According to this, recently Mudò et al. have demonstrate, the neuroprotective effect of PGC-1α, due to its antioxidant actions, in an animal model of PD. PGC-1α is regulated by both transcriptional and posttranslational events, as deacetylation of specific lysine residues performed by specific deacetilase like SIRT-1. These transcriptional and posttranslational modifications involve in addiction the action of growth factors. Therefore, on the basis of these observations, using different approaches, the aim of present study was to investigate the possible interactions between the growth factor FGF-21 and PGC-1α in dopaminergic neurons, and its possible expression in the brain. We demonstrate here that FGF-21 increases the levels of PGC-1 α and its transcription, enhancing the gene promoter activity in human dopaminergic cell culture. Moreover in these cells FGF-21 is able to increase the activity of PGC-1α and elevate mitochondrial antioxidants. The activation of PGC-1α by FGF-21 occurs via the NAD+-dependent deacetylase SIRT-1 subsequent to an increase in the enzyme nicotinamide phosphoribosyltransferase (Nampt), that is the is the rate-limiting enzyme in NAD+ biosynthesis. The increase of mitochondrial antioxidant enzymes levels is accompanied by enhanced mitochondrial respiratory capacity, as shown in real-time analyses of living cells, but not by an increase of the number of these organelles in FGF-21 treated cells. Our results suggest that FGF-21 enhances in human dopaminergic neurons, the mitochondrial activity, by inducing the increase of levels and activity of PGC-1α, via SIRT-1. In vivo, to investigate if FGF-21 was locally produced in the brain, we asses FGF-21 levels in some brain areas using immunoblot analysis. We observed that FGF-21 is expressed in several brain regions, such as the cortex, hippocampus, striatum and substantia nigra. Next, in order to identify brain cells type involved in FFG-21 production , we performed immunohistochemistry assays, using substantia nigra sections from adult rats brain treated with Kainic acid, that induces an excitotoxic damage. These assays reveal that neither the dopaminergic neurons nor astrocytes are involved in the FGF-21 production, microglia cells rather express the growth factor, suggesting a role of FGF-21 in the neuroimmunological response. Taken together these results show that dopaminergic neurons respond to FGF-21 by enhancing the mitochondrial capacity and altering gene pathways regulated by PGC-1α, and that FGF-21 is expressed in the brain by microglial cells, probably following a damage that can active a neuroimmunological response. These findings can open the way to study the potential benefits of FGF-21 treatment in different neurological disorders such as in Parkinson’s Disease

FGF-21 è un fattore di crescita ad azione endocrina principalmente espresso nel fegato con funzioni metaboliche; induce a livello epatico e in altri tessuti incremento di PGC1, ma le sue funzioni a livello cerebrale sono ancora sconosciute. PGC1 è espresso anche nel cervello dove mostra azione neuroprotettiva in neuroni dopaminergici in modelli animali di morbo di Parkinson. Scopo della ricerca era indagare possibili correlazioni tra le due proteine a livello cerebrale. I dati mostrano che FGF-21 induce attivazione di PGC1 mediante la deacetilasi Sirtuina-1 NAD+ dipendente, in neuroni dopaminergici e un incremento dell’attività respiratoria mitocondriale. FGF-21 risulta espresso nel cervello da cellule microgliali sia in vitro che in vivo. Questi risultati suggeriscono un potenziale ruolo di FGF-21 nella malattia di Parkinson, in quanto disordini della catena ossidativa mitocondriale sono di particolare rilievo nei neuroni dopaminergici, alterati in questa patologia