Abstract
BackgroundThe fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription 3 (LepR-STAT3) signalling pathway and FTO was recently suggested in the hypothalamus. Because of the presence of FTO in liver and the role of LepR-STAT3 in the control of hepatic metabolism, we investigated both in vitro and in vivo the potential interrelationship between FTO and LepR-STAT3 signalling pathway in liver and the impact of FTO overexpression on leptin action and glucose homeostasis in liver of mice.ResultsWe found that FTO protein expression is regulated by both leptin and IL-6, concomitantly to an induction of STAT3 tyrosine phosphorylation, in leptin receptor (LepRb) expressing HuH7 cells. In addition, FTO overexpression in vitro altered both leptin-induced Y705 and S727 STAT3 phosphorylation, leading to dysregulation of glucose-6-phosphatase (G6P) expression and mitochondrial density, respectively. In vivo, liver specific FTO overexpression in mice induced a reducetion of Y705 phosphorylation of STAT3 in nuclear fraction, associated with reduced SOCS3 and LepR mRNA levels and with an increased G6P expression. Interestingly, FTO overexpression also induced S727 STAT3 phosphorylation in liver mitochondria, resulting in an increase of mitochondria function and density. Altogether, these data indicate that FTO promotes mitochondrial recruitment of STAT3 to the detriment of its nuclear localization, affecting in turn oxidative metabolism and the expression of leptin-targeted genes. Interestingly, these effects were associated in mice with alterations of leptin action and hyperleptinemia, as well as hyperglycemia, hyperinsulinemia and glucose intolerance.ConclusionsAltogether, these data point a novel regulatory loop between FTO and leptin-STAT3 signalling pathways in liver cells, and highlight a new role of FTO in the regulation of hepatic leptin action and glucose metabolism.
Highlights
The fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown
We investigated in vitro the potential relationships between FTO and the LepRb-STAT3 signalling pathway using human hepatic HuH7 cells, and, we studied the impact of in vivo FTO overexpression in mice liver on leptin signalling and glucose homeostasis
As they poorly respond to leptin treatment (Figure 1A), we transfected them with an expression vector coding for LepRb, and measured leptin-induced STAT3 phosphorylation to validate leptin action in LepRb-transfected HuH7 cells
Summary
The fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription 3 (LepR-STAT3) signalling pathway and FTO was recently suggested in the hypothalamus. Because of the presence of FTO in liver and the role of LepR-STAT3 in the control of hepatic metabolism, we investigated both in vitro and in vivo the potential interrelationship between FTO and LepR-STAT3 signalling pathway in liver and the impact of FTO overexpression on leptin action and glucose homeostasis in liver of mice. The “fat mass and obesity associated” (FTO) gene may be one of the molecular determinants linking both pathologies [1]. JAKmediated phosphorylation of STAT3 on tyrosine (Y705) induced its relocation to nucleus, where, as a dimer, it binds to specific DNA sequences and promotes gene expression. It was recently demonstrated that STAT3 could be phosphorylated on serine residue (S727), mediating the recruitment of STAT3 to mitochondria where it promotes oxydative metabolism [10,11]
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