Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction

Abstract

Glycine N-methyltransferase (GNMT) is a major hepatic enzyme that converts S-adenosylmethionine to S-adenosylhomocysteine while generating sarcosine from glycine, hence it can regulate mediating methyl group availability in mammalian cells. GNMT is also a major hepatic folate binding protein that binds to, and, subsequently, may be inhibited by 5-methyltetrafolate. GNMT is commonly diminished in human hepatoma; yet its role in cellular folate metabolism, in tumorigenesis and antifolate therapies, is not understood completely. In the present study, we investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. GNMT-diminished hepatoma cell lines transfected with GNMT were cultured under folate abundance or restriction. Folate-dependent homocysteine remethylation fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. Folate status was compared between wild-type (WT), GNMT transgenic (GNMT tg ) and GNMT knockout (GNMT ko ) mice. In the cell model, GNMT expression increased folate concentration, induced folate-dependent homocysteine remethylation, and reduced antifolate methotrexate cytotoxicity. In the mouse models, GNMT tg had increased hepatic folate significantly, whereas GNMT ko had reduced folate. Liver folate levels correlated well with GNMT expressions (r = 0.53, P = 0.002); and methionine synthase expression was reduced significantly in GNMT ko , demonstrating impaired methylfolate-dependent metabolism by GNMT deletion. In conclusion, we demonstrated novel findings that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Studies on how GNMT expression impacts the distribution of different folate cofactors and the regulation of specific folate dependent reactions are underway.

Association of FTO , LEPR and MTHFR Gene Polymorphisms with Metabolic Syndrome in Schizophrenia Patients Receiving Antipsychotics

“…The exact mechanism for how this gene affects BMI and obesity remains unclear, but it was hypothesized that the FTO gene is involved in food intake, as it is highly expressed in the hypothalamus [35] and was also found to be involved in leptin signaling at the hypothalamus [36]. Animal studies showed that this gene controls energy expenditure and its absence in mice resulted in a leaner body mass and reduced adipocytes [37,38].…”

Subfatin is a Novel Adipokine and Unlike Meteorin in Adipose and Brain Expression

“…Our works on identification of visfatin (also known as NAMPT) as a target for stroke therapy provide new insights into understanding of adipose-brain axis [5][6][7][8][9]. In addition, we demonstrate a novel leptin receptor signaling in the brain for control of body weight under caloric restriction, suggesting FTO may be a therapeutic target for leptin resistance obesity [10]. We also studied the adipokines in adipose renin-angiotensin system [3] and the inflammatory adipokines such as TNFa [11].…”

Association between FTO gene polymorphism and excess body weight in women from before to after pregnancy: A cohort study

“…Furthermore, homozygous AA individuals are more prone to an elevated post‐prandial appetite level, which is linked to an interaction between the FTO genotype and circulating levels of ghrelin, a key mediator of digestive behavior (Karra et al, ). Other studies also suggest an effect of FTO on the regulation of proteins in pathways involved in energy intake, such as leptin levels (Labayen et al, ) and leptin sensitivity (Wang et al, ), and other signaling proteins (Lin et al, ; Rask‐Andersen et al, ). The FTO ‐rs9939609 genotype is also associated with some metabolites, with evidence having been obtained of changes in phospholipid and amino acid metabolisms that may be linked to obesity and type 2 diabetes in A allele carriers (Kim et al, ).…”