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Keywords:

  • AgRP;
  • appetite control;
  • anti-obesity drug;
  • drug mechanism;
  • energy regulation;
  • ERK1/2;
  • hypothalamus;
  • JAK2;
  • leptin;
  • neuropharmacology;
  • NPY;
  • obesity;
  • obesity therapy;
  • sodium tungstate

Aims: Sodium tungstate is an anti-obesity drug targeting peripheral tissues. In vivo, sodium tungstate reduces body weight gain and food intake through increasing energy expenditure and lipid oxidation, but it also modulates hypothalamic gene expression when orally administered, raising the possibility of a direct effect of sodium tungstate on the central nervous system.

Methods: Sodium tungstate was administered intraperitoneally (ip) to Wistar rats, and its levels were measured in cerebrospinal fluid through mass spectrometry. Body weight gain and food intake were monitored for 24 h after its administration in the third ventricle. Hypothalamic protein was obtained and subjected to western blot. In vitro, hypothalamic N29/4 cells were treated with 100 µM sodium tungstate or 1 nM leptin, and protein and neural gene expression were analysed.

Results: Sodium tungstate crossed the blood–brain barrier, reaching a concentration of 1.31 ± 0.07 mg/l in cerebrospinal fluid 30 min after ip injection. When centrally administered, sodium tungstate decreased body weight gain and food intake and increased the phosphorylation state of the main kinases and proteins involved in leptin signalling. In vitro, sodium tungstate increased the phosphorylation of janus kinase-2 (JAK2) and extracellular signal-regulated kinase-1/2 (ERK1/2), but the activation of each kinase did not depend on each other. It regulated c-myc gene expression through the JAK2/STAT system and c-fos and AgRP (agouti-related peptide) gene expression through the ERK1/2 pathway simultaneously and independently.

Conclusions: Sodium tungstate increased the activity of several kinases involved in the leptin signalling system in an independent way, making it a suitable and promising candidate as a leptin-mimetic compound in order to manage obesity.