title: Sodium tungstate regulates food intake and body weight through activation of the hypothalamic leptin pathway.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratory of Diabetes and Obesity, Institut d'investigacions Biomèdiques August Pi i Sunyer, Endocrinology and Nutrition Unit-Hospital Clínic, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Amigó-Correig
authors.forename: S
authors.initials: S
authors.lastname: Barceló-Batllori
authors.forename: S
authors.initials: S
authors.lastname: Piquer
authors.forename: M
authors.initials: M
authors.lastname: Soty
authors.forename: G
authors.initials: G
authors.lastname: Pujadas
authors.forename: R
authors.initials: R
authors.lastname: Gasa
authors.forename: A
authors.initials: A
authors.lastname: Bortolozzi
authors.forename: M C
authors.initials: MC
authors.lastname: Carmona
authors.forename: R
authors.initials: R
authors.lastname: Gomis
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology; D020738:Leptin / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D017973:Tungsten Compounds / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000494:pharmacology*
chemical_list: D001067:Appetite Depressants; D020738:Leptin; D017973:Tungsten Compounds; C025399:sodium tungstate(VI)