Sodium tungstate regulates food intake and body weight through activation of the hypothalamic leptin pathway

Abstract

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.

Oral tungstate (Na2WO4) exposure reduces adaptive immune responses in mice after challenge

“…We have seen changes in the phosphorylation of histone H1b, which would be consistent with reductions in the proliferative capacity of stimulated lymphocytes (Osterburg et al, 2010). Others have seen reduced ERK1/2, GSK3, and p38 phosphorylation (Amigo-Correig et al, 2011;Gomez-Ramos et al, 2006;Piquer et al, 2007). Many observed effects of tungstate exposure in animals can be explained by this mechanism because changes in phosphorylation can alter key proteins that promote cell cycle progression.…”

Tungstate Reduces the Expression of Gluconeogenic Enzymes in STZ Rats

“…Tungstate also has anti-obesity properties when administered orally to diet-induced obese rats since this compound significantly decreases body weight gain and adiposity without modifying caloric intake or growth rate in these animals [6]. Moreover, it has been recently discovered that the control of food intake and body weight by tungstate is mediated by the activation of the hypothalamic leptin pathway [7].…”

Tungstate promotes β-cell survival inIrs2−/−mice

“…Prior studies have pointed to different target tissues for tungstate actions depending on the model investigated. Thus, tungstate has been shown to normalize hepatic glucose metabolism in streptozotocin (STZ) and Zucker diabetic rats (5,20,37) to improve ␤-cell function in neonatal and adult STZtreated rats (1,3,21) or to modulate energy homeostasis in obese rats (2,7,18). Remarkably, the normoglycemic effects of tungstate in STZ-treated rats were associated with an increase in ␤-cell mass (3,21).…”