Anti-Obesity Sodium Tungstate Treatment Triggers Axonal and Glial Plasticity in Hypothalamic Feeding Centers

Abstract

ObjectiveThis study aims at exploring the effects of sodium tungstate treatment on hypothalamic plasticity, which is known to have an important role in the control of energy metabolism.MethodsAdult lean and high-fat diet-induced obese mice were orally treated with sodium tungstate. Arcuate and paraventricular nuclei and lateral hypothalamus were separated and subjected to proteomic analysis by DIGE and mass spectrometry. Immunohistochemistry and in vivo magnetic resonance imaging were also performed.ResultsSodium tungstate treatment reduced body weight gain, food intake, and blood glucose and triglyceride levels. These effects were associated with transcriptional and functional changes in the hypothalamus. Proteomic analysis revealed that sodium tungstate modified the expression levels of proteins involved in cell morphology, axonal growth, and tissue remodeling, such as actin, CRMP2 and neurofilaments, and of proteins related to energy metabolism. Moreover, immunohistochemistry studies confirmed results for some targets and further revealed tungstate-dependent regulation of SNAP25 and HPC-1 proteins, suggesting an effect on synaptogenesis as well. Functional test for cell activity based on c-fos-positive cell counting also suggested that sodium tungstate modified hypothalamic basal activity. Finally, in vivo magnetic resonance imaging showed that tungstate treatment can affect neuronal organization in the hypothalamus.ConclusionsAltogether, these results suggest that sodium tungstate regulates proteins involved in axonal and glial plasticity. The fact that sodium tungstate could modulate hypothalamic plasticity and networks in adulthood makes it a possible and interesting therapeutic strategy not only for obesity management, but also for other neurodegenerative illnesses like Alzheimer’s disease.

Preclinical and Clinical Studies for Sodium Tungstate: Application in Humans

“…Sodium tungstate (NaW) has shown to be an effective and safety normoglycemic agent in different T1D and T2D experimental animal models, being administered orally ( ad libitum , in tap water) as a non-invasive easy-to-use anti-diabetic agent [ 26 , 27 ]. NaW has proven to effectively normalize blood glucose [ 26 – 29 ] and triglycerides levels [ 28 , 30 , 31 ], to restore hepatic glucose metabolism [ 26 , 27 , 29 ], to stimulate pancreatic [ 32 – 35 ], cardiac [ 36 ] and sexual [ 37 , 38 ] function, to reduce blood pressure [ 39 – 41 ], to exert anti-obesity [ 28 , 30 , 31 , 42 ]; and immunomodulatory [ 43 ] activities. Notably, NaW does not produce hypoglycemic episodes, and it also stimulates weight loss [ 31 , 44 ].…”

“…Excessive caloric intake has been proposed as a negative signal for remodeling of neuronal networks in the adult hypothalamus, while caloric restriction potentiates remodeling of brain areas, suggesting that neuronal plasticity is important for a correct energy balance [ 112 , 113 ]. NaW treatment has shown to alter expression of proteins in arcuate (ARC), lateral (LHA) and paraventricular (PVN) nuclei in the hypothalamus from both lean and obese mice [ 28 ]. Expression of proteins involved in cytoskeleton structure (alpha-internexin (INA), neurofilament medium polypeptide (NEFM), glial fibrillary acidic protein (GFAP), βactin, α and β tubulin) and remodeling (collapsin response mediator protein (CRMP)-2) was influenced by NaW [ 28 ].…”

“…NaW treatment has shown to alter expression of proteins in arcuate (ARC), lateral (LHA) and paraventricular (PVN) nuclei in the hypothalamus from both lean and obese mice [ 28 ]. Expression of proteins involved in cytoskeleton structure (alpha-internexin (INA), neurofilament medium polypeptide (NEFM), glial fibrillary acidic protein (GFAP), βactin, α and β tubulin) and remodeling (collapsin response mediator protein (CRMP)-2) was influenced by NaW [ 28 ]. Interestingly, neurofilament proteins are regulated through MAPK and STAT3 [ 114 ], and CRMP-2 through PI3K, MAPK and GSK3β [ 115 ], which in turn have been shown to be modulated by NaW [ 25 , 27 , 28 , 44 , 108 ].…”

“…Expression of proteins involved in cytoskeleton structure (alpha-internexin (INA), neurofilament medium polypeptide (NEFM), glial fibrillary acidic protein (GFAP), βactin, α and β tubulin) and remodeling (collapsin response mediator protein (CRMP)-2) was influenced by NaW [ 28 ]. Interestingly, neurofilament proteins are regulated through MAPK and STAT3 [ 114 ], and CRMP-2 through PI3K, MAPK and GSK3β [ 115 ], which in turn have been shown to be modulated by NaW [ 25 , 27 , 28 , 44 , 108 ]. In the ARC nucleus, NaW induced an increase in the number of c-fos positive cells, which has been previously shown to be mediated by activation of the MAPK pathway [ 44 ], and also in number and size of GFAP-positive astroglia [ 28 ].…”

“…Interestingly, neurofilament proteins are regulated through MAPK and STAT3 [ 114 ], and CRMP-2 through PI3K, MAPK and GSK3β [ 115 ], which in turn have been shown to be modulated by NaW [ 25 , 27 , 28 , 44 , 108 ]. In the ARC nucleus, NaW induced an increase in the number of c-fos positive cells, which has been previously shown to be mediated by activation of the MAPK pathway [ 44 ], and also in number and size of GFAP-positive astroglia [ 28 ]. A reduction of β tubulin and syntaxin 1 (HPC-1), and an increase of the neurogenic differentiation (NeuroD)-1 transcription factor and synaptosomal-associated protein (SNAP)-25 expression was also detected in the ARC nucleus from NaW-treated mice [ 28 ].…”