title: Hypothalamic action of glutamate leads to body mass reduction through a mechanism partially dependent on JAK2.
abstract: Glutamate acts in the hypothalamus promoting region-, and cell-dependent effects on feeding. Part of these effects are mediated by NMDA receptors, which are up regulated in conditions known to promote increased food intake and thermogenesis, such as exposure to cold and consumption of highly caloric diets. Here, we hypothesized that at least part of the effect of glutamate on hypothalamic control of energy homeostasis would depend on the control of neurotransmitter expression and JAK2 signaling. The expression of NMDA receptors was co-localized to NPY/AgRP, POMC, CRH, and MCH but not to TRH and orexin neurons of the hypothalamus. The acute intracerebroventricular injection of glutamate promoted a dose-dependent increase in JAK2 tyrosine phosphorylation. In obese rats, 5 days intracerebroventricular treatment with glutamate resulted in the reduction of food intake, accompanied by a reduction of spontaneous motility and reduction of body mass, without affecting oxygen consumption. The reduction of food intake and body mass were partially restrained by the inhibition of JAK2. In addition, glutamate produced an increased hypothalamic expression of NPY, POMC, CART, MCH, orexin, CRH, and TRH, and the reduction of AgRP. All these effects on neurotransmitters were hindered by the inhibition of JAK2. Thus, the intracerebroventricular injection of glutamate results in the reduction of body mass through a mechanism, at least in part, dependent on JAK2, and on the broad regulation of neurotransmitter expression. These effects are not impaired by obesity, which suggest that glutamate actions in the hypothalamus may be pharmacologically explored to treat this disease.
authors.affiliation: Laboratory of Cell Signaling, University of Campinas, Campinas, SP, Brazil.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.forename: Carina
authors.initials: C
authors.lastname: Solon
authors.forename: Erika A
authors.initials: EA
authors.lastname: Roman
authors.forename: Letícia M
authors.initials: LM
authors.lastname: Ignacio-Souza
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005247:Feeding Behavior / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005971:Glutamates / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects*; D053614:Janus Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D005971:Glutamates; D020738:Leptin; D014443:Tyrosine; C507927:Jak2 protein, rat; D053614:Janus Kinase 2