title: Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei.
abstract: Mutation of tub gene in mice induces obesity, suggesting that tub could be an important regulator of energy balance. In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism. Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO). Tub tyrosine phosphorylation (Tub-p-tyr) is modulated by nutritional status. Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei. After leptin or insulin stimulation, Tub translocates to the nucleus. Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O(2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression. In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression. These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice.
authors.affiliation: Department of Internal Medicine, State University of Campinas, Campinas, Brazil.
authors.forename: Patrícia O
authors.initials: PO
authors.lastname: Prada
authors.forename: Paula G F
authors.initials: PG
authors.lastname: Quaresma
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Caricilli
authors.forename: Andressa C
authors.initials: AC
authors.lastname: Santos
authors.forename: Dioze
authors.initials: D
authors.lastname: Guadagnini
authors.forename: Joseane
authors.initials: J
authors.lastname: Morari
authors.forename: Laís
authors.initials: L
authors.lastname: Weissmann
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.forename: José Barreto C
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D005215:Fasting; D007031:Hypothalamus / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D054799:Phospholipase C beta / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D020738:Leptin; D016376:Oligonucleotides, Antisense; D011506:Proteins; C098988:Tub protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D054799:Phospholipase C beta