Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei.
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.
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GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
insulin leptin proopiomelanocortin thyroid-releasing hormone melanin-concentrating hormone orexin tub leptin insulin Tub O(2) protein tyrosine phosphatase 1B Tub insulin leptin Tub insulin leptin insulin leptin Tub tyr insulin leptin Tub Tub tub Tub insulin receptor tyrosine kinase IRTK leptin receptor LEPR tyrosine Janus kinase 2 JAK2 leptin insulin Tub Tub Tub insulin leptin glucose tyrosine tyr tyrosine glucose glucose