title: TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient--effects on leptin and insulin signaling pathways.
abstract: Acting in the hypothalamus, tumor necrosis factor-alpha (TNF-alpha) produces a potent anorexigenic effect. However, the molecular mechanisms involved in this phenomenon are poorly characterized. In this study, we investigate the capacity of TNF-alpha to activate signal transduction in the hypothalamus through elements of the pathways employed by the anorexigenic hormones insulin and leptin. High dose TNF-alpha promotes a reduction of 25% in 12h food intake, which is an inhibitory effect that is marginally inferior to that produced by insulin and leptin. In addition, high dose TNF-alpha increases body temperature and respiratory quotient, effects not reproduced by insulin or leptin. TNF-alpha, predominantly at the high dose, is also capable of activating canonical pro-inflammatory signal transduction in the hypothalamus, inducing JNK, p38, and NFkappaB, which results in the transcription of early responsive genes and expression of proteins of the SOCS family. Also, TNF-alpha activates signal transduction through JAK-2 and STAT-3, but does not activate signal transduction through early and intermediary elements of the insulin/leptin signaling pathways such as IRS-2, Akt, ERK and FOXO1. When co-injected with insulin or leptin, TNF-alpha, at both high and low doses, partially impairs signal transduction through IRS-2, Akt, ERK and FOXO1 but not through JAK-2 and STAT-3. This effect is accompanied by the partial inhibition of the anorexigenic effects of insulin and leptin, when the low, but not the high dose of TNF-alpha is employed. In conclusion, TNF-alpha, on a dose-dependent way, modulates insulin and leptin signaling and action in the hypothalamus.
authors: Department of Internal Medicine, State University of Campinas, Brazil.
authors: Talita
authors: T
authors: Romanatto
authors: Maristela
authors: M
authors: Cesquini
authors: Maria E
authors: ME
authors: Amaral
authors: Erika A
authors: EA
authors: Roman
authors: Juliana C
authors: JC
authors: Moraes
authors: Márcio A
authors: MA
authors: Torsoni
authors: Ariovaldo P
authors: AP
authors: Cruz-Neto
authors: Lício A
authors: LA
authors: Velloso
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors; D007328:Insulin; D053614:Janus Kinase 2; D020738:Leptin; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1