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: Talita Romanatto, Maristela Cesquini, Maria E Amaral, Erika A Roman, Juliana C Moraes, Márcio A Torsoni, Ariovaldo P Cruz-Neto, Lício A Velloso
• Journal: Peptides (Peptides) Vol. 28 Issue 5 Pg. 1050-8 (May 2007) ISSN: 0196-9781 [Print] United States
• PMID: 17459524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Transcription Factors
• Insulin
• Leptin
• Nerve Tissue Proteins
• Tumor Necrosis Factor-alpha
• Foxo1 protein, rat
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Respiration (drug effects)
• Dose-Response Relationship, Drug
• Eating (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Forkhead Transcription Factors (metabolism)
• Hypothalamus (drug effects, metabolism)
• Immunoblotting
• Immunoprecipitation
• Insulin (administration & dosage, metabolism, pharmacology)
• Janus Kinase 2 (metabolism)
• Leptin (administration & dosage, metabolism, pharmacology)
• Male
• Nerve Tissue Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Time Factors
• Tumor Necrosis Factor-alpha (administration & dosage, pharmacology)