Hypothalamic actions of tumor necrosis factor alpha provide the thermogenic core for the wastage syndrome in cachexia.

Abstract

TNFalpha is an important mediator of catabolism in cachexia. Most of its effects have been characterized in peripheral tissues, such as skeletal muscle and fat. However, by acting directly in the hypothalamus, TNFalpha can activate thermogenesis and modulate food intake. Here we show that high concentration TNFalpha in the hypothalamus leads to increased O(2) consumption/CO(2) production, increased body temperature, and reduced caloric intake, resulting in loss of body mass. Most of the thermogenic response is produced by beta 3-adrenergic signaling to the brown adipose tissue (BAT), leading to increased BAT relative mass, reduction in BAT lipid quantity, and increased BAT mitochondria density. The expression of proteins involved in BAT thermogenesis, such as beta 3-adrenergic receptor, peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha, and uncoupling protein-1, are increased. In the hypothalamus, TNFalpha produces reductions in neuropeptide Y, agouti gene-related peptide, proopiomelanocortin, and melanin-concentrating hormone, and increases CRH and TRH. The activity of the AMP-activated protein kinase signaling pathway is also decreased in the hypothalamus of TNFalpha-treated rats. Upon intracerebroventricular infliximab treatment, tumor-bearing and septic rats present a significantly increased survival. In addition, the systemic inhibition of beta 3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNFalpha action to be important mediator of the wastage syndrome in cachexia.

• Authors: Ana Paula Arruda, Marciane Milanski, Talita Romanatto, Carina Solon, Andressa Coope, Luciane C Alberici, William T Festuccia, Sandro M Hirabara, Eduardo Ropelle, Rui Curi, José B Carvalheira, Aníbal E Vercesi, Licio A Velloso
• Journal: Endocrinology (Endocrinology) Vol. 151 Issue 2 Pg. 683-94 (Feb 2010) ISSN: 1945-7170 [Electronic] United States
• PMID: 19996183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antibodies, Monoclonal
• Gastrointestinal Agents
• Nerve Tissue Proteins
• Tumor Necrosis Factor-alpha
• cocaine- and amphetamine-regulated transcript protein
• Pro-Opiomelanocortin
• Infliximab

Topics

• Adipose Tissue, Brown (innervation, physiology)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Antibodies, Monoclonal (therapeutic use)
• Body Temperature Regulation (physiology)
• Body Weight
• Cachexia (drug therapy, physiopathology)
• Calorimetry, Indirect
• Denervation
• Gastrointestinal Agents (therapeutic use)
• Hypothalamus (drug effects, physiology, physiopathology)
• Infliximab
• Male
• Nerve Tissue Proteins (genetics)
• Polymerase Chain Reaction
• Pro-Opiomelanocortin (genetics)
• Rats
• Rats, Wistar
• Tumor Necrosis Factor-alpha (physiology)
• Wasting Syndrome (drug therapy, physiopathology)