Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus.
Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.
Department of Internal Medicine, State University of Campinas, Campinas-SP 13083-970, Brazil.
Cláudio T
CT
De Souza
Eliana P
EP
Araujo
Silvana
S
Bordin
Rika
R
Ashimine
Ricardo L
RL
Zollner
Antonio C
AC
Boschero
Mário J A
MJ
Saad
Lício A
LA
Velloso
D000273:Adipose Tissue; D000818:Animals; D001066:Appetite / Q000187:drug effects; D001483:Base Sequence; D017931:DNA Primers; D004041:Dietary Fats / Q000009:adverse effects*; D002149:Energy Intake / Q000187:drug effects; D004822:Epididymis; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007276:Injections, Intraventricular; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004041:Dietary Fats; D007328:Insulin; D016328:NF-kappa B