Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity.
In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.
Milanski
Marciane
M
Department of Internal Medicine , Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
Degasperi
Giovanna
G
Coope
Andressa
A
Morari
Joseane
J
Denis
Raphael
R
Cintra
Dennys E
DE
Tsukumo
Daniela M L
DM
Anhe
Gabriel
G
Amaral
Maria E
ME
Takahashi
Hilton K
HK
Curi
Rui
R
Oliveira
Helena C
HC
Carvalheira
José B C
JB
Bordin
Silvana
S
Saad
Mário J
MJ
Velloso
Lício A
LA
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D007211:Indoles; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D017628:Microglia / Q000187:drug effects; D009154:Mutation; D009765:Obesity / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D016207:Cytokines; D005227:Fatty Acids; D007211:Indoles; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C007293:DAPI