TY - JOUR
T1 - Genetic obesity alters recruitment of TANK-binding kinase 1 and AKT into hypothalamic lipid rafts domains
AU - Delint-Ramirez, Ilse
AU - Maldonado Ruiz, Roger
AU - Torre-Villalvazo, Ivan
AU - Fuentes-Mera, Lizeth
AU - Garza Ocañas, Lourdes
AU - Tovar, Armando
AU - Camacho, Alberto
N1 - Funding Information:
We thank Salvador Luis Said y Fernandez, Herminia Guadalupe Martínez Rodríguez and Brenda Elizabeth Díaz Salinas for their valuable contribution to the technical support. This research was supported by CONACYT-Mexico (Grant 180919 and 168236 ) and funding from ENZACTA S de R. L. de C. V .
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2015/1
Y1 - 2015/1
N2 - Lipid rafts (LRs) are membrane subdomains enriched in cholesterol, glycosphingolipids and sphingolipids containing saturated fatty acid. Signaling proteins become concentrated in these microdomains mainly by saturated fatty acid modification, thus facilitating formation of protein complexes and activation of specific signaling pathways. High intake of saturated fatty acids promotes inflammation and insulin resistance, in part by disrupting insulin signaling pathway. Here we investigate whether lipid-induced toxicity in obesity correlates with altered composition of insulin signaling proteins in LRs in the brain. Our results showed that insulin receptor (IR) is highly concentrated in LRs fraction in comparison with soluble or postsynaptic density (PSD) fractions. Analysis of LRs domains from hippocampus of obese mouse showed a significant decrease of IR and its downstream signaling protein AKT, while in the PSD fraction we detected partial decrease of AKT and no changes in the IR concentration. No changes were shown in the soluble extract. In hypothalamus, genetic obesity also decreases interaction of AKT, but we did not detect changes in the IR distribution. However, in this structure genetic obesity increases recruitment of the IR negative regulator TANK-binding kinase 1 (TBK1) into LRs and PSD fraction. No changes of AKT, IR and TBK1 were found in soluble fractions of obese in comparison with lean mice. In vitro studies showed that incubation with saturated palmitic acid but not with unsaturated docosahexaenoic acid (DHA) or palmitoleic acid decreases association of IR and AKT and increases TBK1 recruitment into LRs and PSD domains, emulating what happens in the obese mice. TBK1 recruitment to insoluble domains correlates with decreases of IR tyrosine phosphorylation and ser473 AKT phosphorylation, markers of insulin resistance. These data support the hypothesis that hyperlipidemia associated with genetic obesity alters targeting of TBK1 and insulin signaling proteins into insoluble LRs domains.
AB - Lipid rafts (LRs) are membrane subdomains enriched in cholesterol, glycosphingolipids and sphingolipids containing saturated fatty acid. Signaling proteins become concentrated in these microdomains mainly by saturated fatty acid modification, thus facilitating formation of protein complexes and activation of specific signaling pathways. High intake of saturated fatty acids promotes inflammation and insulin resistance, in part by disrupting insulin signaling pathway. Here we investigate whether lipid-induced toxicity in obesity correlates with altered composition of insulin signaling proteins in LRs in the brain. Our results showed that insulin receptor (IR) is highly concentrated in LRs fraction in comparison with soluble or postsynaptic density (PSD) fractions. Analysis of LRs domains from hippocampus of obese mouse showed a significant decrease of IR and its downstream signaling protein AKT, while in the PSD fraction we detected partial decrease of AKT and no changes in the IR concentration. No changes were shown in the soluble extract. In hypothalamus, genetic obesity also decreases interaction of AKT, but we did not detect changes in the IR distribution. However, in this structure genetic obesity increases recruitment of the IR negative regulator TANK-binding kinase 1 (TBK1) into LRs and PSD fraction. No changes of AKT, IR and TBK1 were found in soluble fractions of obese in comparison with lean mice. In vitro studies showed that incubation with saturated palmitic acid but not with unsaturated docosahexaenoic acid (DHA) or palmitoleic acid decreases association of IR and AKT and increases TBK1 recruitment into LRs and PSD domains, emulating what happens in the obese mice. TBK1 recruitment to insoluble domains correlates with decreases of IR tyrosine phosphorylation and ser473 AKT phosphorylation, markers of insulin resistance. These data support the hypothesis that hyperlipidemia associated with genetic obesity alters targeting of TBK1 and insulin signaling proteins into insoluble LRs domains.
KW - AKT
KW - Hypothalamus and lipotoxicity
KW - Insulin receptor
KW - Insulin resistance
KW - Obesity
KW - TBK1
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U2 - 10.1016/j.neuint.2014.11.002
DO - 10.1016/j.neuint.2014.11.002
M3 - Article
C2 - 25447767
AN - SCOPUS:84919363522
SN - 0197-0186
VL - 80
SP - 23
EP - 32
JO - Neurochemistry International
JF - Neurochemistry International
ER -