TY - JOUR
T1 - Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents
AU - Benoit, Stephen C.
AU - Kemp, Christopher J.
AU - Elias, Carol F.
AU - Abplanalp, William
AU - Herman, James P.
AU - Migrenne, Stephanie
AU - Lefevre, Anne Laure
AU - Cruciani-Guglielmacci, Céline
AU - Magnan, Christophe
AU - Yu, Fang
AU - Niswender, Kevin
AU - Irani, Boman G.
AU - Holland, William L.
AU - Clegg, Deborah J.
PY - 2009/9/1
Y1 - 2009/9/1
N2 - Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity.
AB - Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity.
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U2 - 10.1172/JCI36714
DO - 10.1172/JCI36714
M3 - Article
C2 - 19726875
AN - SCOPUS:70349200763
SN - 0021-9738
VL - 119
SP - 2577
EP - 2589
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -