First published January 4, 2010 - More info
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.
Stephen C. Benoit, Christopher J. Kemp, Carol F. Elias, William Abplanalp, James P. Herman, Stephanie Migrenne, Anne-Laure Lefevre, Céline Cruciani-Guglielmacci, Christophe Magnan, Fang Yu, Kevin Niswender, Boman G. Irani, William L. Holland, Deborah J. Clegg
Original citation: J. Clin. Invest.119:2577–2589 (2009). doi:10.1172/JCI36714.
Citation for this corrigendum: J. Clin. Invest.120:394 (2010). do:10.1172/JCI36714C1.
During the preparation of the manuscript, the vehicle for ICV fatty acid infusion was incorrectly described. The incorrect description is on page 2586. The corrected paragraph appears below.
Fatty acid infusion. Oleate (Oleic Acid–Cyclodextrin Complex; Sigma-Aldrich) was dissolved in PBS. Palmitate was first dissolved in absolute ethanol to make a 5 mM stock solution, which was then further dissolved in PBS. Rats were implanted with a cannula aimed into the third ventricle as described above. The cannula was connected via a polyethylene catheter to a subcutaneous osmotic minipump (Alza Corporation) filled with either palmitic or oleic acid (equimolar concentrations, 10 μmol/l) or vehicle (PBS) for continuous infusion over 3 days. The fatty acids were infused at a rate of 12 μl/d (or 8.3 nl/min); thus, we infused a total volume of 36 μl/3 d, which represents 1.8 nmol/3 d (i.e., 0.41 pmol/min).
The authors regret the errors.