Research article summary (published 8 Aug 2009):

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents.

Full Abstract

Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-theta, 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-theta 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-theta 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-theta nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-theta 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-theta activation, resulting in reduced insulin activity.

Author information

Author/s: Benoit, Stephen C (SC); Kemp, Christopher J (CJ); Elias, Carol F (CF); Abplanalp, William (W); Herman, James P (JP); Migrenne, Stephanie (S); Lefevre, Anne-Laure (AL); Cruciani-Guglielmacci, Céline (C); Magnan, Christophe (C); Yu, Fang (F); Niswender, Kevin (K); Irani, Boman G (BG); Holland, William L (WL); Clegg, Deborah J (DJ);

Affiliation: Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA.

Grants: DK 056863 (Agency:NIDDK NIH HHS) ; DK 17844 (Agency:NIDDK NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: The Journal of clinical investigation (J Clin Invest), published in United States. (Language: eng)

Reference: 2009-Sep; vol 119 (issue 9) : pp 2577-89

Dates: Created 2009/09/04; Completed 2009/10/02;

PMID: 19726875, status: MEDLINE (last retrieved date: 10/2/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Base Sequence Dietary Fats - administration & dosage; toxicity Gluconeogenesis - drug effects Hypothalamus - drug effects; metabolism Insulin Resistance - physiology Isoenzymes - deficiency; genetics; metabolism Leptin - metabolism Liver - drug effects; metabolism Male

Mice Mice, Inbred C57BL Mice, Knockout Palmitic Acid - administration & dosage; toxicity Protein Kinase C - deficiency; genetics; metabolism RNA, Small Interfering - genetics Rats Rats, Long-Evans Signal Transduction - drug effects Subcellular Fractions - drug effects; enzymology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Dietary Fats (0) ; Isoenzymes (0) ; Leptin (0) ; RNA, Small Interfering (0) ; Palmitic Acid (57-10-3) ; Pkcq protein, rat (EC 2.7.1.-) ; Prkcq protein, mouse (EC 2.7.1.-) ; Protein Kinase C (EC 2.7.11.13)

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