Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents
Open accessAbstract
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.
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In rodents, high saturated fat content causes hyperinsulinemia, liver and muscle insulin resistance, and hypothalamic inflammation.
“which in rodents causes hyperinsulinemia, liver and muscle insulin resistance, and hypothalamic inflammation (137–143).”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [138]
Substitution of unsaturated fat for saturated fat in these protocols, or ablation of toll-like receptor signaling, reduces metabolic dysfunction and adiposity in rodents.
“Substitution of unsaturated fat for saturated fat in these protocols, or ablation of toll-like receptor signaling, reduces metabolic dysfunction and adiposity (137–143).”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [138]
Prolonged saturated fat intake can impair central leptin and insulin signaling in rodents.
“Prolonged saturated fat intake can interfere with energy homeostasis by stimulating visceral adipose deposition and inflammation in humans [23] and impairing central leptin and insulin signaling in rodents [24,25].”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [24]
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References 78 · Cited by 351
- Authors
- Benoit, S. C., Kemp, C. J., Elias, C. F., Abplanalp, W., Herman, J. P., Migrenne, S., Lefevre, A.-L., Cruciani-Guglielmacci, C., Magnan, C., Yu, F., Niswender, K., Irani, B. G., Holland, W. L., & Clegg, D. J.
- Affiliations
- University of Cincinnati (US)
- The University of Texas Southwestern Medical Center (US)
- United States Department of Veterans Affairs (US)
- Corresponding author
- Clegg, Deborah J.
- Venue
- Journal of Clinical Investigation
- Published
- 2009-09-01
- Volume
- 119
- Issue
- 9
- Pages
- 2577-2589
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2735917
- OpenAlex
- W2115138453
- Cited by
- 351
- References
- 78
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 14 · 2023: 7 · 2022: 15 · 2021: 23 · 2020: 19 · 2019: 18 · 2018: 20 · 2017: 35 · 2016: 21 · 2015: 33 · 2014: 30 · 2013: 24 · 2012: 25
- FWCI
- 10.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Cincinnati
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-056863, DK17844, P01DK056863)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD061539)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- palmitic acid, PKC theta, protein kinase C, insulin signaling, leptin signaling, arcuate nucleus, high-fat diet, diet-induced obesity, oleic acid, subcellular localization, energy balance, central nervous system
- MeSH terms
- Protein Kinase C-theta, Animals, Base Sequence, Dietary Fats, Gluconeogenesis, Hypothalamus, Insulin Resistance, Isoenzymes, Liver, Male, Mice, Inbred C57BL, Protein Kinase C, Subcellular Fractions, Signal Transduction, Mice, Knockout, Palmitic Acid, Rats, Long-Evans, Leptin, RNA, Small Interfering, Mice, Rats
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