MON-616 The Effect Of High Fat Diet On Hepatic Insulin Signaling In Liver Pkcε Heterozygous Male Mice

Abstract Disclosure: A. Abdelgawwad: None. M. Rahman: None. Background: Obesity is a major risk factor for insulin resistance and related metabolic diseases such as type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Hepatic insulin resistance is central to these disorders. Diacylglycerol (DAG) accumulation in hepatocytes activates protein kinase C epsilon (PKCε), which may impair insulin receptor (IR) function. However, the role of PKCε remains controversial and incompletely understood. Methods: Male liver-specific PKCε heterozygous (LivPKCε^+/-) mice and littermate controls were fed a high fat diet (HFD, Research Diets Inc RDI #), Control Diet (RDI #), or chow for 4 weeks. Mice were fasted and then injected intraperitoneally with insulin or saline. Liver tissue was harvested 10 minutes post-injection. Western blotting was used to measure phosphorylation of insulin signaling markers including AKT (p-AKT), FOXO1 (p-FOXO1), and IR (p-IR). Results: In wild-type mice, HFD feeding reduced p-AKT and p-FOXO1 levels compared to chow-fed controls, indicating impaired hepatic insulin signaling[1]. Interestingly, LivPKCε^+/- male mice did not retain significantly higher levels of p-AKT and p-FOXO1 after insulin stimulation on the chow or control diet; however, they showed significantly higher levels of p-AKT on the HFD. Insulin-stimulated p-IR was also not better preserved in heterozygous mice on either the chow or control diet, but HFD significantly reduced p-IR, suggesting that liver PKCε Het male mice were not protected at the level of the insulin receptor and downstream targets. Conclusion: Partial deletion of PKCε in the liver does not attenuate HFD-induced hepatic insulin resistance. These findings still support a model in which PKCε activation may mediate lipid-induced defects in insulin signaling. Targeting PKCε may still represent a promising therapeutic strategy for metabolic diseases characterized by hepatic insulin resistance. Future studies will explore sex differences and PKCε-related mechanisms further. [1] Postprandial Hepatic Lipid Metabolism Requires Signaling through Akt2 Independent of the Transcription Factors FoxA2, FoxO1, and SREBP1c. Wan, Min et al. Cell Metabolism, Volume 14, Issue 4, 516 - 527 Presentation: Monday, July 14, 2025