Liver PKCε Heterozygous (LivPKCεfl/Δ) Female Mice Showed Better Glucose Tolerance than LivPKCεfl/Δ Male Mice When Fed on High Fat or High Fructose Diet for One Month

Abstract

Introduction: Excess intake of high fat (HFD) and high fructose (HFrD) diets leads to liver fat accumulation that are linked with insulin resistance, glucose intolerance, hepatosteatosis and diet induced obesity. Activation of liver protein kinase Cε (PKCε) has been implicated as a key mediator of diet induced hepatic insulin resistance. However, this mechanism is not fully understood. Using PKCε knockout (PKCε-KO) mice, we aim to investigate the molecular mechanisms of how PKCε may interact with the insulin signaling cascade in both HFD and HFrD induced insulin resistance and obesity. Hypothesis: Studies have shown that PKCε−/− mice are protected from diet-induced insulin resistance and fasting-state glucose homeostasis was enhanced in PKC-KO mice. We hypothesize that hepatic PKCε deletion will protect against HFD and HFrD induced glucose intolerance in mice. Methods: In order to generate liver specific PKCε−/− mice, we crossed female PKCεfl/fl mice with male Alb Cre+/+ mice. At the time of this study, we have generated heterozygous (PKCεfl/Δ) mice which are being crossed to develop homozygous PKCε knockout (LivPKCεΔ/Δ) mice. Both Male and Female heterozygous (PKCεfl/Δ) mice were placed on three diets: Control (Cntrl, Research Diets Inc, RDI D12450J, Protein (20%), Carbs (70%, corn starch-50%, sucrose-maldextrin-20%, fructose-0%), Fat 10% (lard)), High Fructose (HFrD, RDI D02022704), Protein (20%), Carbs (70%, corn starch-50%, sucrose-maldextrin-20%, fructose-60%), Fat 10% (lard)) and High Fat (HFD, RDI D12492, Protein (20%), Carbs (20%, corn starch-0%, sucrose-maldextrin-20%, fructose-0%), Fat 60% (lard)). Within 1 month on the diets, the mice were genotyped and glucose tolerance tests (GTT, 2 g/kg body weight) were performed following 6 hours of starvation. Results: Our preliminary results showed that within one month, LivPKCεfl/Δ-HFD and LivPKCεfl/Δ-HFrD female mice displayed better glucose tolerance than male mice as seen by their lower glucose level during GTT. Interestingly, both LivPKCεfl/Δ male and LivPKCεfl/Δ female mice did not show significant differences in glucose tolerance when they were on control diet (LivPKCεfl/Δ-Cntrl) within the same duration. Conclusion: Conflicting evidence exists whether liver or adipose tissue specific deletion of PKCε protects mice from diet induced glucose intolerance. Studies in both humans and rodents have demonstrated that female subjects experience less endogenous glucose production and less hepatic insulin resistance than their male counterparts after high fat or high fructose challenge (PMID 23049932, PMID 18332156) and our preliminary findings are in line with these studies. Subsequent studies will use homozygous PKCε (LivPKCεΔ/Δ) mice and their littermates Wild-type mice for in-depth metabolic and molecular analysis. We would like to thank the National Science Foundation for award # NSF1931045 and the National Institutes of Health, award # 1R01DK126892-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.