Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

Stephen J. Peterson,Maria Licari,Ragin Alex,Rita Rezzani,David E. Stec,Nader G. Abraham,Marco Raffaele,Shailendra P. Singh,Sherif Amin,Hsin-hsueh Shen,Francesca Bonomini,Luca Vanella

doi:10.3390/ijms21155469

Abstract

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.

Highlights

According to the World Health Organization (WHO), obesity is defined as an abnormal or excessive accumulation of body fat that increases the risk of many health problems
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Supplementation of dietary-induced, obese mice with PSO improved both the mitochondrial function and dynamics in hepatic steatosis by decreasing the levels of inflammatory markers, nephroblastoma overexpressed gene (NOV), IL-6, and phosphorylated P65, which is a major regulator of IKKβ/NF-KB signaling (Figure 4A–E)

Summary

Introduction

According to the World Health Organization (WHO), obesity is defined as an abnormal or excessive accumulation of body fat that increases the risk of many health problems. Supplementation of dietary-induced, obese mice with PSO improved both the mitochondrial function and dynamics in hepatic steatosis by decreasing the levels of inflammatory markers, NOV, IL-6, and phosphorylated P65, which is a major regulator of IKKβ/NF-KB signaling (Figure 4A–E). This results in increased mitochondrial dynamics (fusion/fission), biogenesis, and function, leading to decreased oxidative stress and inflammation and the activation of anti-apoptotic genes (p65) in obese mice. PSO improved hepatic insulin resistance and increased insulin receptor phosphorylation via increased proteins regulating glucose homeostasis, e.g., p-AMPK, p-AKT, p-IR-tyr972, and p-IR-tyr1146 (Figure 6A–F) All of these pathways play an important role in liver insulin signaling, and all are affected by dietary-induced obesity [65,66].

Western Blot Analysis and Histological Evaluation

Findings

Summary