An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

Abstract

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a global health problem. Currently, no pharmacological treatment is approved for NAFLD. Natural health products, including bioactive peptides, are potential candidates to aid in the management of metabolic syndrome-related conditions, including insulin resistance and obesity. In this study, we hypothesized that an egg-white-derived bioactive peptide QAMPFRVTEQE (Peptide 2) would improve systemic and local white adipose tissue insulin sensitivity, thereby preventing high-fat diet-induced exacerbation of pathological features associated with NAFLD, such as lipid droplet size and number, inflammation, and hepatocyte hypertrophy in high-fat diet-fed mice. Similar to rosiglitazone, Peptide 2 supplementation improved systemic insulin resistance during the hyperinsulinemic-euglycemic clamp and enhanced insulin signalling in white adipose tissue, modulating ex vivo lipolysis. In the liver, compared with high-fat diet fed animals, Peptide 2 supplemented animals presented decreased hepatic cholesterol accumulation (p < 0.05) and area of individual hepatic lipid droplet by around 50% (p = 0.09) and reduced hepatic inflammatory infiltration (p < 0.05) whereas rosiglitazone exacerbated steatosis. In conclusion, Peptide 2 supplementation improved insulin sensitivity and decreased hepatic steatosis, unlike the insulin-sensitizing drug rosiglitazone.

IRW prevents diet-induced non-alcoholic fatty liver disease by preserving mitochondrial content and enhancing hepatic fatty acid oxidation capacity

“…In conclusion, while both IRW45 and rosiglitazone improved glucose tolerance and insulin resistance in previous studies 20,24 , our data indicate that IRW45 uniquely acts in the liver to protect against NAFLD by preserving mitochondrial content. This in turn enhances mitochondria oxidative capacity potentially leading to increased fatty acid oxidation, while decreasing lipogenesis, all of which prevent HFD-induced NAFLD (Fig.…”

“…Rosiglitazone, a PPARγ agonist, was included in our study as a positive control for insulin sensitization. Therefore, even though both IRW45 and rosiglitazone improved glucose homeostasis and insulin resistance in our previous experiments 20,24 , only IRW45 prevented HFD-induced liver steatosis. Differently from its effects in humans, rosiglitazone treatment in mice induces hepatic lipid accumulation via PPARγ activation in the liver 25,26 , which is consistent with our ndings.…”

“…Male C57BL/6 mice age 5 weeks (Charles River Canada, St. Constant, QC, Canada) were fed LFD (10% kcal fat) or HFD (45% kcal fat) for 6 weeks to induce obesity and glucose intolerance 24 . After that, animals receiving HFD were randomly assigned to continue receiving only HFD or HFD supplemented with IRW at 45 mg/Kg BW or 95 µmol/Kg BW (IRW45) in their diet or HFD + rosiglitazone at 2.5 µmol/Kg BW in their drinking water (ROSI) for 8 weeks.…”

“…At week 13, all the animals underwent an OGTT as previously described 24 . Brie y, a bolus of glucose (1g/kg BW) was orally gavaged to overnight-fasted mice and blood glucose measured from the tail vein using a glucometer (Contour ® Next, Mississauga, ON, CA) at 0-, 15-, 30-, 60-, 90-, and 120-min.…”

“…Para n blocks were cut in 5µm sections and the prepared slides stained for hematoxylin & eosin as previously reported 24 . Liver characterization: 3 random photomicroscopic images per mice were taken by one researcher (20×, Axio Vision 4.8 software) and a second researcher blinded to group allocation used the ImageJ software "freehand selections" tool to quantify LD area.…”