Egg-white derived bioactive peptides improve insulin resistance and non-alcoholic fatty liver disease in mice: mechanisms of action
Creators: Zani, Stepheny Carneiro de Campos
Publisher: name: University of Alberta Library
Year: 2023

<p>Metabolic syndrome is a condition characterized by the presence of multiple co-morbidities<br>
including hypertension, dyslipidemia, obesity and hyperglycemia. More recently, non-alcoholic<br>
fatty liver disease (NAFLD) has been included in this cluster as the hepatic manifestation of the<br>
metabolic syndrome. Lifestyle interventions are the first line of therapy for these co-morbidities<br>
and while pharmacological treatment is available for some of them, life-long adherence to<br>
treatment is challenging. Others, such as NAFLD remain without approved pharmacological<br>
therapy.<br>
Food-derived bioactive peptides are short amino acid sequences derived from a parent protein<br>
from a food source. Bioactive peptides, beyond their nutritional value modulate physiological<br>
processes; therefore, they have a role in disease management. We are interested in egg-derived<br>
bioactive peptides and our group showed before that egg white hydrolysate and bioactive<br>
peptides have antihypertensive effects in vivo and anti-inflammatory and adipogenic activity in<br>
vitro. Moreover, in vitro these peptides prevent angiotensin II- and tumor necrosis factor alphainduced<br>
insulin resistance.<br>
Given the crosstalk between the conditions in the metabolic syndrome, I hypothesized that<br>
two bioactive peptides derived from the egg white, Peptide 2 (QAMPFRVTEQE) and IRW,<br>
would promote beneficial effects on diet-induced metabolic dysfunction. More specifically, I<br>
focused on insulin resistance and NAFLD.<br>
To address this hypothesis C57BL/6 mice were fed high-fat diet (HFD) for 6 weeks to induce<br>
obesity and glucose intolerance. After that, their diet was supplemented with either of the<br>
peptides (Peptide 2 or IRW) for another 8 weeks. Another group received HFD and<br>
rosiglitazone, an insulin sensitizer and the third group continued receiving HFD only. Throughout the 14-week period one group received a low-fat diet. Glucose tolerance, insulin<br>
sensitivity and body composition were assessed in vivo. After euthanasia, blood, skeletal muscle,<br>
adipose tissue, and liver tissues were collected. Plasma biochemical analysis was performed<br>
using ELISA and colorimetric commercial kits. Insulin signaling, lipolysis, adipogenesis<br>
markers, renin-angiotensin system components, mitochondria and lipid metabolism were<br>
assessed by western blot, qPCR or functional assays. NAFLD features were characterized by<br>
biochemical and histological analysis.<br>
Overall, Peptide 2 improved systemic insulin resistance and restored adipose tissue insulin<br>
signaling, thereby normalizing the lipolytic response to insulin. The actions of Peptide 2 on<br>
adipose tissue may in part explain the observed decrease in hepatic lipid accumulation. IRW<br>
improved insulin resistance and insulin signaling in skeletal muscle but not in adipose tissue.<br>
IRW prevented NAFLD, concurrent with increasing fatty acid oxidation and mitochondria<br>
content in the liver. I propose that the peptides are exerting their effects via membrane bound<br>
receptors, such as via angiotensin II type 2 receptor (AT2R) or angiotensin 1-7 receptor (MasR);<br>
however, this requires further evaluation.<br>
In conclusion, in this thesis I provide evidence that bioactive peptides promote beneficial<br>
effects in an obese, glucose intolerant mouse model. More specifically, these peptides both<br>
improve insulin signaling and reduce hepatic steatosis, thus providing a potential novel<br>
therapeutic option for NAFLD, which currently lacks approved pharmacological treatment.</p>