Egg-white derived bioactive peptides improve insulin resistance and non-alcoholic fatty liver disease in mice: mechanisms of action

• Author / Creator

  Zani, Stepheny Carneiro de Campos

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

• Subjects / Keywords

  • Bioactive peptides
  • Insulin resistance
  • non-alcoholic fatty liver disease (NAFLD)
  • IRW

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-wt11-6375

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.