Oral Presentation ANZOS Annual Scientific Meeting 2021

A Novel Role of Endogenous Interleukin-22 as a Regulator of Glucose and Lipid Metabolism (#102)

Haressh Sajiir 1 2 , Sahar Keshvari 1 2 , Kuan Yau Wong 1 2 , Amelia Fotheringham 1 2 , Ran Wang 1 2 , Percival Wiid 1 2 , Jack Lockett 1 3 , Grant Ramm 4 , Graeme Macdonald 3 , John Prins 5 , Michael A. McGuckin 5 , Sumaira Z. Hasnain 1 2 6
  1. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  2. Mater Research Institute, Translational Research Instutute, Brisbane, Queensland, Australia
  3. Princess Alexandra Hospital, Brisbane, Queensland, Australia
  4. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  5. University of Melbourne, Melbourne, Victoria, Australia
  6. Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia

We had previously discovered that exogenous IL-22 is highly efficacious in metabolic disease, with benefits including: complete restoration of glucose tolerance, suppression of fasting hyperinsulinemia/hyperproinsulinemia, and restoration of insulin sensitivity [1]. Importantly, obese animals treated with IL-22, show significant improvements in circulating triglycerides, an improvement in liver function (AST:ALT ratio) and a reduction in lipid accumulation in the liver. However, the role of endogenous IL-22 in maintaining metabolic homeostasis remained unknown. To evaluate the role of endogenous IL-22 in metabolic tissue, we generated tissue specific IL-22 receptor (IL-22RA1) knockout mice lacking the receptor in pancreatic β-cells (IL-22RA1-/- Ins2Cre) and hepatocytes (IL-22RA1-/- AlbCre), and challenged these mice with a high fat diet. Assessments included glucose tolerance and insulin resistance tests, changes in histology, changes in gene expression of inflammatory, ER, oxidative stress markers, assessing changes in lipid accumulation and hormone secretion. As the IL-22RA1-/-Ins2Cre mice aged, they had inappropriate glucose control compared with IL-22RA1fl/fl control animals, and this was exacerbated when the mice were challenged with a high fat diet. Our data demonstrates the importance of endogenous IL-22 in the liver as the ablation of hepatic IL-22RA1 signaling induced insulin resistance, with an increase in fasting blood glucose observed in the 20-week-old animals. Expression of lipogenic markers (Srebp1c and Chrebp), glucose transporter (Glut-2) and glycogen metabolism (Gys2, Pygl) were significantly reduced in the absence of hepatic IL-22-signaling. This was accompanied by increased inflammatory cytokines (Tnfa, Il1b, Il10, Ccl2), and increased cellular stress (Nos2, Grp78) in the liver; supporting the hypothesis that endogenous IL-22 is hepatoprotective. Our work provides new evidence that IL-22RA1 signaling plays an essential regulatory role in pancreas and liver homeostasis under physiological conditions, which is exacerbated during obesity.

  1. Hasnain, S.Z., et al., Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med, 2014. 20(12): p. 1417-26.