Interleukin-10 is a protective factor against diet-induced insulin resistance in liver.
OBJECTIVE
The anti-inflammatory cytokine, interleukin-10 (IL-10), is known to exert a protective role in hepatic damage caused by viruses, alcohol, autoimmunity and a number of experimental aggressors. Recently, a protective role for IL-10 has also been proposed in diet-induced hepatic dysfunction. However, studies about the mechanisms involved in this process are controversial. The objective of this study was to evaluate the role of endogenous IL-10 in the development of hepatic insulin resistance, associated with diet-induced fatty liver disease.


METHODS
Male Swiss mice treated for eight weeks with a high-fat diet became diabetic and developed non-alcoholic fatty liver disease, which is characterized by increased hepatic fat deposition and liver infiltration by F4/80 positive cells. This was accompanied by an increased hepatic expression of TNF-alpha, IL-6, IL-1beta and IL-10, and by an impaired insulin signal transduction through the insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1 signaling pathway.


RESULTS
Upon endogenous IL-10 inhibition for 5 days, using two distinct methods, a neutralizing anti-IL-10 antibody and an antisense oligonucleotide against IL-10, increased hepatic expression of the inflammatory markers TNF-alpha, IL-6, IL-1beta and F4/80 was observed. This was accompanied by a significant negative modulation of insulin signal transduction through insulin receptor/IRS1-IRS2/PI3-kinase/Akt/FOXO1, and by the stimulation of hepatic signaling proteins involved in gluconeogenesis and lipid synthesis.


CONCLUSIONS
Thus, in an animal model of diet-induced fatty liver disease, the inhibition of IL-10 promotes the increased expression of inflammatory cytokines, the worsening of insulin signaling and the activation of gluconeogenic and lipidogenic pathways.
Cintra
Dennys E
DE
Department of Internal Medicine, State University of Campinas, Brazil.
Pauli
José R
JR
Araújo
Eliana P
EP
Moraes
Juliana C
JC
de Souza
Cláudio T
CT
Milanski
Marciane
M
Morari
Joseane
J
Gambero
Alessandra
A
Saad
Mário J
MJ
Velloso
Licio A
LA
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012313:RNA / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D016753:Interleukin-10; D012313:RNA