Background: Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances
progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like-
Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity
and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity. Glucagon treatment reduces
lipids after acute and chronic treatment.
Objective: In this study, we have investigated the effect of co-agonist on the prevention of NAFLD induced
by long-term feeding of High Fat Diet (HFD).
Method: We have used HFD to induce NAFLD after chronic feeding in mice. Co-agonist treatment
(150 µg.kg-1, s.c.) was initiated with induction of HFD, which was continued for 40 weeks. Body
weight, food intake, glucose homeostasis, lipid profile, inflammatory and fibrotic markers were assessed
at the end of treatment.
Results: Co-agonist treatment prevented body weight gain, glucose intolerance and insulin resistance.
Treatment with co-agonist reduced NEFA, increased FGF21 and adiponectin levels. Co-agonist increased
glycerol release and energy expenditure, while decreased respiratory quotient. Co-agonist reduced
lipids in circulation and liver. Expression of SREBP-1C, SCD-1, ACC and FAS were decreased,
while ACOX1 and CPT1 were increased after co-agonist treatment. Inflammatory cytokine TNF-α and
IL-6 in plasma and expression of MCP-1, TGF-ß, MMP-9, TNF-α, TIMP-1, α-SMA, and COL1A1
were decreased after co-agonist treatment. Plasma transaminases, hepatic TBARS, hepatic hydroxyproline
and relative liver weight were suppressed after co-agonist treatment. Fat accumulation, inflammation
and fibrosis were reduced in histological assessment of liver in co-agonist treated animals.
Conclusion: Co-agonist prevented development of HFD-induced NAFLD by ameliorating obesity, diabetes,
inflammation and fibrosis.