Accumulation of
lipids and their metabolites induces lipotoxicity in
diabetic cardiomyopathy. Lowering
ceramide concentration could reduce the impact of metabolic damage to target organs.
Adiponectin improves lipotoxicity through its receptors (AdiopRs), which have sequence homology with
ceramidase enzymes. Therefore, cardioprotective role of AdipoR agonism by
AdipoRon was investigated. Sixteen-week-old male db/m and db/db mice were fed a diet containing
AdipoRon for four weeks. Phenotypic and metabolic profiles with associated cellular signaling pathways involved in lipid metabolism were investigated in the mice heart and human cardiomyocytes to establish treatment effect of
AdipoRon.
AdipoRon ameliorated
insulin resistance,
fibrosis, M1-dominant
inflammation, and apoptosis in association with reduced accumulations of
free fatty acid,
triglycerides, and TLR4-related
ceramide in the heart. This resulted in overall reduction in the level of oxidative stress which ameliorated
cardiac hypertrophy and its function.
AdipoRon increased the expression of AdipoR1 and AdipoR2 via pAMPK/FoxO1-induced Akt phosphorylation resulting from a decrease in PP2A level. It also increased
acid ceramidase activity which reduced
ceramide and increased sphingosine-1
phosphate levels in the heart of db/db mice and cultured human cardiomyocytes. Consistent upregulation of AdipoRs and their downstream regulatory pathways involving pAMPK/PPARα/PGC-1α levels led to lipid metabolism enhancement, thereby improving lipotoxicity-induced peroxisome biogenesis and oxidative stress.
AdipoRon might control oxidative stress,
inflammation, and apoptosis in the heart through increased AdipoR expression,
acid ceramidase activity, and activation of AMPK-PPARα/PGC-1α and related downstream pathways, collectively improving cardiac lipid metabolism,
hypertrophy, and functional parameters.