To summary, we have revealed a negative modulation pattern of MD‐1 and MAPK/NF‐κB signalling pathways to protect myocardial structure and function in against hyperlipaemia‐induced pathological remodelling, providing novel insights into the mechanisms of obesity cardiomyopathy and targeting MD‐1 may be a feasible strategy for obesity cardiomyopathy in clinical. This evidence concerns the gene LY86 and obesity due to melanocortin 4 receptor deficiency.