INS and obesity due to melanocortin 4 receptor deficiency: In detail, the remodeled and reshaped metabolic microenvironment in obesity drastically dampens insulin signaling and favors the gradual elevation of blood glucose owing to the excessive detrimental accumulation of certain nutrients and metabolites, hyperactive low-grade inflammation, disrupted autophagic process, and energy imbalance resulting from dysregulated microbiome-gut-brain axis.