LEP and obesity due to melanocortin 4 receptor deficiency: Conversely, leptin, secreted by adipocytes, acts on the ObR receptor via JAK2/STAT3 and PI3K/MAPK pathways, and under conditions of obesity and hyperleptinemia, induces a pro-inflammatory state that favors macrophage polarization toward the M1 phenotype, leading to the release of cytokines such as TNF-α, IL-6, and IL-1β, thereby contributing to the development of insulin resistance [92,93,94,95].