Converging preclinical evidence reinforces this mechanism: in diet-induced obesity, adipose tissue macrophages upregulate Netrin-1 and, through Unc5b, become pathologically retained within adipose depots, perpetuating chronic inflammation and insulin resistance; conversely, myeloid-specific deletion of Netrin-1 facilitates macrophage egress, attenuates adipose inflammation, and improves insulin sensitivity (Ramkhelawon et al., 2014; Sharma et al., 2019; Hsu et al., 2021). This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.