Moreover, M1 macrophages inhibit the activity of lipolytic enzymes (such as ATGL) by secreting TNF-α, thereby disrupting lipid storage homoeostasis; activation of the EPAC2–ST2 pathway may further reinforce this process, which is associated with obesity-related metabolic disorders [188,189]. Here, RAPGEF4 is linked to obesity due to melanocortin 4 receptor deficiency.