Interleukin‐4 inhibits the hypothalamic appetite control by modulating the insulin‐AKT and JAK‐STAT signaling in leptin mutant mice

Abstract Our previous research identified interleukin‐4 (IL‐4) as a key regulator of glucose/lipid metabolism, circulatory leptin levels, and insulin action, suggesting its potential as a therapeutic target for obesity and related complications. This study aimed to further elucidate the role of IL‐4 in regulating hypothalamic appetite‐controlling neuropeptides using leptin dysfunctional Leptin 145E/145E mice as the experimental model. IL‐4 significantly reduces body weight, food intake, and serum glucose levels. Our data demonstrated that IL‐4 exhibits multiple functions in regulating hypothalamic appetite control, including downregulating orexigenic agouti‐related peptide and neuropeptide Y levels, promoting expression of anorexigenic proopiomelanocortin, alleviating microenvironmental hypothalamic inflammation, enhancing leptin and insulin pathway, and attenuating insulin resistance. Furthermore, IL‐4 promotes uncoupling protein 1 expression of white adipose tissue (WAT), suggesting its role in triggering WAT‐beige switch. In summary, this study uncovers novel function of IL‐4 in mediating food‐intake behaviors and metabolic efficiency by regulating hypothalamic appetite‐control and WAT browning activities. These findings support the therapeutic potential of targeting hypothalamic inflammation and reducing adiposity through IL‐4 intervention for tackling the pandemic increasing prevalence of obesity and associated metabolic disorders.