Description
Variants in the gene encoding ankyrin repeat and SOCS box-containing 4 () are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic expression was suppressed by fasting in wild-type mice but not in mice deficient in , which encodes Agouti-related protein (AgRP), an appetite-stimulating hormone, suggesting that ASB4 is a negative target of AgRP. Many ASB4 neurons in the brain were adjacent to AgRP terminals, and feeding induced by AgRP neuronal activation was disrupted in -deficient mice. Acute knockdown of in the brain caused marked hyperphagia due to increased meal size, and deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. -deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of , which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and deficiency specifically in POMC neurons resulted in glucose intolerance that was independent of obesity. Furthermore, individuals with type 2 diabetes showed reduced ASB4 abundance in the infundibular nuclei, the human equivalent of the arcuate nucleus. Together, our results indicate that ASB4 acts in the brain to improve glucose homeostasis and to induce satiety after substantial meals, particularly those after food deprivation.