ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis.

Variants in the gene encoding ankyrin repeat and SOCS box–containing 4 (ASB4) are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic Asb4 expression was suppressed by fasting in wild-type mice but not in mice deficient in AgRP, 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 Asb4-deficient mice. Acute knockdown of Asb4 in the brain caused marked hyperphagia due to increased meal size, and Asb4 deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. Asb4-deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of Calcr, which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and Asb4 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. The metabolic attributes of ASB4: Variants in the ASB4 gene are associated with obesity. Using mice with acute, global, or neuron-specific deficiency in Asb4, Vagena et al. characterized how ASB4-positive neurons participated in the neural circuits that drive food intake, mediate satiety, and affect glucose homeostasis. ASB4 was required for limiting excessive feeding after fasting and for the effects of the satiety signal calcitonin. Moreover, ASB4 was required for proper glucose handling mediated by a specific neuron subset in a mouse brain region called the arcuate nucleus, and diabetic individuals showed decreased ASB4 abundance in the human equivalent of the arcuate nucleus. Thus, ASB4-positive neurons control behaviors and physiological processes that are important for metabolic health. [ABSTRACT FROM AUTHOR]