ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis
Sci Signal. 2022 May 10;15(733):eabj8204. doi: 10.1126/scisignal.abj8204. Epub 2022 May 10.ABSTRACTVariants 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 ...
Source: Science Signaling - Category: Biomedical Science Authors: Eirini Vagena Jasmina Crneta Pauline Engstr öm Li He Ernie Yulyaningsih Nikita L Korpel Rachel T Cheang Tomas P Bachor Alyssa Huang Guillermina Michel Kush Attal David I Berrios Martin Valdearcos Suneil K Koliwad David P Olson Chun-Xia Yi Allison W Xu Source Type: research
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