4.5 Article

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

Journal

SCIENCE SIGNALING
Volume 15, Issue 733, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abj8204

Keywords

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Funding

  1. American Diabetes Association [1-18-IBS-309, 1-18-PDF-023]
  2. Joseph and Vera Long Foundation
  3. Larry L. Hillbrom Foundation [2017-D-010-FEL]
  4. Mouse Metabolism Core at the UCSF Nutrition Obesity Center [NIH NIDDK 1P30DK098722-01A1]
  5. Microscopy Core at the UCSF Diabetes Endocrinology Research Center [NIH NIDDK P30 DK63720-06A1]
  6. Dutch Diabetes Research Foundation (Diabetes Fonds), The Netherlands [2015.82.1826]

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Variants in the ASB4 gene are associated with human obesity. ASB4 acts in the brain to improve glucose homeostasis and induce satiety.
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.

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