Trappc9 deficiency causes obesity and fatty liver disease by constraining dopamine neurotransmission
Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice gain body weight normally in early developmental periods but become overweight shortly after being weaned. Here, we report that trappc9 deficiency in mice disrupts systemic glucose homeostasis and triggers the onset of obesity and NAFLD. Chronic treatment combining drugs suppressing dopamine receptor D1 (DRD1) and stimulating DRD2 restores systemic glucose homeostasis and counteracts abnormal body weight gain and lipid accumulation in adipose and liver tissues in trappc9-deficient mice. Additional pharmacological studies imply that the disruption of systemic glucose homeostasis in trappc9-deficient mice originates from deficient stimulation of DRD2 in the brain. Transcriptomic and proteomic analyses reveal signs of impairments in dopamine secretion in trappc9-deficient mice. Brain examinations indicate that trappc9-deficient mice synthesize dopamine normally, but their dopamine-secreting neurons have a lower abundance of structures for releasing dopamine. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine neurotransmission.