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MAD2-dependent insulin receptor endocytosis regulates metabolic homeostasis

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posted on 2023-09-19, 22:12 authored by Junhee Park, Catherine Hall, Brandon Hubbard, Traci LaMoia, Rafael Gaspar, Ali Nasiri, Fang Li, Hanrui Zhang, Jiyeon Kim, Rebecca A. Haeusler, Domenico Accili, Gerald I. Shulman, Hongtao Yu, Eunhee Choi

Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis upon insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR–MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR–MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis.


Article highlights

· Physiological function of IR trafficking on insulin sensitivity remains unresolved.

· Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling.

· IR-MAD2 controls insulin clearance and glucose metabolism.

· IR-MAD2 maintains energy homeostasis.

Funding

American Cancer Society RSG-21-153-01-CCB

American Heart Association 20POST35130003 23CDA1052177

American Lung Association IA-828202

Columbia University Digestive and Liver Disease Research Center x P30DK132710

National Institutes of Health (NIH) P30DK045735 P30DK063608 P30DK132710 R00HL130574 R01DK115825 R01DK132361 R01DK133143 R01HL125649 R01HL151611 UC2DK134901 UL1TR001873

NIH/NCI Cancer Center x P30CA013696

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