Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons

Sai P. Pydi, Zhenzhong Cui, Zhenyan He, Luiz F. Barella, Jonathan Pham, Yinghong Cui, Douglas J. Oberlin, Hale Ergin Egritag, Nikhil Urs, Oksana Gavrilova, Gary J. Schwartz, Christoph Buettner, Kevin W. Williams, Jürgen Wess

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Abstract

β-Arrestin-1 and β-arrestin-2 have emerged as important signaling molecules that modulate glucose fluxes in several peripheral tissues. The potential roles of neuronally expressed β-arrestins in regulating glucose homeostasis remain unknown. We here report that mice lacking β-arrestin-1 (barr1) selectively in AgRP neurons displayed impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet, while mice overexpressing barr1 selectively in AgRP neurons were protected against obesity-associated metabolic impairments. Additional physiological, biochemical, and electrophysiological data indicated that the presence of barr1 is essential for insulin-mediated hyperpolarization of AgRP neurons. As a result, barr1 expressed by AgRP neurons regulates efferent neuronal pathways that suppress hepatic glucose production and promote lipolysis in adipose tissue. Mice lacking β-arrestin-2 (barr2) selectively in AgRP neurons showed no substantial metabolic phenotypes. Our data suggest that agents able to enhance the activity of barr1 in AgRP neurons may prove beneficial as antidiabetic drugs.

Original languageEnglish (US)
Article numberEAAZ1341
JournalScience Advances
Volume6
Issue number23
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • General

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    Pydi, S. P., Cui, Z., He, Z., Barella, L. F., Pham, J., Cui, Y., Oberlin, D. J., Egritag, H. E., Urs, N., Gavrilova, O., Schwartz, G. J., Buettner, C., Williams, K. W., & Wess, J. (2020). Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons. Science Advances, 6(23), [EAAZ1341]. https://doi.org/10.1126/sciadv.aaz1341