GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding

Ivone Gomes, Dipendra K. Aryal, Jonathan H. Wardman, Achla Gupta, Khatuna Gagnidze, Ramona M. Rodriguiz, Sanjai Kumar, William C. Wetsel, John E. Pintar, Lloyd D. Fricker, Lakshmi A. Devi

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Multiple peptide systems, including neuropeptide Y, leptin, ghrelin, and others, are involved with the control of food intake and body weight. The peptide LENSSPQAPARRLLPP (BigLEN) has been proposed to act through an unknown receptor to regulate body weight. In the present study, we used a combination of ligandbinding and receptor-activity assays to characterize a Gαi/o proteincoupled receptor activated by BigLEN in the mouse hypothalamus and Neuro2A cells. We then selected orphan G protein-coupled receptors expressed in the hypothalamus and Neuro2A cells and tested each for activation by BigLEN. G protein-coupled receptor 171 (GPR171) is activated by BigLEN, but not by the C terminally truncated peptide LittleLEN. The four C-terminal amino acids of BigLEN are sufficient to bind and activate GPR171. Overexpression of GPR171 leads to an increase, and knockdown leads to a decrease, in binding and signaling by BigLEN and the C-terminal peptide. In the hypothalamus GPR171 expression complements the expression of BigLEN, and its level and activity are elevated in mice lacking BigLEN. In mice, shRNA-mediated knockdown of hypothalamic GPR171 leads to a decrease in BigLEN signaling and results in changes in food intake and metabolism. The combination of GPR171 shRNA together with neutralization of BigLEN peptide by antibody absorption nearly eliminates acute feeding in food-deprived mice. Taken together, these results demonstrate that GPR171 is the BigLEN receptor and that the BigLEN-GPR171 system plays an important role in regulating responses associated with feeding and metabolism in mice.

Original languageEnglish (US)
Pages (from-to)16211-16216
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
StatePublished - Oct 1 2013

Keywords

  • Deorphanization
  • NPY/AgRP
  • Neuroendocrine peptide
  • Orexigenic
  • ProSAAS

ASJC Scopus subject areas

  • General

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    Gomes, I., Aryal, D. K., Wardman, J. H., Gupta, A., Gagnidze, K., Rodriguiz, R. M., Kumar, S., Wetsel, W. C., Pintar, J. E., Fricker, L. D., & Devi, L. A. (2013). GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proceedings of the National Academy of Sciences of the United States of America, 110(40), 16211-16216. https://doi.org/10.1073/pnas.1312938110