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 Pintar, Lloyd D. Fricker, Lakshmi A. Devi

Research output: Contribution to journalArticle

29 Citations (Scopus)

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

Fingerprint

G-Protein-Coupled Receptors
Neuropeptides
Peptides
Hypothalamus
Small Interfering RNA
Eating
Body Weight
Ghrelin
Neuropeptide Y
Leptin
Amino Acids
Food
Antibodies

All Science Journal Classification (ASJC) codes

  • General

Keywords

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

Cite this

Gomes, Ivone ; Aryal, Dipendra K. ; Wardman, Jonathan H. ; Gupta, Achla ; Gagnidze, Khatuna ; Rodriguiz, Ramona M. ; Kumar, Sanjai ; Wetsel, William C. ; Pintar, John ; Fricker, Lloyd D. ; Devi, Lakshmi A. / GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 40. pp. 16211-16216.
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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.",
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author = "Ivone Gomes and Aryal, {Dipendra K.} and Wardman, {Jonathan H.} and Achla Gupta and Khatuna Gagnidze and Rodriguiz, {Ramona M.} and Sanjai Kumar and Wetsel, {William C.} and John Pintar and Fricker, {Lloyd D.} and Devi, {Lakshmi A.}",
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Gomes, I, Aryal, DK, Wardman, JH, Gupta, A, Gagnidze, K, Rodriguiz, RM, Kumar, S, Wetsel, WC, Pintar, J, Fricker, LD & Devi, LA 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, vol. 110, no. 40, pp. 16211-16216. https://doi.org/10.1073/pnas.1312938110

GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. / Gomes, Ivone; Aryal, Dipendra K.; Wardman, Jonathan H.; Gupta, Achla; Gagnidze, Khatuna; Rodriguiz, Ramona M.; Kumar, Sanjai; Wetsel, William C.; Pintar, John; Fricker, Lloyd D.; Devi, Lakshmi A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 40, 01.10.2013, p. 16211-16216.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding

AU - Gomes, Ivone

AU - Aryal, Dipendra K.

AU - Wardman, Jonathan H.

AU - Gupta, Achla

AU - Gagnidze, Khatuna

AU - Rodriguiz, Ramona M.

AU - Kumar, Sanjai

AU - Wetsel, William C.

AU - Pintar, John

AU - Fricker, Lloyd D.

AU - Devi, Lakshmi A.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

KW - Deorphanization

KW - NPY/AgRP

KW - Neuroendocrine peptide

KW - Orexigenic

KW - ProSAAS

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JO - Proceedings of the National Academy of Sciences of the United States of America

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