The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones

Olga Rudenko; Jin Shang; Alexander Munk; Jeppe P. Ekberg; Natalia Petersen; Maja S Engelstoft; Kristoffer L. Egerod; Siv A. Hjorth; Margaret Wu; Yue Feng; Yun-Ping Zhou; Jacek Mokrosinski; Peter Thams; Frank Reimann; Fiona Gribble; Jens F Rehfeld; Jens J. Holst; Jonas T. Treebak; Andrew D Howard; Thue W Schwartz

doi:10.1016/j.molmet.2018.10.012

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones

Olga Rudenko, Jin Shang, Alexander Munk, Jeppe P. Ekberg, Natalia Petersen, Maja S Engelstoft, Kristoffer L. Egerod, Siv A. Hjorth, Margaret Wu, Yue Feng, Yun-Ping Zhou, Jacek Mokrosinski, Peter Thams, Frank Reimann, Fiona Gribble, Jens F Rehfeld, Jens J. Holst, Jonas T. Treebak, Andrew D Howard, Thue W Schwartz

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Abstract

OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear.

METHODS AND RESULTS: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity.

CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

Original language	English
Journal	Molecular Metabolism
Volume	19
Pages (from-to)	49-64
Number of pages	6
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2018.10.012
Publication status	Published - Jan 2019

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The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormonesFinal published version, 3.45 MBLicence: CC BY-NC-ND

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Rudenko, O., Shang, J., Munk, A., Ekberg, J. P., Petersen, N., Engelstoft, M. S., Egerod, K. L., Hjorth, S. A., Wu, M., Feng, Y., Zhou, Y-P., Mokrosinski, J., Thams, P., Reimann, F., Gribble, F., Rehfeld, J. F., Holst, J. J., Treebak, J. T., Howard, A. D., & Schwartz, T. W. (2019). The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones. Molecular Metabolism, 19, 49-64. https://doi.org/10.1016/j.molmet.2018.10.012

Rudenko, O, Shang, J, Munk, A, Ekberg, JP, Petersen, N, Engelstoft, MS, Egerod, KL , Hjorth, SA, Wu, M, Feng, Y, Zhou, Y-P, Mokrosinski, J, Thams, P, Reimann, F, Gribble, F, Rehfeld, JF , Holst, JJ , Treebak, JT, Howard, AD & Schwartz, TW 2019, 'The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones', Molecular Metabolism, vol. 19, pp. 49-64. https://doi.org/10.1016/j.molmet.2018.10.012

@article{520e9174bdbf46168b5c108e08cdd6f6,

title = "The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones",

abstract = "OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear.METHODS AND RESULTS: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity.CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.",

author = "Olga Rudenko and Jin Shang and Alexander Munk and Ekberg, {Jeppe P.} and Natalia Petersen and Engelstoft, {Maja S} and Egerod, {Kristoffer L.} and Hjorth, {Siv A.} and Margaret Wu and Yue Feng and Yun-Ping Zhou and Jacek Mokrosinski and Peter Thams and Frank Reimann and Fiona Gribble and Rehfeld, {Jens F} and Holst, {Jens J.} and Treebak, {Jonas T.} and Howard, {Andrew D} and Schwartz, {Thue W}",

note = "Copyright {\textcopyright} 2018. Published by Elsevier GmbH.",

year = "2019",

month = jan,

doi = "10.1016/j.molmet.2018.10.012",

language = "English",

volume = "19",

pages = "49--64",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

}

TY - JOUR

T1 - The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones

AU - Rudenko, Olga

AU - Shang, Jin

AU - Munk, Alexander

AU - Ekberg, Jeppe P.

AU - Petersen, Natalia

AU - Engelstoft, Maja S

AU - Egerod, Kristoffer L.

AU - Hjorth, Siv A.

AU - Wu, Margaret

AU - Feng, Yue

AU - Zhou, Yun-Ping

AU - Mokrosinski, Jacek

AU - Thams, Peter

AU - Reimann, Frank

AU - Gribble, Fiona

AU - Rehfeld, Jens F

AU - Holst, Jens J.

AU - Treebak, Jonas T.

AU - Howard, Andrew D

AU - Schwartz, Thue W

PY - 2019/1

Y1 - 2019/1

N2 - OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear.METHODS AND RESULTS: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity.CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

AB - OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear.METHODS AND RESULTS: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity.CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

U2 - 10.1016/j.molmet.2018.10.012

DO - 10.1016/j.molmet.2018.10.012

M3 - Journal article

C2 - 30472415

SN - 2212-8778

VL - 19

SP - 49

EP - 64

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones

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