Dataset Information

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 ?- but also in ?-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.

SUBMITTER: Rudenko O

PROVIDER: S-EPMC6323244 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Rudenko Olga O Shang Jin J Munk Alexander A Ekberg Jeppe P JP Petersen Natalia N Engelstoft Maja S MS Egerod Kristoffer L KL Hjorth Siv A SA Wu Margaret M Feng Yue Y Zhou Yun-Ping YP Mokrosinski Jacek J Thams Peter P Reimann Frank F Gribble Fiona F Rehfeld Jens F JF Holst Jens J JJ Treebak Jonas T JT Howard Andrew D AD Schwartz Thue W TW

Molecular metabolism 20181105

<h4>Objectives</h4>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.<h4>Methods and results</h4>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- ...[more]

PMID: 30472415

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy: it has a 5-year survival rate of less than 9%. Although surgical resection is an effective treatment for PDAC, only a small number of patients can have their tumors surgically removed. Thus, an urgent need to find new therapeutic targets for PDAC exists. Understanding the molecular mechanism of PDAC development is essential for the treatment of this malignancy. This research aimed to study the mechanisms of pancreatic stellate cells (PSCs), which regulate branched-chain amino acid (BCAA) metabolism in PDAC.MethodsDifferentially expressed proteins were detected via nanoliquid chromatography coupled to mass spectrometry (nano-LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods were used to find the valine-leucine-isoleucine (BCAA) degradation pathway. The levels of BCAAs in the sera and tissues of patients with PDAC were measured by using nuclear magnetic resonance (NMR). The functions of BCAA concentrations and the effects of activated pancreatic stellate cells (aPSCs) were also evaluated by performing Cell Counting Kit-8, colony formation, and wound healing assays.ResultsA total of 1,519 proteins with significantly differential expression were discovered in PDAC and adjacent tissues by using nano-LC-MS/MS. KEGG pathway enrichment analysis identified the BCAA degradation pathway. The content of BCAA in PDAC clinical samples was up-regulated. However, the addition of different concentrations of BCAA to PDAC cell culture medium failed to promote the proliferation and migration of PDAC cells. Given that analysis based on The Cancer Genome Atlas database showed that the number of aPSCs gradually increased with the progression of PDAC, the effects of aPSCs on PDAC cells were explored. After coculture with aPSCs, PDAC cell proliferation showed a significant increase, and the proteins involved in the BCAA degradation pathway in PDAC cells had also changed.ConclusionsaPSCs could regulate BCAA metabolism to enhance the progression of PDAC, indicating that the regulation of BCAA metabolism may serve as a new therapeutic direction for PDAC.

Dataset Information

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

Objectives

Methods and results

Conclusions

Publications

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

Similar Datasets

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