GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

Lin, Hua; Efanov, Alexander M.; Fang, Xiankang; Beavers, Lisa S.; Wang, Xuesong; Wang, Jingru; Valcarcel, Isabel C. Gonzalez; Li, Zhenning

doi:10.1371/journal.pone.0157298

Cited by 63 publications

(69 citation statements)

References 38 publications

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“…The GPCR repertoire of human EECs largely mirrored their well-studied murine counterparts(9, 23-25), including expression of receptors for amino acids ( CASR , GPR142 ), triglyceride digestion products ( FFAR1, FFAR4, GPR119 ) and bile acids (GPBAR1), as well as for hormones such as somatostatin ( SSTR1, SSTR2, SSTR5 ), GIP ( GIPR ) and arginine vasopressin ( AVPR1B ). Interestingly, GPR142 was highly expressed in human EECs, supporting current studies looking to exploit its ability to stimulate both insulin and incretin hormone secretion(24).…”

Section: Discussionmentioning

confidence: 68%

Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

Roberts

Larraufie

Richards

et al. 2018

Preprint

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Enteroendocrine cells (EECs) produce hormones that regulate food absorption, insulin secretion and appetite. Both EECs and their peptide products are foci of drug discovery programmes for diabetes and obesity. We compared the human and mouse EEC transcriptome and peptidome to validate mouse as a model of the human enteroendocrine axis. We present the first RNA sequencing analysis of human EECs, and demonstrate strong correlation with mouse, although with outliers including some low abundance G-protein coupled receptors. Liquid chromatography mass spectrometry (LC-MS) identified peptide hormone gradients along the human and mouse gut that should enhance progress in gut physiology and therapeutics.

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Section: Discussionmentioning

confidence: 68%

Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

Roberts

Larraufie

Richards

et al. 2018

Preprint

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“…GPR142, yet another GPCR involved in protein sensing in the GI tract, is a Gq-coupled sensor of the essential aromatic amino acids tryptophan and phenylalanine. GPR142 is expressed rather selectively in enteroendocrine cells, where it responds to tryptophan to stimulate secretion of GIP and GLP-1, thus improving glucose metabolism (Lin et al, 2016).…”

Section: Sensing Of Nutrient Metabolites By Enteroendocrine Cells Inmentioning

confidence: 99%

GPCR-Mediated Signaling of Metabolites

et al. 2017

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In addition to their bioenergetic intracellular function, several classical metabolites act as extracellular signaling molecules activating cell-surface G-protein-coupled receptors (GPCRs), similar to hormones and neurotransmitters. "Signaling metabolites" generated from nutrients or by gut microbiota target primarily enteroendocrine, neuronal, and immune cells in the lamina propria of the gut mucosa and the liver and, through these tissues, the rest of the body. In contrast, metabolites from the intermediary metabolism act mainly as metabolic stress-induced autocrine and paracrine signals in adipose tissue, the liver, and the endocrine pancreas. Importantly, distinct metabolite GPCRs act as efficient pro- and anti-inflammatory regulators of key immune cells, and signaling metabolites may thus function as important drivers of the low-grade inflammation associated with insulin resistance and obesity. The concept of key metabolites as ligands for specific GPCRs has broadened our understanding of metabolic signaling significantly and provides a number of novel potential drug targets.

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“…Stimulates incretin secretion and improves glucose disposal in vivo [166] Gpr35 Kynurenic acid Mediates leucocyte recruitment [135]. Involved in thermogenesis and antiinflammatory responses in adipose tissue [97] T1R2/T1R3 Glucose, sucrose, maltose Leptin downregulates T1R2 and T1R3 in hypothalamic neurons [168] Gpr81 Lactate Inhibits lipolysis in adipocytes [169].…”

Section: -Hydroxybutyrate Inhibits Adipocyte Lipolysis [164]mentioning

confidence: 99%

The weight of nutrients: kynurenine metabolites in obesity and exercise

et al. 2018

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Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.

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GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

Cited by 63 publications

References 38 publications

Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

GPCR-Mediated Signaling of Metabolites

The weight of nutrients: kynurenine metabolites in obesity and exercise

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