Glukoosihomeostaasin alueelta geenejä GLP2R

 The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis.Guan X.Am J Physiol Regul Integr Comp Physiol. 2014 Sep 15;307(6):R585-96. doi: 10.1152/ajpregu.00096.2014. Epub 2014 Jul 2.PMID: 24990862 Free PMC article. Review.

The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance.
GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies.
Keywords: central nervous system; food intake; gastric emptying; glucagon-like peptides; glucose homeostasis; gut-brain axis; insulin sensitivity.

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Insights into the structure and activation mechanism of some class B1 GPCR family members.Aksu H, Demirbilek A, Uba AI.Mol Biol Rep. 2024 Sep 6;51(1):966. doi: 10.1007/s11033-024-0987Abstract

  In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs.

Molecular evolution of GIP and Exendin and their receptors.

Irwin DM.Peptides. 2020 Mar;125:170158. doi: 10.1016/j.peptides.2019.170158. Epub 2019 Sep 30.PMID: 31582191 Review.

In mammals, GIP acts through its specific receptor, encoded by the Gipr gene, which belongs to a subfamily of 7-transmembrane G-protein coupled receptor (GPCR) genes that also includes those for the proglucagon-derived peptides (Gcgr, Glp1r, and Glp2r), and the rece …

5

 
Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport.Lee J, Koehler J, Yusta B, Bahrami J, Matthews D, Rafii M, Pencharz PB, Drucker DJ.Mol Metab. 2017 Jan 17;6(3):245-255. doi: 10.1016/j.molmet.2017.01.005. eCollection 2017 Mar.PMID: 28271031 Free PMC article.

METHODS: Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r(+/+) and Glp2r …Results: Acute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo. GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo. Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r-/- mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage, was significantly attenuated in Glp2r-/- mice. Conclusions: These findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption. Keywords: 4E-BP1, eukaryotic translation initiation factor 4E (eIF4e)-binding protein 1; AA, amino acid; Amino acid absorption; BBMV, brush border membrane vesicles; EAA, essential amino acid; EECs, enteroendocrine cells; ENS, enteric nervous system; GLP-1; GLP-1, Glucagon-like peptide-1; GLP-2; GLP-2, glucagon-like peptide-2; GLP-2R, GLP-2 receptor; Gut peptides; LC-MS/MS, liquid chromatography triple quadrupole mass spectrometry; PGDP, proglucagon-derived peptides; Rapamycin; S6K1, 70 kDa ribosomal protein S6 kinase 1; mTORC1, mechanistic target of rapamycin complex 1.

6

 

Modulating effects of RAMPs on signaling profiles of the glucagon receptor family.

Shao L, Chen Y, Zhang S, Zhang Z, Cao Y, Yang D, Wang MW.Acta Pharm Sin B. 2022 Feb;12(2):637-650. doi: 10.1016/j.apsb.2021.07.028. Epub 2021 Aug 4.PMID: 35256936 Free PMC article.

7

 

Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway.

Yusta B, Matthews D, Flock GB, Ussher JR, Lavoie B, Mawe GM, Drucker DJ.Mol Metab. 2017 Mar 31;6(6):503-511. doi: 10.1016/j.molmet.2017.03.006. eCollection 2017 Jun.PMID: 28580281 Free PMC article.

METHODS: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flo …

8

 

Evolution of receptors for peptides similar to glucagon.

Irwin DM.Gen Comp Endocrinol. 2014 Dec 1;209:50-60. doi: 10.1016/j.ygcen.2014.03.002. Epub 2014 Mar 17.PMID: 24650782 Review.

A total of five types of genes for receptors for these peptides have been identified, three for the products of GCG (GCGR, GLP1R, and GLP2R) and one each for the products of GIP (GIPR) and the ortholog of exendin (Grlr). ...Despite their ancient origins, some of the …

9

Comparison of the effects of intracerebroventricular administration of glucagon-like peptides 1 and 2 on hypothalamic appetite regulating factors and sleep-like behavior in chicks.

Kewan A, Shimatani T, Saneyasu T, Kamisoyama H, Honda K.Neurosci Lett. 2022 Jan 18;768:136362. doi: 10.1016/j.neulet.2021.136362. Epub 2021 Nov 25.PMID: 34838926
GLP-1 and GLP-2 specifically activate their receptors GLP-1 receptor (GLP1R) and GLP-2 receptor (GLP2R), respectively in chickens. In adult chickens, GLP1R and GLP2R are expressed in different brain regions. ...In the present study, we compared several …

10

 

Variation in the Evolution and Sequences of Proglucagon and the Receptors for Proglucagon-Derived Peptides in Mammals.

Irwin DM.Front Endocrinol (Lausanne). 2021 Jul 12;12:700066. doi: 10.3389/fendo.2021.700066. eCollection 2021.PMID: 34322093 Free PMC article.

The mammalian proglucagon gene (Gcg) encodes three glucagon like sequences, glucagon, glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 that are of similar length and share sequence similarity, with these hormones having cell surface receptors, glucagon receptor (Gcgr) …

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