VFG-Derived Peptide TLQP-21

VFG-Derived Peptide TLQP-21 Biology and Pathophysiology

T21_C3ar1

We pioneered the research on Vgf gene derived peptides with special reference to their role in metabolic functions, neuroendocrine regulation and pain. We have identified a VGF peptide designated TLQP-21 in the rodent brain and later we identified its expression in sympathetic nerve terminals innervating the adipose organ and identified for the first time its role as enhancer of beta-adrenergic induced-lipolysis. We recently generated a selective TLQP-21 deficient knock-in mouse which is currently available at Jackson Labs (JAX Stock No. 039020  B6;129S-Vgftm5Srjs/AbarJ).

STD&HFD_microglia

 

We established that TLQP-21 activates multiple functions via C3aR1 activation: 1) we identified critical amino acids in the receptor binding pocket and the peptide pharmacophore, crucial to understand the biochemical mechanism of receptor activation and design of C3aR1 agonists; 2) we characterized the TLQP-21/C3aR1-mediated pro-lipolytic and anti-obesity mechanism in mice; 3) we identified the co-evolution of critical amino acids in the binding pocket and the peptide pharmacophore in the Murinae sub-family of rodents (including rats and mice) which resulted in enhanced potency at the C3aR1; 4) We characterized a ligand mediated biased C3aR1 signaling and its functional significance for lipolysis and immune function using several human and murine cellular models; 5) We are currently characterizing the role of TLQP-21/C3aR1 in obesity-associated CNS disorders using novel genetic mouse models as well as rodent and human cellular systems.

 

relevant_publications

Relevant publications

Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism. Rodriguez P, Laskowski LJ, Pallais JP, Bock HA, Cavalco NG, Anderson EI, Calkins MM, Razzoli M, Sham YY, McCorvy JD, Bartolomucci A. J Biol Chem. 2024 Jan;300(1):105549. doi:10.1016/j.jbc.2023.105549. Epub 2023 Dec 10. PMID: 38072064; PMCID: PMC10796979.

Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis. Sahu BS, Razzoli M, McGonigle S, Pallais JP, Nguyen ME, Sadahiro M, Jiang C, Lin WJ, Kelley KA, Rodriguez P, Mansk R, Cero C, Caviola G, Palanza P, Rao L, Beetch M, Alejandro E, Sham YY, Frontini A, Salton SR, Bartolomucci A. Mol Metab. 2023 Oct;76:101781. doi:
10.1016/j.molmet.2023.101781. Epub 2023 Jul 21. PMID: 37482186; PMCID:
PMC10400922.

The molecular identity of the TLQP-21 peptide receptor. Sahu BS, Nguyen ME, Rodriguez P, Pallais JP, Ghosh V, Razzoli M, Sham YY, Salton SR, Bartolomucci A.Cell Mol Life Sci. 2021 Dec;78(23):7133-7144. doi:
10.1007/s00018-021-03944-1. Epub 2021 Oct 9. Erratum in: Cell Mol Life Sci. 2023 Feb 20;80(3):66. doi: 10.1007/s00018-023-04718-7. PMID: 34626205; PMCID: PMC8629782.

Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21. Sahu BS, Rodriguez P, Nguyen ME, Han R, Cero C, Razzoli M, Piaggi P, Laskowski LJ, Pavlicev M, Muglia L, Mahata SK, O'Grady S, McCorvy JD, Baier LJ, Sham YY, Bartolomucci A.Cell Rep. 2019 Sep  3;28(10):2567-2580.e6. doi: 10.1016/j.celrep.2019.07.101. PMID: 31484069; PMCID: PMC6753381.

Clearance kinetics of the VGF-derived neuropeptide TLQP-21. Guo Z, Sahu BS, He R, Finan B, Cero C, Verardi R, Razzoli M, Veglia G, Di Marchi RD, Miles JM, Bartolomucci A. Neuropeptides. 2018 Oct;71:97-103. doi: 10.1016/j.npep.2018.06.003. Epub 2018 Jun 19. PMID: 29958697; PMCID: PMC6166661.

The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis. Cero C, Razzoli M, Han R, Sahu BS, Patricelli J, Guo Z, Zaidman NA, Miles JM, O'Grady SM, Bartolomucci A. Mol Metab. 2016 Oct 31;6(1):148-158. doi: 10.1016/j.molmet.2016.10.005. PMID: 28123945; PMCID: PMC5220279.

The VGF-derived peptide TLQP-62 modulates insulin secretion and glucose homeostasis. Petrocchi-Passeri P, Cero C, Cutarelli A, Frank C, Severini C, Bartolomucci A, Possenti R.J Mol Endocrinol. 2015 Jun;54(3):227-39. doi:
10.1530/JME-14-0313. Epub 2015 Apr 27. PMID: 25917832.

Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: analysis of "humanized" knockin mice expressing full-length or truncated VGF. Sadahiro M, Erickson C, Lin WJ, Shin AC, Razzoli M, Jiang C, Fargali S, Gurney A, Kelley KA, Buettner C, Bartolomucci A, Salton SR.Endocrinology. 2015 May;156(5):1724-38. doi: 10.1210/en.2014-1826. Epub 2015 Feb 12. PMID: 25675362; PMCID: PMC4398760.

The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism. Cero C, Vostrikov VV, Verardi R, Severini C, Gopinath T, Braun PD, Sassano MF, Gurney A, Roth BL, Vulchanova L, Possenti R, Veglia G, Bartolomucci A.Structure. 2014 Dec 2;22(12):1744-1753. doi: 10.1016/j.str.2014.10.001. Epub 2014 Nov 13. PMID: 25456411; PMCID: PMC4353613.

The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. Fargali S, Garcia AL, Sadahiro M, Jiang C, Janssen WG, Lin WJ, Cogliani V, Elste A, Mortillo S, Cero C, Veitenheimer B, Graiani G, Pasinetti GM, Mahata SK, Osborn JW, Huntley GW, Phillips GR, Benson DL, Bartolomucci A, Salton SR.FASEB J. 2014 May;28(5):2120-33. doi: 10.1096/fj.13-239509. Epub 2014 Feb 4. Erratum in: FASEB J. 2015 Jun;29(6):2679. doi: 10.1096/fj.13-239509ERR. PMID: 24497580; PMCID: PMC3986843.

Granins and catecholamines: functional interaction in chromaffin cells and adipose tissue. Borges R, Dominguez N, Smith CB, Bandyopadhyay GK, O'Connor DT, Mahata SK, Bartolomucci A. Adv Pharmacol. 2013;68:93-113. doi:10.1016/B978-0-12-411512-5.00005-1. PMID: 24054141.

Neuropeptide TLQP-21, a VGF internal fragment, modulates hormonal gene expression and secretion in GH3 cell line. Petrocchi Passeri P, Biondini L, Mongiardi MP, Mordini N, Quaresima S, Frank C, Baratta M, Bartolomucci A, Levi A, Severini C, Possenti R.Neuroendocrinology. 2013;97(3):212-24. doi:
10.1159/000339855. Epub 2012 Aug 25. PMID: 22699300.

Implication of the VGF-derived peptide TLQP-21 in mouse acute and chronic stress responses. Razzoli M, Bo E, Pascucci T, Pavone F, D'Amato FR, Cero C, Sanghez V, Dadomo H, Palanza P, Parmigiani S, Ceresini G, Puglisi-Allegra S, Porta M, Panzica GC, Moles A, Possenti R, Bartolomucci A. Behav Brain Res. 2012 Apr 15;229(2):333-9. doi: 10.1016/j.bbr.2012.01.038. Epub 2012 Jan 24. PMID: 22289198.

Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of
VGF-derived peptide TLQP-21. Possenti R, Muccioli G, Petrocchi P, Cero C, Cabassi A, Vulchanova L, Riedl MS, Manieri M, Frontini A, Giordano A, Cinti S, Govoni P, Graiani G, Quaini F, Ghè C, Bresciani E, Bulgarelli I, Torsello A, Locatelli V, Sanghez V, Larsen BD, Petersen JS, Palanza P, Parmigiani S, Moles A, Levi A, Bartolomucci A.Biochem J. 2012 Jan 1;441(1):511-22. doi:
10.1042/BJ20111165. PMID: 21880012.

The extended granin family: structure, function, and biomedical implications. Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SR.
Endocr Rev. 2011 Dec;32(6):755-97. doi: 10.1210/er.2010-0027. Epub 2011 Aug 23. PMID: 21862681; PMCID: PMC3591675.

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice. Bartolomucci A, Bresciani E, Bulgarelli I, Rigamonti AE, Pascucci T, Levi A, Possenti R, Torsello A, Locatelli V, Muller EE, Moles A. Genes Nutr. 2009 Mar;4(1):49-57. doi:
10.1007/s12263-009-0110-0. Epub 2009 Feb 27. PMID: 19247701; PMCID: PMC2654049.

 Pathophysiological role of TLQP-21: gastrointestinal and metabolic functions. Bartolomucci A, Moles A, Levi A, Possenti R.Eat Weight Disord. 2008
Sep;13(3):e49-54. PMID: 19011364.

Advancements in neuroendocrine and autonomic control of metabolic functions and their pathological significance. Bartolomucci A, Moles A, Müller EE. 
Eat Weight Disord. 2008 Sep;13(3):e40-1. PMID: 19011362.

The VGF-derived peptide TLQP-21: a new modulatory peptide for inflammatory pain. Rizzi R, Bartolomucci A, Moles A, D'Amato F, Sacerdote P, Levi A, La Corte G, Ciotti MT, Possenti R, Pavone F. Neurosci Lett. 2008 Aug
15;441(1):129-33. doi: 10.1016/j.neulet.2008.06.018. Epub 2008 Jun 12. PMID:
18586396.

Bartolomucci A, Possenti R, Levi A, Pavone F, Moles A. The role of the vgf
gene and VGF-derived peptides in nutrition and metabolism. Genes Nutr. 2007
Nov;2(2):169-80. doi: 10.1007/s12263-007-0047-0. Epub 2007 Oct 18. PMID:
18850173; PMCID: PMC2474945.

Chronic intracerebroventricular TLQP-21 delivery does not modulate the GH/IGF-1-axis and muscle strength in mice. Bartolomucci A, Rigamonti AE, Bulgarelli I, Torsello A, Locatelli V, Pavone F, Levi A, Possenti R, Muller EE, Moles A. Growth Horm IGF Res. 2007 Aug;17(4):342-5. doi:
10.1016/j.ghir.2007.02.002. Epub 2007 Apr 2. PMID: 17400498.

TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity. Bartolomucci A, La Corte G, Possenti R, Locatelli V, Rigamonti AE, Torsello A, Bresciani E, Bulgarelli I, Rizzi R, Pavone F, D'Amato FR, Severini C, Mignogna G, Giorgi A, Schininà ME, Elia G, Brancia C, Ferri GL, Conti R, Ciani B, Pascucci T, Dell'Omo G, Muller EE, Levi A, Moles A. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14584-9. doi:10.1073/pnas.0606102103. Epub 2006 Sep 18. PMID: 16983076; PMCID: PMC1600003.