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ANNA MOLES Institute of Neuroscience CNR- Rome, Italy

A metabolic role for the VGF-derived peptides. ANNA MOLES Institute of Neuroscience CNR- Rome, Italy.

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ANNA MOLES Institute of Neuroscience CNR- Rome, Italy

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  1. A metabolic role for the VGF-derived peptides ANNA MOLES Institute of Neuroscience CNR- Rome, Italy

  2. Neurotrophins are proteins required for neuronal differentiation and survival. Pioneering work by Rita Levi-Montalcini, Stanley Cohen and Viktor Hamburger in the 1950s and early 1960s identified nerve growth factor (NGF) and demonstrated that this protein was required for sympathetic neuron survival both in vivo and in vitro. The later purification and characterization of brain-derived neurotrophic factor (BDNF), a close relative of NGF, allowed the cloning of additional family members. Six members of the neurotrophin family have been identified in vertebrates, namely NGF, BDNF, NT-3, NT-4/5, NT-6 and NT-7. These polypeptides bind, with different affinities, to the Trk family of receptor tyrosine kinases (TrkA, TrkB and TrkC) and with similar affinities to the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor

  3. Vgf gene discovered in PC12 cells following NGF treatment (Levi et al., Science 1985) Possenti et al PNAS, 1992

  4. TISSUE SPECIFIC EXPRESSION OF VGF Salton et al. Front Neuroendocrinol, 2000

  5. VGF a possible link between neurotrophines and energy homeostasis? Nature Neuroscience  6, 736 - 742 (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor Baoji Xu1, 5, Evan H Goulding2, Keling Zang1, David Cepoi3, Roger D Cone3, Kevin R Jones4, Laurence H Tecott2 & Louis F Reichardt1

  6. Resistant to several types of obesity

  7. VGF-gene acts downstream of MC4R in PVN, LH or brain stem nuclei, that project via the autonomic nervous system to peripheral metabolic tissues and regulate energy homeostasis

  8. Vgf encodes a 617 amino acid protein in rodents that, upon processing by the neuroendocrine-specific prohormone convertases (PC)1/3 and PC2, yields several peptides that are stored in dense core granules and secreted through the regulated pathway Ferri & Possenti, Trends Endocrinol Metab, 1996

  9. VGF CONSTRUCTS Trombin cleaves at : …...LVPRGSPRTLQ….. NAPPEPVPPPRAAPAPTHVRSPQPPPPAPARDELPDWNEVLPPWDREEDEVFPPGPYHPFPNYIRPR TLQPPASSRRRHFHHALPPARHHPDLEAQARRAQEEADAEERRLQEQEELENYIEHVLLHRP

  10. IDENTIFICATION OF VGF DERIVED PEPTIDE TLQPPASSRRRHFHHALPPARHHPDLEAQARRAQEEADAEERRLQEQEELENYIEHVLLHRP

  11. Mouse TLQP-21 sequence Human TLQP-21 sequence

  12. Can TLQP-21 modulate energy homeostasis? Experimental procedure: Male CD1 mice injected icv with TLQP-21 (6nmol/day) for 14 days with Alzet microsmotic pumps. basal Chronic TLQP-21 icv treatment Body weight Food intake 0 1 3 5 7 9 11 13 days Surgery, start treatment

  13. HYPOTHALAMUS AGRP POMC NPY CRH MCH GHS-R BAT b1AR b2AR b3AR UCP1 UCP2 UCP3 Norepi Body weight Food intake Locomotor activity Temperature Energy expenditure Triglycerides FFA/TG Leptine Ghreline BAT THYROID fT3 fT4 WAT UCP1 UCP2 b1AR b2AR b3AR UCP3 PPAR-d PGC-1a Adipon HemeOx1 Norepi ADRENALS Epinephrine Norepinephrine Corticosterone WAT

  14. Increased T, epinephrine and resting EE & adrenal weight Normal food intake and locomotor activity,and thyroid hormones

  15. Decreased TG and increased FFA/TG ratio; slight reduction in WAT and leptin

  16. No changes in the hypothalamus; b2-AR increase in BAT; UCP1, PPAR-delta and b3-AR in WAT BAT WAT WAT WAT

  17. CONCLUSION 1 Central TLQP-21 determines: Increased EE, hyperthermia, conversion of TG in FFA Proposed mechanism: Increased sympathetic stimulation to WAT and adrenomedullary release of E  Increased UCP1 and catabolic mediator in the WAT 

  18. Experimental procedure: Male CD1 mice injected icv with TLQP-21 (6nmol/day) for 14 days with Alzet microsmotic pumps. Starting the day of surgery mice received a HF diet (+20% lard). basal Chronic TLQP-21 icv treatment Body weight Food intake 0 1 3 5 7 9 11 13 days Surgery, start treatment Can central TLQP-21 affects development of diet induced obesity?

  19. Food intake Body weight Leptin Ghrelin White adipose tissue

  20. Can TLQP-21 modulate energy homeostasis and somatic growth by modulating the GH/IGF-1 axis? NO

  21. EFFECTS OF TLQP-21 • Increases energy expenditure • Increase epinephrine and inhibit norepinephrine in the long term • Activate catabolic markers in the adipose tissue • Prevents diet-induced in obesity prone individuals • Increase heart rate • ….. • Modulation of the ANS and the sympathoadrenomodellurary pathways.

  22. VGF -/- TLQP-21 Other VGF-derived peptides should have an anabolic role GENERAL CONCLUSION 1 TLQP-21 is the first VGF-derived peptide which is involved in energy metabolism

  23. GENERAL CONCLUSION 2 TLQP-21 centrally increases energy expenditure

  24. GENERAL CONCLUSION 3 TLQP-21 blocks development of diet induced obesity by increasing energy expenditure

  25. PSYCHOSOCIAL STRESS PROCEDURE BASELINE (3 days) PSYCHOSOCIAL SOCIAL INTERACTION (twice a day x 5 days) STRESS COHABITATION (16 days)

  26. FOOD INTAKE IN DOM, SUB AND CONTROL MICE DURING PS (COHABITATION) ** ** 110 100 90 80 70 60 food ingested from day 5-day 21 (gr) 50 40 30 20 10 0 ANOVA F 2,25= 4.75 p< 0.05 ** p< 0.01 vs CONTROL

  27. MEAN DAILY METABOLIC RATE (kcal/h),AND LOCOMOTION IN DOM SUB AND CONTROL MICE BEFORE AND AFTER THE PS PROCEDURE Mean daily Metabolic rate ** 0,85 0,8 0,75 0,7 0,65 0,6 0,55 0,5 dom sub con dom sub con Basale Basale Basale Post Post Post ANOVA F2,13= 6,77 p< 0.01 **p< 0.01 vs CONTROL ANOVA F2,13= 0.00 NS

  28. Institute of Neuroscience CNR Rome FRANCESCA D’AMATO ALESSANDRO BARTOLOMUCCI FLAMINIA PAVONE LUCIANA GARBUGINO ROBERTO COCCURELLO Univ. of Cagliari GIAN LUCA FERRI CARLA BRANCIA S.Lucia Foundation, Rome T. PASCUCCI Institute of Neurobiology and Molecular Medicine CNR Rome and Department of Neurobiology Univ. of Rome Tor Vergata ANDREA LEVI ROBERTA POSSENTI ROBERTO RIZZI CINZIA SEVERINI GIORGIO LA CORTE Sigma Tau,SPA, Pomezia R. CONTI A.CAPRIOLI F.BORSINI O.GHIRARDI Univ. Milan-Bicocca TORSELLO, V. LOCATELLI Univ. of Rome La Sapienza DONATELLA BARRA EUGENIA SCHININA’ PINA MIGNOGNA ALESSANDRA GIORGI Univ. Of Milan A.E. RIGAMONTI, E.E. MULLER

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