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TLQP-21, a VGF-Derived Peptide, Increases Energy Expenditure and Prevents the Early Phase of Diet-Induced Obesity

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TLQP-21, a VGF-Derived Peptide, Increases Energy Expenditure and Prevents the Early Phase of Diet-Induced Obesity TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity A. Bartolomuccia,b,c, G. La Corteb,d, R. Possentid,e, V. Locatellif, A. E. Rigamontig, A. Torsellof, E. Brescianif, I. Bulgarellif, R. Rizzie, F. Pavonea, F. R. D’Amatoa, C. Severinid, G. Mignognah, A. Giorgih, M. E. Schinina` h, G. Eliai, C. Branciaj, G.-L. Ferrij, R. Contik, B. Cianik, T. Pascuccil, G. Dell’Omom, E. E. Mullerg, A. Levic,d,n, and A. Molesa,c,n aInstitute of Neuroscience, Consiglio Nazionale delle Ricerche, 00143 Rome, Italy; dInstitute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, 00143 Rome, Italy; eDepartment of Neuroscience, University of Roma II–Tor Vergata, 00161 Rome, Italy; fDepartment of Experimental and Environmental Medicine and Biotechnology and Interdepartmental Center for Bioinformatics and Proteomics, University of Milan–Bicocca, 20052 Monza, Italy; gDepartment of Pharmacology, Chemotherapy, and Medical Toxicology, University of Milan, 20129 Milan, Italy; hDepartment of Biochemical Science, University ‘‘La Sapienza,’’ 00185 Rome, Italy; iDepartment of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Eidgeno¨ssische Technische Hochschule Zu¨rich, CH-8093 Zu¨rich, Switzerland; jNEF Laboratory, Department of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy; kDepartment of Endocrinology and Metabolism, Sigma-Tau Pharmaceuticals Industries S.p.A., 00040 Rome, Italy; lFoundation Santa Lucia, 00143 Rome, Italy; and mInstitute of Anatomy and Center for Neuroscience, University of Zu¨rich, CH-8057 Zu¨rich, Switzerland Communicated by Rita Levi-Montalcini, European Brain Research Institute, Rome, Italy, July 20, 2006 (received for review May 15, 2006) The vgf gene has been identified as an energy homeostasis arcuate nucleus of fasted rats (14) and hamsters that are exposed regulator. Vgf encodes a 617-aa precursor protein that is processed to a short or long day’s length (16). However, up until now, it was to yield an incompletely characterized panel of neuropeptides. still unproved that VGF-derived peptides are metabolic neuro- Until now, it was an unproved assumption that VGF-derived modulators (13). Vgf encodes a 617-aa protein in rodents that, upon peptides could regulate metabolism. Here, a VGF peptide desig- processing by prohormone convertase (PC) 1͞3 and PC2, yields nated TLQP-21 was identified in rat brain extracts by means of several peptides that are stored in dense core granules and secreted immunoprecipitation, microcapillary liquid chromatography–tan- through the regulated pathway (13, 17). Based on the phenotype of dem MS, and database searching algorithms. Chronic intracerebro- VGFϪ/Ϫ mice (14, 15), we predicted that VGF-derived peptides are ventricular (i.c.v.) injection of TLQP-21 (15 ␮g͞day for 14 days) anabolic neuropeptides. Here, we identified in rat brain extracts a increased resting energy expenditure (EE) and rectal temperature previously uncharacterized VGF-derived peptide, designated as in mice. These effects were paralleled by increased epinephrine TLQP-21, which spans from residue 556 to residue 576 of the and up-regulation of brown adipose tissue ␤2-AR (␤2 adrenergic precursor sequence. Contrary to our prediction, TLQP-21 increases receptor) and white adipose tissue (WAT) PPAR-␦ (peroxisome energy expenditure (EE) and blocks the early phase of high-fat proliferator-activated receptor ␦), ␤3-AR, and UCP1 (uncoupling diet-induced obesity. protein 1) mRNAs and were independent of locomotor activity and thyroid hormones. Hypothalamic gene expression of orexigenic Results and anorexigenic neuropeptides was unchanged. Furthermore, in Identification of TLQP-21. VGF peptides were immunopurified and mice that were fed a high-fat diet for 14 days, TLQP-21 prevented characterized from rat brain extracts by means of an antiserum the increase in body and WAT weight as well as hormonal changes raised against the N terminus of TLQP-62 (residues 556–617), a that are associated with a high-fat regimen. Biochemical and major VGF form in the CNS (18). MALDI-TOF MS analysis of molecular analyses suggest that TLQP-21 exerts its effects by immunoprecipitates revealed one pseudomolecular ion (MHϩ)at stimulating autonomic activation of adrenal medulla and adipose a mass-to-charge ratio (m͞z) of 2,433.53 (Fig. 1a) corresponding to tissues. In conclusion, we present here the identification in the CNS the peptide at position 556–576 of the VGF sequence, designated of a previously uncharacterized VGF-derived peptide and prove TLQP-21. In addition, the singly charged as well as the doubly that its chronic i.c.v. infusion effected an increase in EE and limited charged ions of TLQP-62 were detected at m͞z ϭ 7,403.19 and the early phase of diet-induced obesity. 3,701.79, respectively (Fig. 1a). TLQP-21 was unambiguously iden- tified by microcapillary liquid chromatography–tandem MS (MS͞ autonomic nervous system ͉ ␤ adrenergic receptor ͉ MALDI-TOF ͉ MS) analysis of the immunoprecipitates and sequence database neuropeptide ͉ peroxisome proliferator-activated receptor ␦ searching algorithms. TLQP-21 was separated and detected as a doubly charged ion at m͞z ϭ 1,217.27 (Fig. 1b). On the basis of the nergy homeostasis is a complex physiological function that is MS͞MS spectra resulting from low-energy collision-induced disso- Ecoordinated at multiple levels. Stimulated by the discovery of ciation of the precursor ion (Fig. 1c), an automated SEQUEST leptin and the pandemic diffusion of obesity and type-2 diabetes, search against the National Center for Biotechnology Information the regulation of energy homeostasis has received increasing at- nonredundant database indicated a cross-correlation value (Xcorr) tention (1–4). New players are being continuously identified and of 1.75 and a ⌬ correlation value (dCn) of 0.09 (Table 1, which is screened as molecular candidates to counteract obesity (5–10). Vgf, initially identified as a nerve growth factor-responsive gene, is also robustly induced by BDNF and neurotrophin 3 and marginally Conflict of interest statement: No conflicts declared. induced by epidermal and fibroblast growth factors, IL-6, and Abbreviations: BAT, brown adipose tissue; ␤-AR, ␤ adrenergic receptor; UCP1, uncoupling protein 1; WAT, white adipose tissue; i.c.v., intracerebroventricular; PPAR-␦, peroxisome insulin (11–13). Vgf received great attention after the observation proliferator-activated receptor ␦;MS͞MS, tandem MS; EE, energy expenditure; NE, nor- that VGF-deficient mice are lean, hypermetabolic, and resistant to epinephrine; E, epinephrine; WAT͞bw, WAT͞body weight; TG, triglyceride; FFA, free fatty various types of obesity (14, 15). In the rat brain, VGF is abundant acid; aCSF, artificial cerebrospinal fluid. in the cortex, hypothalamus, hippocampus, and olfactory system bA.B. and G.L.C. contributed equally to this work. and in a number of thalamic, septal, amygdaloid, and brainstem nA.L. and A.M. contributed equally to this work. nuclei, with the local availability of neurotrophins for receptor cTo whom correspondence may be addressed. E-mail: [email protected], a.levi@ occupation being the critical parameter in determining its selective inmm.cnr.it, or [email protected]. expression (12, 13). Changes in vgf expression also increase in the © 2006 by The National Academy of Sciences of the USA 14584–14589 ͉ PNAS ͉ September 26, 2006 ͉ vol. 103 ͉ no. 39 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606102103 Downloaded by guest on September 25, 2021 Fig. 2. Physiological effects in mice receiving TLQP-21. (a)EE(n ϭ 6 per group). (b) Rectal temperature (n ϭ 8 per group). (c) E levels. (d) NE levels. (e) TG levels. (f) FFA͞TG ratio. Unless otherwise stated, n ϭ 16–18 per group. *, P Ͻ 0.05. weight and food intake were unaffected, whereas WAT͞bw and circulating leptin were slightly reduced (Fig. 7 and Table 2). TLQP-21 treatment also lowered circulating triglycerides (TGs) but not free fatty acids (FFAs) or glucose; therefore, an increased FFA͞TG ratio was observed (Fig. 2 e and f; TG, U(17,18) ϭ 66, P Ͻ 0.01; FFA͞TG, U(17,18) ϭ 72, P Ͻ 0.01). TG also was positively Fig. 1. TLQP-21 indentification. (a) MALDI-TOF MS spectrum-immuno- ͞ r ϭ P Ͻ selected VGF peptides. (b) MicroLC MS͞MS full mass spectrum recorded at a correlated with WAT bw ( 0.35; 0.05). retention time of 21 min and 41 sec, showing the doubly charged ion corre- In the glucose tolerance test, TLQP-21 treatment reduced TG sponding to TLQP-21 at an m͞z of 1,217.3. (c) Fragment ion spectrum. levels (F(1,9) ϭ 6.1, P Ͻ 0.05; post hoc, P Ͻ 0.05) and, to a lesser extent, FFA levels (F(3,27) ϭ 6.4, P Ͻ 0.01; post hoc, P ϭ 0.079) 30 min after glucose load (Fig. 3 c and d), leading to a transient ͞ ϭ Ͻ published as supporting information on the PNAS web site). normalization in the FFA TG ratio (Fig. 3e; F(3,27) 3.1, P Manual interpretation of the MS͞MS analysis by a MASCOT 0.05; control vs. TLQP-21 at baseline, 60 min, and 120 min, Ͻ search in the Sequence Query mode led to the identification of the P 0.05; TLQP-21 at 30 min vs. baseline, 60 min, and 120 Ͻ TLQPPASSRRRHFHHALPPAR peptide with a high confidence min, P 0.05). (ion score ϭ 62; P ϭ 0.0083). Furthermore, TLQP-21 was identified TLQP-21 Up-Regulates ␤ Adrenergic Receptor (␤-AR), Peroxisome as a triply charged ion by SEQUEST in a second independent ␦ ␦ experiment (Xcorr ϭ 2.98; dCn ϭ 0.44; data not shown). Proliferator-Activated Receptor (PPAR- ), and Uncoupling Protein 1 (UCP1) Gene Expression in the Adipose Tissue. Hypothalamic expres- sion of agouti-related peptide, neuropeptide Y, melanocyte- TLQP-21 Upsets Energy Balance. Fourteen-day i.c.v. TLQP-21 treat- concentrating hormone, proopiomelanocortin, and corticotropin- ment increased EE at rest (ϩ12%; P Ͻ 0.05) but less so when releasing hormone was unaffected by TLQP-21 (Table 3, which is animals showed moderate (ϩ7%) or high (ϩ4%) activity level published as supporting information on the PNAS web site).
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