A novel peptide that improves metabolic parameters without adverse central nervous system effects

Autor(es):Mostrar menos -

Reckziegel, Patricia ^[1] ; Festuccia, William T. ^[2] ; Britto, Luiz R. G. ^[2] ; Lopes Jang, Karen L. ^{[3, 4]} ; Romao, Carolina M. ^{[3, 4]} ; Heimann, Joel C. ^[3] ; Fogaca, Manoela V. ^[5] ; Rodrigues, Naielly S. ^[5] ; Silva, Nicole R. ^[5] ; Guimaraes, Francisco S. ^[5] ; Eichler, Rosangela A. S. ^[1] ; Gupta, Achla ^[6] ; Gomes, Ivone ^[6] ; Devi, Lakshmi A. ^[6] ; Heimann, Andrea S. ^[4] ; Ferro, Emer S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Biomed Sci Inst, Dept Pharmacol, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Biomed Sci Inst, Dept Physiol & Biophys, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Sch Med, Dept Internal Med, BR-01246903 Sao Paulo, SP - Brazil

^[4] Proteimax Biotechnol LTDA, BR-05581001 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 - USA

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 7, NOV 1 2017.
• Citações Web of Science: 6

Resumo

Intracellular peptides generated by limited proteolysis are likely to function inside and outside cells and could represent new possibilities for drug development. Here, we used several conformational-sensitive antibodies targeting G-protein coupled receptors to screen for novel pharmacological active peptides. We find that one of these peptides, DITADDEPLT activates cannabinoid type 1 receptors. Single amino acid modifications identified a novel peptide, DIIADDEPLT (Pep19), with slightly better inverse agonist activity at cannabinoid type 1 receptors. Pep19 induced uncoupling protein 1 expression in both white adipose tissue and 3T3-L1 differentiated adipocytes; in the latter, Pep19 activates pERK1/2 and AKT signaling pathways. Uncoupling protein 1 expression induced by Pep19 in 3T3-L1 differentiated adipocytes is blocked by AM251, a cannabinoid type 1 receptors antagonist. Oral administration of Pep19 into diet-induced obese Wistar rats significantly reduces adiposity index, whole body weight, glucose, triacylglycerol, cholesterol and blood pressure, without altering heart rate; changes in the number and size of adipocytes were also observed. Pep19 has no central nervous system effects as suggested by the lack of brain c-Fos expression, cell toxicity, induction of the cannabinoid tetrad, depressive-and anxiety-like behaviors. Therefore, Pep19 has several advantages over previously identified peripherally active cannabinoid compounds, and could have clinical applications. (AU)

• Processo FAPESP: 15/20657-0 - Avaliação do potencial uso farmacológico da hemopressina (HP) no tratamento da obesidade
• Beneficiário: Patrícia Reckziegel
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/04000-3 - Farmacologia de oligopeptidases e peptídeos intracelulares
• Beneficiário: Emer Suavinho Ferro
• Modalidade de apoio: Auxílio à Pesquisa - Temático