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

作者：Reckziegel Patricia; Festuccia William T; Britto Luiz R G; Lopes Jang Karen L; Romao Carolina M; Heimann Joel C; Fogaca Manoela V; Rodrigues Naielly S; Silva Nicole R; Guimaraes Francisco S; Eichler Rosangela A S; Gupta Achla; Gomes Ivone; Devi Lakshmi A; Heimann Andrea S^*; Ferro Emer S^*

来源：Scientific Reports, 2017, 7(1): 14781.

DOI：10.1038/s41598-017-13690-9

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.

• 出版日期2017-11-1