A novel anti-obesity peptide that targets the hypothalamus

Abstract

Computational tools that predict which amino acid sequences are produced by cleavage enzymes can accelerate the discovery of bioactive peptides with therapeutic potential. A study recently published in Nature presents a peptide prediction programme that was used to search for novel anti-obesity peptides made by prohormone convertase enzymes (also known as proprotein convertase subtilisin/kexin (PCSK) enzymes).

After using their programme to predict the amino acid sequences of putative peptide products of PCSK enzyme activity, the team created a library containing 100 predicted peptides that had no known function. Next, they tested which of these peptides might be able to influence neuronal signalling and pancreatic β-cell activity to regulate metabolism. They treated cells from a rat phaeochromocytoma cell line and cells from a rat β-cell line with the peptides, then measured changes in Fos mRNA transcription. BRP, which is a predicted product of PCSK cleavage of the protein BRINP2, elicited a notable increase in Fos expression in both of the cell lines. To confirm whether BRP is produced in humans and in mice, the researchers performed liquid chromatography–mass spectrometry on samples of cerebrospinal fluid from human donors and mouse brain tissue. Their results showed that BRP was present in both sample types. They also tested whether PCSK1 produces BRP in vivo by measuring brain levels of BRP in wild-type mice and in transgenic mice in which PCSK1 function is impaired. They found that the levels of BRP were considerably reduced in the brains of the transgenic mice, which suggests that PCSK1 activity contributes to BRP production.