Control of obesity by an appetite-suppressing peptide

About This Grant

SUMMARY There is an urgent need for new therapies for metabolic disorders, including obesity, which is associated with a significant decrease in life expectancy by 5–10 years and increased mortality resulting from diabetes and cardiovascular diseases. Peptide hormones comprise a class of small (<100 amino acids), low abundance, bioactive molecules involved in regulating physiological processes such as glucose and insulin levels, food intake, and energy expenditure, making them attractive targets for modulation of energy metabolism. However, the functional identification and characterization of small, proteolytically cleaved peptides have traditionally been challenging because of their low abundance and the difficulties in distinguishing bioactive from inactive fragments or degradation products. Recently, my lab discovered a 12-mer secreted non-incretin human peptide called BRP that controls obesity by lowering food intake through the central activation of Fos. This innovative proposal will explore the mechanisms and biology of BRP to validate the receptor target for this promising cleavage product. Based on preliminary data, we hypothesize that BRP is endogenously cleaved from the precursor BRINP2 by the proconvertase PCSK1, and degraded by proteolytic processing. Based on a receptor screen, we also hypothesize that its function is linked to its binding to a GPCR, thereby activating a CREB signaling pathway leading to Fos transcription. Our hypotheses are based on robust preliminary data generated using in vitro models, structure- activity relationships, and in vivo studies. In Aim 1 of this proposal, we will test the hypothesis that BRP is generated by cleavage of a proconvertase and that BRP is regulated by degradation. These studies will be important to understand the endogenous mechanism of regulation. In Aim 2, we determine the causal hypothalamic region and cell type activated by BRP. In Aim 3, we will validate the target receptor candidate and the signaling mechanism for BRP that is responsible for its appetite-suppressing effects. In conclusion, these studies will determine the endogenous regulation and mechanistic action of BRP, which will open up a new pathway of peptide signaling in body weight regulation.