Role of ProSAAS-derived peptides in human energy homeostasis

My overarching research goal is to understand the mechanisms by which body weight and hypothalamic-pituitary-gonadal axis function are coupled, and how this becomes disrupted in obesity. We have identified three girls with severe obesity harbouring duplications at chromosome Xp11.22-p11.23. Duplications at this locus are associated with obesity and precocious puberty in other patients.

The minimal critical region encompasses PCSK1N, a gene that encodes ProSAAS, a propeptide highly expressed in the hypothalamus and neuroendocrine tissues. Very little is known about the function of ProSAAS in humans.

In cells, ProSAAS-derived peptides inhibit prohormone convertase 1/3 (PC1/3), an enzyme that cleaves and activates hormones and neuropeptides including those regulating food intake.

In the hypothalamus, Pro-opiomelanocortin (POMC) is cleaved into α melanocyte stimulating hormone (αMSH) which activates melanocortin-4 receptor (MC4R) to suppress food intake. Our team has previously shown that genetic loss of function of PC1/3, POMC or MC4R causes obesity in humans.

In this fellowship, I will test the hypothesis that excess ProSAAS causes obesity in patients with Xp11.22-p11.23 duplication.

Combining mass spectrometric peptide analysis, advanced microscopy and metabolic phenotyping in patients, I will evaluate ProSAAS’s role in regulating the intracellular processing, trafficking, secretion and function of key neuropeptides involved in energy homeostasis.