Abstract
ObjectiveThe lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study was to determine which POMC-derived peptides are present in the human brain, to establish their relative concentrations, and to test if their production is dynamically regulated. MethodsWe analysed both fresh post-mortem human hypothalamic tissue and hypothalamic neurons derived from human pluripotent stem cells (hPSCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the sequence and quantify the production of hypothalamic neuropeptides, including those derived from POMC. ResultsIn both in vitro and in vivo hypothalamic cells, LC-MS/MS revealed the sequence of hundreds of neuropeptides as a resource for the field. Although the existence of β-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl α-MSH (d-α-MSH) were produced in considerable excess of acetylated α-MSH. In hPSC-derived hypothalamic neurons, these POMC derivatives were appropriately trafficked, secreted, and their production was significantly (P < 0.0001) increased in response to the hormone leptin. ConclusionsOur findings challenge the assumed pre-eminence of α-MSH and suggest that in humans, d-α-MSH and β-MSH are likely to be the predominant physiological products acting on melanocortin receptors.
Highlights
In order to develop effective treatments for obesity, it is important to understand the mechanisms that regulate energy homeostasis
Our findings challenge the assumed pre-eminence of a-melanocyte stimulating hormone (MSH) and suggest that in humans, desacetyl a-MSH (d-a-MSH) and b-MSH are likely to be the predominant physiological products acting on melanocortin receptors
We used LC-MS/MS to analyse POMC processing in both hPSCderived hypothalamic neurons and primary human brain samples to address several outstanding questions: Is b-MSH produced in the human brain? What are the relative concentrations of POMC-derived peptides that regulate human energy homeostasis? Are the concentrations of these peptides regulated by leptin in humans, as they are in mice? We found that human pluripotent stem cells (hPSC)-derived hypothalamic neurons trafficked and secreted POMC and its derivatives, including b-MSH(1-18), and appropriately processed POMC into neuropeptides previously established to regulate energy balance
Summary
In order to develop effective treatments for obesity, it is important to understand the mechanisms that regulate energy homeostasis. Obese patients with POMC deficiency dramatically lose weight in response to a drug mimicking the effects of POMCderived peptides [3]. The potential of these drugs to find more widespread clinical use highlights the importance of better understanding human POMC biology. These peptides include desacetyl a-melanocyte stimulating hormone (ACTH(1-13) amide, d-a-MSH(1-13), d-a-MSH), which can be acetylated to produce a-MSH(1-13).
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