Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.
Mountjoy, Kathleen G
Harris, Paul WR
Brimble, Margaret A
Piper, Sarah J
Elmquist, Joel K
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Mountjoy, K. G., Caron, A., Hubbard, K., Shome, A., Grey, A. C., Sun, B., Bould, S., et al. (2018). Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.. Molecular metabolism, 9 207-216. https://doi.org/10.1016/j.molmet.2017.11.008
Objective: Regulation of energy balance depends on pro-opiomelanocortin (POMC)- derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite34 regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. Methods: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). Results: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39(ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses5 excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. Conclusions: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH.
Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Weight Gain, alpha-MSH, Receptor, Melanocortin, Type 2, Receptor, Melanocortin, Type 4, Protein Binding, Energy Metabolism, Mutation, Female, Male, Proteolysis
External DOI: https://doi.org/10.1016/j.molmet.2017.11.008
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271751