| First Author | Mountjoy KG | Year | 2018 |
| Journal | Mol Metab | Volume | 9 |
| Pages | 207-216 | PubMed ID | 29226825 |
| Mgi Jnum | J:263640 | Mgi Id | MGI:6161894 |
| Doi | 10.1016/j.molmet.2017.11.008 | Citation | Mountjoy KG, et al. (2018) Desacetyl-alpha-melanocyte stimulating hormone and alpha-melanocyte stimulating hormone are required to regulate energy balance. Mol Metab 9:207-216 |
| abstractText | OBJECTIVE: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (alpha-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-alpha-MSH, the precursor for alpha-MSH, is present in brain and blood. Desacetyl-alpha-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with alpha-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-alpha-MSH is still unclear. METHODS: We created a novel mouse model to determine whether desacetyl-alpha-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-alpha-MSH and alpha-MSH from adrenocorticotropin (ACTH1-39). RESULTS: The mutant ACTH1-39 (ACTH(QKQR)) functions similar to native ACTH1-39 (ACTH(KKRR)) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomc(tm1/tm1)) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-alpha-MSH or alpha-MSH over 14 days into Pomc(tm1/tm1) mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomc(wt/wt)) mice. Here, we identify both desacetyl-alpha-MSH and alpha-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-alpha-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-alpha-MSH and alpha-MSH. |
