Abstract
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 appetite-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 (ACTH 1-39 ). Results: The mutant ACTH 1-39 (ACTH QKQR ) functions similar to native ACTH 1-39 (ACTH KKRR ) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH 1-39 (Pomc tm1/tm1 ) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-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-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.
Original language | English (US) |
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Pages (from-to) | 207-216 |
Number of pages | 10 |
Journal | Molecular Metabolism |
Volume | 9 |
DOIs | |
State | Published - Mar 2018 |
Keywords
- Desacetyl-α-MSH
- Obese mouse model
- Obesity
- POMC
- α-MSH
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology