Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance

Kathleen G. Mountjoy, Alexandre Caron, Kristina Hubbard, Avik Shome, Angus C. Grey, Bo Sun, Sarah Bould, Martin Middleditch, Beau Pontré, Ailsa McGregor, Paul W.R. Harris, Renata Kowalczyk, Margaret A. Brimble, Rikus Botha, Karen M.L. Tan, Sarah J. Piper, Christina Buchanan, Syann Lee, Anthony P. Coll, Joel K. Elmquist

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (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 reverses 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.

Original languageEnglish (US)
Pages (from-to)207-216
Number of pages10
JournalMolecular Metabolism
Volume9
DOIs
StatePublished - Mar 1 2018

Fingerprint

Melanocyte-Stimulating Hormones
Pro-Opiomelanocortin
Receptor, Melanocortin, Type 4
Peptides
Receptor, Melanocortin, Type 2
Obesity
Melanocortins
alpha-MSH
Brain
Appetite

Keywords

  • Desacetyl-α-MSH
  • Obese mouse model
  • Obesity
  • POMC
  • α-MSH

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance. / Mountjoy, Kathleen G.; Caron, Alexandre; Hubbard, Kristina; Shome, Avik; Grey, Angus C.; Sun, Bo; Bould, Sarah; Middleditch, Martin; Pontré, Beau; McGregor, Ailsa; Harris, Paul W.R.; Kowalczyk, Renata; Brimble, Margaret A.; Botha, Rikus; Tan, Karen M.L.; Piper, Sarah J.; Buchanan, Christina; Lee, Syann; Coll, Anthony P.; Elmquist, Joel K.

In: Molecular Metabolism, Vol. 9, 01.03.2018, p. 207-216.

Research output: Contribution to journalArticle

Mountjoy, KG, Caron, A, Hubbard, K, Shome, A, Grey, AC, Sun, B, Bould, S, Middleditch, M, Pontré, B, McGregor, A, Harris, PWR, Kowalczyk, R, Brimble, MA, Botha, R, Tan, KML, Piper, SJ, Buchanan, C, Lee, S, Coll, AP & Elmquist, JK 2018, 'Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance', Molecular Metabolism, vol. 9, pp. 207-216. https://doi.org/10.1016/j.molmet.2017.11.008
Mountjoy, Kathleen G. ; Caron, Alexandre ; Hubbard, Kristina ; Shome, Avik ; Grey, Angus C. ; Sun, Bo ; Bould, Sarah ; Middleditch, Martin ; Pontré, Beau ; McGregor, Ailsa ; Harris, Paul W.R. ; Kowalczyk, Renata ; Brimble, Margaret A. ; Botha, Rikus ; Tan, Karen M.L. ; Piper, Sarah J. ; Buchanan, Christina ; Lee, Syann ; Coll, Anthony P. ; Elmquist, Joel K. / Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance. In: Molecular Metabolism. 2018 ; Vol. 9. pp. 207-216.
@article{524f3b2ea47440df99b0bb67fb96a1d6,
title = "Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance",
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 (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 reverses 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.",
keywords = "Desacetyl-α-MSH, Obese mouse model, Obesity, POMC, α-MSH",
author = "Mountjoy, {Kathleen G.} and Alexandre Caron and Kristina Hubbard and Avik Shome and Grey, {Angus C.} and Bo Sun and Sarah Bould and Martin Middleditch and Beau Pontr{\'e} and Ailsa McGregor and Harris, {Paul W.R.} and Renata Kowalczyk and Brimble, {Margaret A.} and Rikus Botha and Tan, {Karen M.L.} and Piper, {Sarah J.} and Christina Buchanan and Syann Lee and Coll, {Anthony P.} and Elmquist, {Joel K.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.molmet.2017.11.008",
language = "English (US)",
volume = "9",
pages = "207--216",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",

}

TY - JOUR

T1 - Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance

AU - Mountjoy, Kathleen G.

AU - Caron, Alexandre

AU - Hubbard, Kristina

AU - Shome, Avik

AU - Grey, Angus C.

AU - Sun, Bo

AU - Bould, Sarah

AU - Middleditch, Martin

AU - Pontré, Beau

AU - McGregor, Ailsa

AU - Harris, Paul W.R.

AU - Kowalczyk, Renata

AU - Brimble, Margaret A.

AU - Botha, Rikus

AU - Tan, Karen M.L.

AU - Piper, Sarah J.

AU - Buchanan, Christina

AU - Lee, Syann

AU - Coll, Anthony P.

AU - Elmquist, Joel K.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 (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 reverses 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.

AB - 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 (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 reverses 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.

KW - Desacetyl-α-MSH

KW - Obese mouse model

KW - Obesity

KW - POMC

KW - α-MSH

UR - http://www.scopus.com/inward/record.url?scp=85042908995&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042908995&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2017.11.008

DO - 10.1016/j.molmet.2017.11.008

M3 - Article

VL - 9

SP - 207

EP - 216

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

ER -