Mouse models for V103I and I251L gain of function variants of the human MC4R display decreased adiposity but are not protected against a hypercaloric diet.
CRISPR/Cas9
Melaconocortins
Mouse models
Obesity
Type 2 diabetes
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
16
07
2020
revised:
20
08
2020
accepted:
06
09
2020
pubmed:
12
9
2020
medline:
8
9
2021
entrez:
11
9
2020
Statut:
ppublish
Résumé
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor that plays major roles in the central control of energy balance. Loss-of-function mutations of MC4R constitute the most common monogenic cause of early-onset extreme obesity in humans, whereas gain-of-function mutations appear to be protective. In particular, two relatively frequent alleles carrying the non-synonymous coding mutations V103I or I251L are associated with lower risks of obesity and type-2 diabetes. Although V103I and I251L MC4Rs showed more efficient signalling in transfected cells, their specific effects in live animals remain unexplored. Here, we investigated whether the introduction of V103I and I251L mutations into the mouse MC4R leads to a lean phenotype and provides protection against an obesogenic diet. Using CRISPR/Cas9, we generated two novel strains of mice carrying single-nucleotide mutations into the mouse Mc4r which are identical to those present in V103I and I251L MCR4 human alleles, and studied their phenotypic outcomes in mice fed with normal chow or a high-fat diet. In particular, we measured body weight progression, food intake and adiposity. In addition, we analysed glucose homeostasis through glucose and insulin tolerance tests. We found that homozygous V103I females displayed shorter longitudinal length and decreased abdominal white fat, whereas homozygous I251L females were also shorter and leaner due to decreased weight in all white fat pads examined. Homozygous Mc4r Our results demonstrate that mice carrying V103I and I251L MC4R mutations displayed gain-of-function phenotypes that were more evident in females. However, hypermorphic MC4R mutants were as susceptible as their control littermates to the obesogenic and diabetogenic effects elicited by a long-term hypercaloric diet, highlighting the importance of healthy feeding habits even under favourable genetic conditions.
Identifiants
pubmed: 32916307
pii: S2212-8778(20)30151-4
doi: 10.1016/j.molmet.2020.101077
pmc: PMC7559519
pii:
doi:
Substances chimiques
Insulin
0
MC4R protein, human
0
MC4R protein, mouse
0
Receptor, Melanocortin, Type 4
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101077Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK068400
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.
Références
Neuroscience. 2017 Mar 27;346:102-112
pubmed: 28093215
Nat Genet. 2008 Jun;40(6):768-75
pubmed: 18454148
Clin Chem. 2018 Jan;64(1):24-29
pubmed: 29295834
J Clin Invest. 2012 Nov;122(11):4203-12
pubmed: 23093774
Genet Mol Res. 2013 Feb 28;12(3):3230-45
pubmed: 23479169
Eur J Neurosci. 2014 Sep;40(5):2755-65
pubmed: 24943127
J Endocrinol Invest. 2006 Nov;29(10):894-8
pubmed: 17185898
Physiol Rep. 2017 May;5(9):
pubmed: 28483861
BMC Pediatr. 2018 Aug 22;18(1):278
pubmed: 30134862
Hum Mol Genet. 2009 Apr 15;18(8):1489-96
pubmed: 19164386
Diabetologia. 2013 May;56(5):1129-39
pubmed: 23423668
Nat Neurosci. 2016 Feb;19(2):206-19
pubmed: 26814590
Nat Genet. 1998 Jun;19(2):155-7
pubmed: 9620771
Obesity (Silver Spring). 2010 Mar;18(3):573-9
pubmed: 19696756
Bioinformatics. 2007 Nov 1;23(21):2947-8
pubmed: 17846036
Nat Rev Genet. 2019 Jan;20(1):24-38
pubmed: 30385867
Am J Hum Genet. 2004 Mar;74(3):572-81
pubmed: 14973783
Endocrinology. 2000 Sep;141(9):3072-9
pubmed: 10965876
Cell. 2019 Apr 18;177(3):597-607.e9
pubmed: 31002796
Ann Hum Genet. 1999 Nov;63(Pt 6):483-7
pubmed: 11246450
Nat Commun. 2018 Apr 18;9(1):1544
pubmed: 29670083
Int J Obes (Lond). 2007 Sep;31(9):1437-41
pubmed: 17356525
J Med Genet. 2004 Oct;41(10):795-800
pubmed: 15466016
Cell. 2005 Nov 4;123(3):493-505
pubmed: 16269339
J Clin Endocrinol Metab. 2011 Jan;96(1):E181-8
pubmed: 21047921
J Pediatr. 2010 Apr;156(4):598-605.e1
pubmed: 20070976
Bioinformatics. 2014 May 15;30(10):1473-5
pubmed: 24463181
N Engl J Med. 2003 Mar 20;348(12):1085-95
pubmed: 12646665
Best Pract Res Clin Endocrinol Metab. 2012 Apr;26(2):211-26
pubmed: 22498250
Nat Genet. 1998 Oct;20(2):113-4
pubmed: 9771699
Cell. 1997 Jan 10;88(1):131-41
pubmed: 9019399
Hum Mol Genet. 2007 Aug 1;16(15):1837-44
pubmed: 17519222
Nat Genet. 2015 Dec;47(12):1415-25
pubmed: 26551672
Diabetologia. 1997 Aug;40(8):976-9
pubmed: 9267995
Biochemistry. 2006 Jun 13;45(23):7277-88
pubmed: 16752916
J Med Genet. 2005 Apr;42(4):e21
pubmed: 15805150
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5268-73
pubmed: 12704245
J Clin Invest. 2000 Jul;106(2):253-62
pubmed: 10903341
Int J Obes (Lond). 2017 Jan;41(1):13-22
pubmed: 27654141
Diabetes. 2006 Apr;55(4):978-87
pubmed: 16567519
Science. 2006 Jul 7;313(5783):101-4
pubmed: 16825572
J Intern Med. 2003 Aug;254(2):114-25
pubmed: 12859692
PLoS One. 2013 Sep 16;8(9):e74362
pubmed: 24066140
Nat Genet. 1998 Oct;20(2):111-2
pubmed: 9771698
Diabetes. 2003 Mar;52(3):682-7
pubmed: 12606509
Nat Genet. 2009 Jan;41(1):18-24
pubmed: 19079260
Pediatr Res. 1985 Sep;19(9):879-86
pubmed: 2413420
Mol Metab. 2016 Jan 22;5(3):245-252
pubmed: 26977396
Nat Genet. 2013 May;45(5):513-7
pubmed: 23563609