Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis.
Adipocytes
/ cytology
Adipose Tissue
/ cytology
Animals
Cells, Cultured
Diabetes Mellitus, Type 2
/ metabolism
Diet, High-Fat
/ adverse effects
Dioxoles
/ pharmacology
Female
Glucose
/ metabolism
Glucose Intolerance
/ metabolism
Homeostasis
Humans
Hyaluronic Acid
/ metabolism
Hypoglycemic Agents
/ pharmacology
Lipolysis
/ drug effects
Male
Mice
Mice, Transgenic
Obesity
/ etiology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 08 2021
10 08 2021
Historique:
received:
13
04
2020
accepted:
08
07
2021
entrez:
11
8
2021
pubmed:
12
8
2021
medline:
24
8
2021
Statut:
epublish
Résumé
Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.
Identifiants
pubmed: 34376643
doi: 10.1038/s41467-021-25025-4
pii: 10.1038/s41467-021-25025-4
pmc: PMC8355239
doi:
Substances chimiques
Dioxoles
0
Hypoglycemic Agents
0
disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
138908-40-4
Hyaluronic Acid
9004-61-9
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4829Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG051459
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099110
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK055758
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR024992
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK114498
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK127274
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK118620
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Mol Endocrinol. 2013 Jan;27(1):172-84
pubmed: 23204326
Circulation. 2010 Nov 30;122(22):2313-22
pubmed: 21098434
J Vis Exp. 2020 Nov 24;(165):
pubmed: 33311436
Nat Rev Mol Cell Biol. 2014 Dec;15(12):786-801
pubmed: 25415508
Matrix Biol. 2019 Jul;80:46-58
pubmed: 30196101
Int J Cell Biol. 2015;2015:563818
pubmed: 26448754
Genomics. 1997 May 1;41(3):493-7
pubmed: 9169154
Diabetes. 2017 Nov;66(11):2789-2799
pubmed: 28877911
Cell Metab. 2016 Sep 13;24(3):420-433
pubmed: 27626200
Diabetes. 2016 Sep;65(9):2742-53
pubmed: 27246914
Oncol Lett. 2013 Mar;5(3):1068-1074
pubmed: 23426189
Endocrinology. 2012 Jul;153(7):3493-503
pubmed: 22529214
Sci Rep. 2016 Nov 09;6:36866
pubmed: 27827441
Matrix Biol. 2019 May;78-79:284-291
pubmed: 29458140
Hepatology. 1996 Dec;24(6):1399-403
pubmed: 8938169
J Biol Chem. 2004 Aug 6;279(32):33281-9
pubmed: 15190064
World J Biol Chem. 2015 Aug 26;6(3):110-20
pubmed: 26322170
Nat Cell Biol. 2015 Sep;17(9):1099-111
pubmed: 26280538
Nat Metab. 2019 May;1(5):546-559
pubmed: 31602424
Clin Dermatol. 2008 Mar-Apr;26(2):106-22
pubmed: 18472055
Am J Clin Nutr. 1990 Feb;51(2):241-7
pubmed: 2305711
Plant Physiol. 1973 May;51(5):875-8
pubmed: 16658431
Adv Drug Deliv Rev. 2016 Feb 1;97:4-27
pubmed: 26562801
Mol Immunol. 2009 Dec;47(2-3):449-56
pubmed: 19781786
Diabetes. 2017 Jun;66(6):1479-1490
pubmed: 28254844
J Clin Invest. 2015 Oct 1;125(10):3928-40
pubmed: 26368307
Nat Med. 2013 Oct;19(10):1338-44
pubmed: 23995282
J Control Release. 2018 Jun 10;279:89-98
pubmed: 29649530
Sci Transl Med. 2016 Jan 27;8(323):323ps4
pubmed: 26819194
Nutr J. 2016 Jan 27;15:11
pubmed: 26818459
Nucleic Acids Res. 2012 Jan;40(Database issue):D1144-9
pubmed: 22086960
J Clin Invest. 2002 Mar;109(5):629-39
pubmed: 11877471
Nature. 2013 Jul 18;499(7458):346-9
pubmed: 23783513
Nat Commun. 2015 Aug 05;6:7906
pubmed: 26243466
J Clin Invest. 2014 Dec;124(12):5481-9
pubmed: 25384213
Nat Metab. 2019 Feb;1(2):212-221
pubmed: 31245789
Clin Exp Immunol. 2016 Sep;185(3):372-81
pubmed: 27218304
Liver Int. 2005 Aug;25(4):779-86
pubmed: 15998429
Gastroenterology. 2009 Dec;137(6):2041-51
pubmed: 19732774
Cell Metab. 2015 Aug 4;22(2):266-278
pubmed: 26190650
Nat Med. 2016 Nov;22(11):1285-1293
pubmed: 27694932
Cell Metab. 2019 Oct 1;30(4):706-719.e6
pubmed: 31495688
Diabetes. 2013 Jun;62(6):1888-96
pubmed: 23349492
Knee Surg Sports Traumatol Arthrosc. 2019 Jun;27(6):1974-1983
pubmed: 30046992
Cell. 2014 Apr 10;157(2):447-458
pubmed: 24725410
Exp Dermatol. 2014 May;23(5):295-303
pubmed: 24628940
Gastroenterology. 1993 Aug;105(2):470-4
pubmed: 8335201
Biochem Pharmacol. 1985 Apr 15;34(8):1325-9
pubmed: 3994749
Gen Comp Endocrinol. 2004 Dec;139(3):206-14
pubmed: 15560867
Diabetologia. 1985 Jul;28(7):412-9
pubmed: 3899825
Exp Cell Res. 2009 Jul 1;315(11):1914-23
pubmed: 19285976
Diabetes. 2007 Sep;56(9):2260-73
pubmed: 17563062
Interdiscip Toxicol. 2013 Sep;6(3):111-25
pubmed: 24678248
J Intern Med. 2005 Nov;258(5):460-6
pubmed: 16238682