Effects of Microbiota on the Treatment of Obesity with the Natural Product Celastrol in Rats.
Gastrointestinal microbiome
Leptin
Tripterine
Energy metabolism
Journal
Diabetes & metabolism journal
ISSN: 2233-6087
Titre abrégé: Diabetes Metab J
Pays: Korea (South)
ID NLM: 101556588
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
24
06
2019
accepted:
31
10
2019
pubmed:
21
5
2020
medline:
10
9
2021
entrez:
21
5
2020
Statut:
ppublish
Résumé
Obesity has become one of the most serious issues threatening the health of humankind, and we conducted this study to examine whether and how celastrol protects against obesity. We fed male Sprague-Dawley rats a high-fat diet and administered celastrol to obese rats for 3 weeks. By recording body weight (BW) and other measures, we identified the effective dose of celastrol for obesity treatment. Feces were collected to perform 16S rRNA sequencing, and hypothalami were extracted for transcriptome sequencing. We then treated leptin knockout rats with celastrol and explored the changes in energy metabolism. Male Institute of Cancer Research (ICR) mice were used to test the acute toxicity of celastrol. We observed that celastrol reduced BW and promoted energy expenditure at a dose of 500 µg/kg BW but that food intake was not changed after administration. The diversity of the gut microbiota was improved, with an increased ratio of Bacteroidetes to Firmicutes, and the gut microbiota played an important role in the anti-obesity effects of celastrol. Hypothalamic transcriptome analysis showed a significant enrichment of the leptin signaling pathway, and we found that celastrol significantly enhanced energy expenditure, which was mediated by the leptin signaling pathway. Acute lethal toxicity of celastrol was not observed at doses ranging from 0 to 62.5 mg/kg BW. Our study revealed that celastrol decreased the BW of obese rats by enhancing energy expenditure but not by suppressing food intake and that this effect was mediated by the improvement of the gut microbiota and the activation of the hypothalamic leptin signaling pathway.
Sections du résumé
Background
Obesity has become one of the most serious issues threatening the health of humankind, and we conducted this study to examine whether and how celastrol protects against obesity.
Methods
We fed male Sprague-Dawley rats a high-fat diet and administered celastrol to obese rats for 3 weeks. By recording body weight (BW) and other measures, we identified the effective dose of celastrol for obesity treatment. Feces were collected to perform 16S rRNA sequencing, and hypothalami were extracted for transcriptome sequencing. We then treated leptin knockout rats with celastrol and explored the changes in energy metabolism. Male Institute of Cancer Research (ICR) mice were used to test the acute toxicity of celastrol.
Results
We observed that celastrol reduced BW and promoted energy expenditure at a dose of 500 µg/kg BW but that food intake was not changed after administration. The diversity of the gut microbiota was improved, with an increased ratio of Bacteroidetes to Firmicutes, and the gut microbiota played an important role in the anti-obesity effects of celastrol. Hypothalamic transcriptome analysis showed a significant enrichment of the leptin signaling pathway, and we found that celastrol significantly enhanced energy expenditure, which was mediated by the leptin signaling pathway. Acute lethal toxicity of celastrol was not observed at doses ranging from 0 to 62.5 mg/kg BW.
Conclusion
Our study revealed that celastrol decreased the BW of obese rats by enhancing energy expenditure but not by suppressing food intake and that this effect was mediated by the improvement of the gut microbiota and the activation of the hypothalamic leptin signaling pathway.
Identifiants
pubmed: 32431112
pii: 44.e20
doi: 10.4093/dmj.2019.0124
pmc: PMC7643605
doi:
Substances chimiques
Biological Products
0
Pentacyclic Triterpenes
0
RNA, Ribosomal, 16S
0
celastrol
L8GG98663L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
747-763Subventions
Organisme : NSFC
ID : 81330067
Pays : International
Organisme : NSFC
ID : 81573182
Pays : International
Organisme : Jiangsu Province
ID : JY-052
Pays : International
Organisme : Jiangsu Higher Education Institutions
Pays : International
Références
Science. 2013 Sep 6;341(6150):1241214
pubmed: 24009397
Science. 2006 Aug 25;313(5790):1137-40
pubmed: 16931765
Diabetes. 2018 Nov;67(11):2456-2465
pubmed: 30158241
Sci Rep. 2016 Jul 05;6:28508
pubmed: 27378381
Cell Metab. 2016 Jul 12;24(1):63-74
pubmed: 27411009
Gut. 2019 Feb;68(2):248-262
pubmed: 30007918
Nature. 2009 Jan 22;457(7228):480-4
pubmed: 19043404
Diabetes. 2011 Nov;60(11):2775-86
pubmed: 21933985
Lancet. 2016 May 7;387(10031):1947-56
pubmed: 26868660
Trends Neurosci. 2013 Sep;36(9):504-12
pubmed: 23790727
Cell Rep. 2015 Apr 28;11(4):527-38
pubmed: 25892234
J Endocrinol Invest. 2015 Dec;38(12):1249-63
pubmed: 26062517
N Engl J Med. 1996 Feb 1;334(5):292-5
pubmed: 8532024
Nat Commun. 2014 Nov 25;5:5493
pubmed: 25423280
Nat Med. 2015 Dec;21(12):1497-1501
pubmed: 26569380
Nat Commun. 2015 Jun 23;6:7489
pubmed: 26102296
F1000Res. 2015 Oct 14;4:1070
pubmed: 26674615
Cell Metab. 2017 May 2;25(5):1075-1090.e5
pubmed: 28467926
F1000Res. 2016 Jun 24;5:1492
pubmed: 27508062
Nat Med. 2012 May;18(5):820-3
pubmed: 22522563
Diabetes. 2008 Jun;57(6):1470-81
pubmed: 18305141
Nat Med. 2015 Jan;21(1):27-36
pubmed: 25485909
Nature. 2006 Dec 21;444(7122):1027-31
pubmed: 17183312
Nat Rev Microbiol. 2013 Sep;11(9):639-47
pubmed: 23912213
Cancer Lett. 2011 Apr 1;303(1):9-20
pubmed: 21168266
Gut. 2010 Dec;59(12):1635-42
pubmed: 20926643
Physiol Rev. 2018 Jul 1;98(3):1113-1141
pubmed: 29717927
Metabolism. 2015 Jan;64(1):146-56
pubmed: 25156686
Diabetes Care. 2015 Jan;38(1):159-65
pubmed: 25538312
Cell Host Microbe. 2012 Sep 13;12(3):277-88
pubmed: 22980325
Cell Metab. 2017 Oct 3;26(4):611-619.e6
pubmed: 28978426
Nature. 2006 Dec 21;444(7122):1022-3
pubmed: 17183309
Diabetes. 2016 Oct;65(10):2990-3001
pubmed: 27431457
Nat Commun. 2017 Oct 12;8(1):878
pubmed: 29026082
Nat Rev Drug Discov. 2010 Jun;9(6):465-82
pubmed: 20514071
Sci Transl Med. 2016 Jan 27;8(323):323rv2
pubmed: 26819198
Cell. 2015 May 21;161(5):999-1011
pubmed: 26000480
Nat Neurosci. 2005 Oct;8(10):1289-91
pubmed: 16158063
Nature. 2012 Sep 13;489(7415):242-9
pubmed: 22972297
FASEB J. 2015 Jun;29(6):2397-411
pubmed: 25713030
Nat Med. 1995 Dec;1(12):1311-4
pubmed: 7489415
Endocr Rev. 2006 Dec;27(7):736-49
pubmed: 17077189
Gut. 2013 Feb;62(2):220-6
pubmed: 22345653
Nature. 2013 Jul 4;499(7456):97-101
pubmed: 23803760
Cell Metab. 2015 Oct 6;22(4):695-708
pubmed: 26344102
Nat Rev Endocrinol. 2015 Aug;11(8):444
pubmed: 26055047
Nature. 2016 Jun 08;534(7606):213-7
pubmed: 27279214
Science. 2018 Mar 9;359(6380):1151-1156
pubmed: 29590046