Mitochondrial dysfunction caused by SIRT3 inhibition drives proinflammatory macrophage polarization in obesity.
Journal
Obesity (Silver Spring, Md.)
ISSN: 1930-739X
Titre abrégé: Obesity (Silver Spring)
Pays: United States
ID NLM: 101264860
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
revised:
29
11
2022
received:
27
07
2022
accepted:
16
12
2022
pubmed:
10
3
2023
medline:
23
3
2023
entrez:
9
3
2023
Statut:
ppublish
Résumé
Metabolic reprogramming is a main feature of proinflammatory macrophage polarization, a process that leads to inflammation in dysfunctional adipose tissue. Therefore, the study aim was to explore whether sirtuin 3 (SIRT3), a mitochondrial deacetylase, participates in this pathophysiological process. Macrophage-specific Sirt3 knockout (Sirt3-MKO) mice and wild-type littermates were treated with a high-fat diet. Body weight, glucose tolerance, and inflammation were evaluated. Bone marrow-derived macrophages and RAW264.7 cells were treated with palmitic acid to explore the mechanism of SIRT3 on inflammation. The expression of SIRT3 was significantly repressed in both bone marrow-derived macrophages and adipose tissue macrophages in mice fed with a high-fat diet. Sirt3-MKO mice exhibited accelerated body weight and severe inflammation, accompanied with reduced energy expenditure and worsened glucose metabolism. In vitro experiments showed that SIRT3 inhibition or knockdown exacerbated palmitic acid-induced proinflammatory macrophage polarization, whereas SIRT3 restoration displayed opposite effects. Mechanistically, SIRT3 deficiency resulted in hyperacetylation of succinate dehydrogenase that led to succinate accumulation, which suppressed the transcription of Kruppel-like factor 4 via increasing histone methylation on its promoter, thus evoking proinflammatory macrophages. This study emphasizes an important preventive role of SIRT3 in macrophage polarization and implies that SIRT3 is a promising therapeutic target for obesity.
Substances chimiques
Sirtuin 3
EC 3.5.1.-
Palmitic Acid
2V16EO95H1
Sirt3 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1050-1063Informations de copyright
© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.
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