Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue.

Details

Serval ID
serval:BIB_4A74CF1A260A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue.
Journal
Cells
Author(s)
Hinds T.D., Kipp Z.A., Xu M., Yiannikouris F.B., Morris A.J., Stec D.F., Wahli W., Stec D.E.
ISSN
2073-4409 (Electronic)
ISSN-L
2073-4409
Publication state
Published
Issued date
2022
Peer-reviewed
Oui
Volume
11
Number
1
Pages
4
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (Ppara <sup>FatKO</sup> ) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male Ppara <sup>FatKO</sup> animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK-SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.
Keywords
FAS, SCD1, adipocyte, adipogenesis, cholesterol esters, fatty acid synthase, inflammation, lipid signaling, obesity, sexual dimorphism
Pubmed
Open Access
Yes
Create date
17/01/2022 10:49
Last modification date
03/04/2022 6:35
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