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

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 (PparaFatKO) 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 PparaFatKO 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.

Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin

“…It should be noted that all of the PPAR isoforms are considered to drive anti-inflammatory pathways. A hepatocyte-specific and adipocyte-specific knockout of PPARα in mice fed a high-fat diet showed greater fat content in each of the KOs, which both also exhibited significantly higher inflammation compared to control littermates [ 88 , 89 ]. Similarly, studies showing that overexpression of inflammatory meditator glucocorticoid receptor beta (GRβ) in the liver of C57/bl6 mice induced hepatic lipid accumulation in 5 days on a normal chow diet by suppression of hepatic PPARα [ 90 ].…”

“…These kinases are found to increase the transactivation of PPARα and thus an increase in FA oxidation and glucose production, which can be used as fuel during exercise [ 100 ]. PPARα, in particular, has strong actions on improving the efficacy of FA oxidation in the liver and adipose tissues [ 88 , 89 ]. PPARα mRNA upregulates in bouts of exercise and in times of starvation in order to metabolize fat and use it for an effective energy source [ 101 , 102 ].…”

Characterization of Plocamium telfairiae Extract-Functionalized Au Nanostructures and Their Anti-Adipogenic Activity through PLD1

“…Following MDI induction of preadipocytes, which no longer grow owing to the formation of intercellular hyperjunctions, differentiation into mature adipocytes starts. During adipocyte differentiation and lipid deposition, SREBP-1c, PPAR-γ, and C/EBPα are the major adipogenic transcription factors, and these genes regulate the transcription of FAS and aP2, which are responsible for morphological changes and lipid accumulation in adipocytes [ 12 , 18 ]. SREBP-1c augments the expression of genes involved in adipogenesis, particularly fatty acid biosynthesis and triglyceride maturation.…”

“…During adipocyte differentiation, triglycerides are accumulated, and the expression of adipocyte-specific proteins—such as fatty acid synthase (FAS) and adipocyte fatty acid-binding protein (aP2)—is induced. The transcription factors peroxisome proliferator-activated receptorγ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), and adipocyte determination- and differentiation-dependent factor 1 (ADD1)/sterol regulatory element-binding protein-1c (SREBP1c) play key roles as upstream factors, inducing the expression of these proteins and promoting direct triglyceride production by transporting free fatty acids into the cytoplasm [ 16 , 17 , 18 ]. Mouse embryonic fibroblasts (3T3-L1) are a widely used cell line in biological studies on adipose tissues.…”

Genome-wide characterization of lncRNAs and mRNAs in muscles with differential intramuscular fat contents

“…These key lncRNAs will be the emphasis in clarifying the differential IMF content between LT and ST muscles in the future study. In addition, 50 key DEGs engaged in differential fat deposition between the two muscles were characterized including widely known fat-related genes such as PPARα ( 34 ), PPARGC-1 ( 35 ), mTOR ( 36 ), EGF and its receptor, EGFR ( 37 ).…”