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

Terry D Hinds,Andrew J Morris,Frederique B Yiannikouris,Walter Wahli,Donald F Stec,Mei Xu,Zachary A Kipp,David E Stec

doi:10.3390/cells11010004

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.

Highlights

Despite it being over three decades since the discovery of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [1], its role in extrahepatic tissues remains ambiguous
Very low PPARα expression was observed in epididymal white adipose tissue for males and females; this same observation has been reported previously [37]
We found that the male PparaFatKO mice compared to Pparafl/fl on an high-fat diet (HFD) had significantly higher inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT), but no significant differences in body weight, total fat, or epididymal white adipose tissue (eWAT) between the groups (Figure 2A)

Summary

Introduction

Despite it being over three decades since the discovery of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [1], its role in extrahepatic tissues remains ambiguous. While most studies have revealed the primary function of PPARα is in the liver, others have shown that the nuclear receptor regulates body weight and adiposity [10,11,12,13]. Most anti-adiposity mechanisms have been supported in studies using PPARα ligands that elicit whole-body responses or global PPARα knockout (KO) animals. The explicit tissue-specific mechanisms are not yet clearly understood.

Methods

Results

Conclusion