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The Loss of PPARα in Adipocytes Induces Lipogenesis via the PASK‐SREBP1 Signaling Axis

PPARα is a nuclear receptor and a key player in regulating adiposity by activating b‐oxidation while inhibiting de novo lipogenesis within the liver. Its role in extrahepatic tissues is currently unknown. Therefore, we established the first adipose‐specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion and adipocyte hypertrophy 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) (p=0.0091) and brown adipose tissue (BAT) (p=0.0031) with HFD compared to littermates. No changes in adiposity were observed in female mice compared to littermate controls. Lipidomics analysis of iWAT via liquid chromatography–mass spectrometry (LC‐MS) showed that PparaFatKO males had an increase in cholesterol esters. Interrogation of the signaling mechanisms with the loss of PPARα in adipocytes showed that the transcription factor sterol regulatory element‐binding protein‐1 (SREBP‐1) had more of the mature form present in the KO males and its target genes were higher, which might be due to the significantly (p=0.009) elevated expression of the Per‐Arnt‐Sim Kinase (PASK), a kinase that activates SREBP‐1. The hyperactivity of the PASK‐SREBP‐1 axis significantly (p<0.05) 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). Hence, we have uncovered a new signaling paradigm, the PASK‐SREBP‐1 axis in adipocytes, that drives lipogenesis, which PPARα inhibits. Our results demonstrate the first adipose‐specific actions for PPARα in protecting against lipogenesis and cholesterol ester accumulation that leads to adipocyte hypertrophy in obesity.