Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting

Sander Kersten, Josiane Seydoux, Jeffrey M. Peters, Frank J. Gonzalez, Béatrice Desvergne, Walter Wahli

Research output: Contribution to journalArticlepeer-review

1257 Scopus citations

Abstract

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor α (PPARα) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARα may be involved in the transcriptional response to fasting. To investigate this possibility, PPARα-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wildtype mice. PPARα-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARα-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARα mRNA is induced during fasting in wildtype mice. The data indicate that PPARα plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

Original languageEnglish (US)
Pages (from-to)1489-1498
Number of pages10
JournalJournal of Clinical Investigation
Volume103
Issue number11
DOIs
StatePublished - Jun 1999

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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