Peroxisome Proliferator-Activated Receptor Alpha Mediates the Adaptive Response to Fasting

J Clin Invest. 1999 Jun;103(11):1489-98. doi: 10.1172/JCI6223.

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 alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-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, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenase
  • Adaptation, Physiological / physiology*
  • Animals
  • Apolipoproteins B / genetics
  • Apolipoproteins E / genetics
  • Carnitine O-Palmitoyltransferase / genetics
  • Carrier Proteins / genetics
  • Dietary Fats / metabolism
  • Fasting*
  • Fatty Acid Desaturases / genetics
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Fatty Acids / metabolism
  • Fatty Liver / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Hormones / metabolism
  • Hypothermia, Induced
  • Lipoproteins, VLDL / metabolism
  • Mice
  • Mice, Knockout
  • Microbodies*
  • Myelin P2 Protein / genetics
  • Neoplasm Proteins*
  • Nerve Tissue Proteins*
  • Oxidation-Reduction
  • Phenotype
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic

Substances

  • Apolipoproteins B
  • Apolipoproteins E
  • Carrier Proteins
  • Dietary Fats
  • Fabp5 protein, mouse
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Fatty Acids
  • Hormones
  • Lipoproteins, VLDL
  • Myelin P2 Protein
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • microsomal triglyceride transfer protein
  • Fatty Acid Desaturases
  • Acyl-CoA Dehydrogenase
  • Carnitine O-Palmitoyltransferase