Genetic Control of Carbon Utilization During Hibernation: Mechanistic Considerations

  • Teresa L. Squire
  • Matthew T. Andrews
Conference paper


During hibernation, mammals rely heavily on lipid stores to provide the fuel necessary to survive the winter. Pyruvate dehydrogenase kinase isozyme 4 (PDK-4) plays a key role in gating carbohydrate catabolism and allowing the switch to lipid metabolism. Earlier we reported that PDK-4 was up-regulated in the heart of the thirteen-lined ground squirrel during hibernation (Andrews et al., 1998). A similar induction of PDK-4 was seen in rat skeletal muscle after administration of WY-14,643, a known peroxisome proliferator and ligand for peroxisome proliferator-activated receptor subtype alpha (PPARoc; Wu et al., 1999). In light of this evidence that PPARα may activate PDK-4 expression, we review the role that PPARs play in lipid metabolism and thermogenesis and discuss their potential as regulators of metabolism during hibernation.


Brown Adipose Tissue White Adipose Tissue Ground Squirrel Peroxisome Proliferator Fatty Acid Transport Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Andrews MT, Squire TL, Bowen CM, Rollins MB (1998) Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal. Proc Natl Acad Sci USA 95: 8392–8397PubMedCrossRefGoogle Scholar
  2. Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPAR α). J Biol Chem 273: 5678–5684PubMedCrossRefGoogle Scholar
  3. Bitting L, Sutin EL, Watson FL, Leard LE, O’Hara BF, Heller HC, Kilduff TS (1994) C-fos mRNA increases in the ground squirrel suprachiasmatic nucleus during arousal from hibernation. Neurosci Lett 165: 117–121PubMedCrossRefGoogle Scholar
  4. Boyer BB, Barnes BM (1999) Molecular and metabolic aspects of mammalian hibernation. Bioscience 49: 713–724CrossRefGoogle Scholar
  5. Boyer BB, Barnes BM, Lowell BB, Grujic D (1998) Differential regulation of uncoupling protein gene homologues in multiple tissues of hibernating ground squirrels. Am J Physiol 275 (Regulatory Integrative Comp Physiol 44): R1232-R1238Google Scholar
  6. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -ß, -y in the adult rat. Endocrinology 137: 354–366PubMedCrossRefGoogle Scholar
  7. Brandt JM, Djouadi F, Kelly DP (1998) Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor α. J Biol Chem 273: 23786–23797PubMedCrossRefGoogle Scholar
  8. Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, Villarroya F (1999) Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 expression at birth. Diabetes 48: 1217–1222PubMedCrossRefGoogle Scholar
  9. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156 – 159PubMedCrossRefGoogle Scholar
  10. Devine JH, Eubank DW, Clouthier DE, Tontonoz P, Spiegelman BM, Hammer RE, Beale EG (1999) Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor gamma and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo. J Biol Chem 274: 13604–12PubMedCrossRefGoogle Scholar
  11. Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors a and b. Proc Natl Acad Sci USA 94: 4312–4317PubMedCrossRefGoogle Scholar
  12. Gorham DA, Bretscher A, Carey HV (1998) Hibernation induces expression of moesin in intestinal epithelial cells. Cryobiology 37: 146–154PubMedCrossRefGoogle Scholar
  13. Gunning P, Ponte P, Okayama H, Engel J, Blau H, Kedes L (1983) Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol 3: 787–795PubMedGoogle Scholar
  14. Hertz R, Bishara-Shieban J, Bar-Tana J (1995) Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J Biol Chem 270: 13470–13475PubMedCrossRefGoogle Scholar
  15. Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650PubMedCrossRefGoogle Scholar
  16. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91: 7355–7359PubMedCrossRefGoogle Scholar
  17. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83: 813–819PubMedCrossRefGoogle Scholar
  18. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and y. Proc Natl Acad Sci USA 94: 4318–4323PubMedCrossRefGoogle Scholar
  19. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome prolierator signalling pathways through heterodimer formation of their receptors. Nature 358: 771–774PubMedCrossRefGoogle Scholar
  20. Kliewer SA, Willson TM (1998) The nuclear receptor PPARy — bigger than fat. Curr Opn Gen Dev 8: 576–581CrossRefGoogle Scholar
  21. Latruffe N, Vamecq J (1997) Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism. Biochimie 79: 81–94PubMedCrossRefGoogle Scholar
  22. Leone TC, Weinheimer CJ, Kelly DP (1999) A critical role for the peroxisome proliferatoractivated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 96: 7473–7478PubMedCrossRefGoogle Scholar
  23. Lyman CP, Willis JS, Malan A, Wang LCH (1982) Hibernation and torpor in mammals and birds. Academic Press, New YorkGoogle Scholar
  24. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83: 835–839PubMedCrossRefGoogle Scholar
  25. Martin G, Schoonjans K, Lefebvre A, Staels B, Auwerx J (1997) Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARα and PPARy activators. J Biol Chem 272: 28210–28217PubMedCrossRefGoogle Scholar
  26. Mukherjee R, Jow L, Noonan D, McDonnell DP (1994) Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Molec Biol 51: 157–166PubMedCrossRefGoogle Scholar
  27. O’Hara BF, Watson FL, Srere HK, Kumar H, Wiler SW, Welch SK, Bitting L, Heller HC, Kilduff TS (1999) Gene expression in the brain across the hibernation cycle. J Neurosci 19: 3781–3790PubMedGoogle Scholar
  28. Pengelley ET, Fisher KC (1961) Rhythmical arousal from hibernation in the golden-mantled ground squirrel, Citellus lateralis tescorum. Can J Zool 39: 105–120.CrossRefGoogle Scholar
  29. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-ind ld ucible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829–839PubMedCrossRefGoogle Scholar
  30. Reddy JK, Moody DE, Azarnoff DL, Tomarelli RM (1977) Hepatic effects of some [4-chloro-6(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) analogs in the mouse. Arch Int Pharmacodyn Ther 225: 51–57PubMedGoogle Scholar
  31. Schoonjans K, Peinado-Onsurbe J, Lefebvre A, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J (1996a) PPARα and PPARy activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 15: 5336–5348PubMedGoogle Scholar
  32. Schoonjans K, Staels B, Auwerx J (1996b) The peroxisome proliferator activated receptor (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1302: 93–109PubMedCrossRefGoogle Scholar
  33. Schoonjans K, Staels B, Auwerx J (1996c) Role of peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 37: 907–925PubMedGoogle Scholar
  34. Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J (1995) Induction of the acyl-CoA synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem 270: 19269–19276PubMedCrossRefGoogle Scholar
  35. Sorensen HN, Treuter E, Gustafsson J (1998) Regulation of peroxisome proliferator-activated receptors. Vitam Horm 54: 121–166PubMedCrossRefGoogle Scholar
  36. Soukri A, Valverde F, Hafid N, Elkebbaj MS, Serrano A (1996) Occurrence ot a ditterential expression of the glyceraldehyde-3-phosphate dehydrogenase gene in muscle and liver from euthermic and induced hibernating jerboa (Jaculus orientalis). Gene 181: 139–145PubMedCrossRefGoogle Scholar
  37. Srere HK, Wang LCH, Martin SL (1992) Central role for differential gene expression in mammalian hibernation. Proc Natl Acad Sci USA 89: 7119–7123PubMedCrossRefGoogle Scholar
  38. Storey KB (1997) Metabolic regulation in mammalian hibernation: enzyme and protein adaptations. Comp Biochem Physiol 118A: 1115–1124CrossRefGoogle Scholar
  39. Takamatsu N, Ohba K, Kondo J, Kondo N, Shiba T (1993) Hibernation-associated gene regulation of plasma proteins with a collagen-like domain in mammalian hibernators. Mol Cell Biol 13: 1516–1521PubMedGoogle Scholar
  40. Tontonoz P, Hu E, Devine J, Beale EG, Spiegelman BM (1995) PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 15: 351–7PubMedGoogle Scholar
  41. Tontonoz P, Hu E, Graves RA, Budavari Al, Spiegelman BM (1994) mRRARy2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8: 1224–1234PubMedCrossRefGoogle Scholar
  42. Wilson BE, Deeb S, Florant GL (1992) Seasonal changes in hormone-sensitive and lipoprotein lipase mRNA concentrations in marmot white adipose tissue. Am J Physiol 262: R177–R181.Google Scholar
  43. Wu P, Inskeep K, Bowker-Kinley MM, Popov KM, Harris RA (1999) Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 48: 1593–1599PubMedCrossRefGoogle Scholar
  44. Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA (1998) Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J 329: 197–201PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Teresa L. Squire
    • 1
  • Matthew T. Andrews
    • 1
  1. 1.Department of GeneticsNorth Carolina State UniversityRaleighUSA

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