Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Nov 1;102(9):1724–1731. doi: 10.1172/JCI4532

Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation.

C Guerra 1, R A Koza 1, K Walsh 1, D M Kurtz 1, P A Wood 1, L P Kozak 1
PMCID: PMC509120  PMID: 9802886

Abstract

When placed in the cold (4 degreesC), BALB/cByJ mice of both genders rapidly lose body temperature as compared with the control strain, C57BL/6J. This sensitivity to cold resembles that previously described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1. Genetic mapping of the trait placed the gene on chromosome 5 near Acads, a gene encoding the short chain acyl CoA dehydrogenase, which is mutated in BALB/cByJ mice. The analysis of candidate genes in the region indicated a defect only in the expression of Acads. Confirmation of the importance of fatty acid oxidation to thermogenesis came from our finding that mice carrying the targeted inactivation of the long chain acyl CoA dehydrogenase gene (Acadl) are also sensitive to the cold. Both of these mutations attenuate the induction of genes normally responsive to adrenergic signaling in brown adipocytes. These results suggest that the action of fatty acids as regulators of gene expression has been perturbed in the mutant mice. From a clinical perspective, it is important to determine whether defects in thermogenesis may be a phenotype in human neonates with inherited deficiencies in fatty acid beta-oxidation.

Full Text

The Full Text of this article is available as a PDF (749.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoyama T., Peters J. M., Iritani N., Nakajima T., Furihata K., Hashimoto T., Gonzalez F. J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem. 1998 Mar 6;273(10):5678–5684. doi: 10.1074/jbc.273.10.5678. [DOI] [PubMed] [Google Scholar]
  2. Arriza J. L., Dawson T. M., Simerly R. B., Martin L. J., Caron M. G., Snyder S. H., Lefkowitz R. J. The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain. J Neurosci. 1992 Oct;12(10):4045–4055. doi: 10.1523/JNEUROSCI.12-10-04045.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aubert J., Champigny O., Saint-Marc P., Negrel R., Collins S., Ricquier D., Ailhaud G. Up-regulation of UCP-2 gene expression by PPAR agonists in preadipose and adipose cells. Biochem Biophys Res Commun. 1997 Sep 18;238(2):606–611. doi: 10.1006/bbrc.1997.7348. [DOI] [PubMed] [Google Scholar]
  4. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bianco A. C., Sheng X. Y., Silva J. E. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis. J Biol Chem. 1988 Dec 5;263(34):18168–18175. [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Coleman D. L. Thermogenesis in diabetes-obesity syndromes in mutant mice. Diabetologia. 1982 Mar;22(3):205–211. doi: 10.1007/BF00283754. [DOI] [PubMed] [Google Scholar]
  8. Collins S., Kuhn C. M., Petro A. E., Swick A. G., Chrunyk B. A., Surwit R. S. Role of leptin in fat regulation. Nature. 1996 Apr 25;380(6576):677–677. doi: 10.1038/380677a0. [DOI] [PubMed] [Google Scholar]
  9. Croteau W., Davey J. C., Galton V. A., St Germain D. L. Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. J Clin Invest. 1996 Jul 15;98(2):405–417. doi: 10.1172/JCI118806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Derman E., Krauter K., Walling L., Weinberger C., Ray M., Darnell J. E., Jr Transcriptional control in the production of liver-specific mRNAs. Cell. 1981 Mar;23(3):731–739. doi: 10.1016/0092-8674(81)90436-0. [DOI] [PubMed] [Google Scholar]
  11. Dreyer C., Krey G., Keller H., Givel F., Helftenbein G., Wahli W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992 Mar 6;68(5):879–887. doi: 10.1016/0092-8674(92)90031-7. [DOI] [PubMed] [Google Scholar]
  12. Enerbäck S., Jacobsson A., Simpson E. M., Guerra C., Yamashita H., Harper M. E., Kozak L. P. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997 May 1;387(6628):90–94. doi: 10.1038/387090a0. [DOI] [PubMed] [Google Scholar]
  13. Heaton G. M., Wagenvoord R. J., Kemp A., Jr, Nicholls D. G. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem. 1978 Jan 16;82(2):515–521. doi: 10.1111/j.1432-1033.1978.tb12045.x. [DOI] [PubMed] [Google Scholar]
  14. Hinsdale M. E., Farmer S. C., Johnson K. R., Davisson M. T., Hamm D. A., Tolwani R. J., Wood P. A. RNA expression and chromosomal location of the mouse long-chain acyl-CoA dehydrogenase gene. Genomics. 1995 Jul 20;28(2):163–170. doi: 10.1006/geno.1995.1127. [DOI] [PubMed] [Google Scholar]
  15. Hinsdale M. E., Kelly C. L., Wood P. A. Null allele at Bcd-1 locus in BALB/cByJ mice is due to a deletion in the short-chain acyl-CoA dehydrogenase gene and results in missplicing of mRNA. Genomics. 1993 Jun;16(3):605–611. doi: 10.1006/geno.1993.1237. [DOI] [PubMed] [Google Scholar]
  16. Hwang S., Benjamin L. E., Oh B., Rothstein J. L., Ackerman S. L., Beddington R. S., Solter D., Knowles B. B. Genetic mapping and embryonic expression of a novel, maternally transcribed gene Mem3. Mamm Genome. 1996 Aug;7(8):586–590. doi: 10.1007/s003359900174. [DOI] [PubMed] [Google Scholar]
  17. Ikeda Y., Okamura-Ikeda K., Tanaka K. Purification and characterization of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases from rat liver mitochondria. Isolation of the holo- and apoenzymes and conversion of the apoenzyme to the holoenzyme. J Biol Chem. 1985 Jan 25;260(2):1311–1325. [PubMed] [Google Scholar]
  18. Jacobsson A., Stadler U., Glotzer M. A., Kozak L. P. Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression. J Biol Chem. 1985 Dec 25;260(30):16250–16254. [PubMed] [Google Scholar]
  19. Kelly C. L., Hinsdale M. E., Wood P. A. Cloning and characterization of the mouse short-chain acyl-CoA dehydrogenase cDNA. Genomics. 1993 Oct;18(1):137–140. doi: 10.1006/geno.1993.1438. [DOI] [PubMed] [Google Scholar]
  20. Kelly C. L., Wood P. A. Cloning and characterization of the mouse short-chain acyl-CoA dehydrogenase gene. Mamm Genome. 1996 Apr;7(4):262–264. doi: 10.1007/s003359900078. [DOI] [PubMed] [Google Scholar]
  21. Kliewer S. A., Forman B. M., Blumberg B., Ong E. S., Borgmeyer U., Mangelsdorf D. J., Umesono K., Evans R. M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355–7359. doi: 10.1073/pnas.91.15.7355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kozak L. P., Kozak U. C., Clarke G. T. Abnormal brown and white fat development in transgenic mice overexpressing glycerol 3-phosphate dehydrogenase. Genes Dev. 1991 Dec;5(12A):2256–2264. doi: 10.1101/gad.5.12a.2256. [DOI] [PubMed] [Google Scholar]
  23. Lee S. S., Pineau T., Drago J., Lee E. J., Owens J. W., Kroetz D. L., Fernandez-Salguero P. M., Westphal H., Gonzalez F. J. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995 Jun;15(6):3012–3022. doi: 10.1128/mcb.15.6.3012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moinat M., Deng C., Muzzin P., Assimacopoulos-Jeannet F., Seydoux J., Dulloo A. G., Giacobino J. P. Modulation of obese gene expression in rat brown and white adipose tissues. FEBS Lett. 1995 Oct 9;373(2):131–134. doi: 10.1016/0014-5793(95)01030-i. [DOI] [PubMed] [Google Scholar]
  25. Nada M. A., Rhead W. J., Sprecher H., Schulz H., Roe C. R. Evidence for intermediate channeling in mitochondrial beta-oxidation. J Biol Chem. 1995 Jan 13;270(2):530–535. doi: 10.1074/jbc.270.2.530. [DOI] [PubMed] [Google Scholar]
  26. Nicholls D. G., Locke R. M. Thermogenic mechanisms in brown fat. Physiol Rev. 1984 Jan;64(1):1–64. doi: 10.1152/physrev.1984.64.1.1. [DOI] [PubMed] [Google Scholar]
  27. Ogura T., Yokoyama T., Fujisawa H., Kurashima Y., Esumi H. Structural diversity of neuronal nitric oxide synthase mRNA in the nervous system. Biochem Biophys Res Commun. 1993 Jun 30;193(3):1014–1022. doi: 10.1006/bbrc.1993.1726. [DOI] [PubMed] [Google Scholar]
  28. Puigserver P., Wu Z., Park C. W., Graves R., Wright M., Spiegelman B. M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998 Mar 20;92(6):829–839. doi: 10.1016/s0092-8674(00)81410-5. [DOI] [PubMed] [Google Scholar]
  29. Reue K., Cohen R. D. Acads gene deletion in BALB/cByJ mouse strain occurred after 1981 and is not present in BALB/cByJ-fld mutant mice. Mamm Genome. 1996 Sep;7(9):694–695. doi: 10.1007/s003359900208. [DOI] [PubMed] [Google Scholar]
  30. Ricquier D., Kader J. C. Mitochondrial protein alteration in active brown fat: a soidum dodecyl sulfate-polyacrylamide gel electrophoretic study. Biochem Biophys Res Commun. 1976 Dec 6;73(3):577–583. doi: 10.1016/0006-291x(76)90849-4. [DOI] [PubMed] [Google Scholar]
  31. Sears I. B., MacGinnitie M. A., Kovacs L. G., Graves R. A. Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma. Mol Cell Biol. 1996 Jul;16(7):3410–3419. doi: 10.1128/mcb.16.7.3410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Smith R. E., Horwitz B. A. Brown fat and thermogenesis. Physiol Rev. 1969 Apr;49(2):330–425. doi: 10.1152/physrev.1969.49.2.330. [DOI] [PubMed] [Google Scholar]
  33. Swartz D. A., Park E. I., Visek W. J., Kaput J. The e subunit gene of murine F1F0-ATP synthase. Genomic sequence, chromosomal mapping, and diet regulation. J Biol Chem. 1996 Aug 23;271(34):20942–20948. doi: 10.1074/jbc.271.34.20942. [DOI] [PubMed] [Google Scholar]
  34. Taylor B. A., Phillips S. J. Detection of obesity QTLs on mouse chromosomes 1 and 7 by selective DNA pooling. Genomics. 1996 Jun 15;34(3):389–398. doi: 10.1006/geno.1996.0302. [DOI] [PubMed] [Google Scholar]
  35. Thomas S. A., Palmiter R. D. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature. 1997 May 1;387(6628):94–97. doi: 10.1038/387094a0. [DOI] [PubMed] [Google Scholar]
  36. Tontonoz P., Hu E., Graves R. A., Budavari A. I., Spiegelman B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994 May 15;8(10):1224–1234. doi: 10.1101/gad.8.10.1224. [DOI] [PubMed] [Google Scholar]
  37. Trayhurn P., James W. P. Thermoregulation and non-shivering thermogenesis in the genetically obese (ob/ob) mouse. Pflugers Arch. 1978 Feb 22;373(2):189–193. doi: 10.1007/BF00584859. [DOI] [PubMed] [Google Scholar]
  38. Vidal-Puig A., Solanes G., Grujic D., Flier J. S., Lowell B. B. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun. 1997 Jun 9;235(1):79–82. doi: 10.1006/bbrc.1997.6740. [DOI] [PubMed] [Google Scholar]
  39. Wang N. D., Finegold M. J., Bradley A., Ou C. N., Abdelsayed S. V., Wilde M. D., Taylor L. R., Wilson D. R., Darlington G. J. Impaired energy homeostasis in C/EBP alpha knockout mice. Science. 1995 Aug 25;269(5227):1108–1112. doi: 10.1126/science.7652557. [DOI] [PubMed] [Google Scholar]
  40. Wood P. A., Amendt B. A., Rhead W. J., Millington D. S., Inoue F., Armstrong D. Short-chain acyl-coenzyme A dehydrogenase deficiency in mice. Pediatr Res. 1989 Jan;25(1):38–43. doi: 10.1203/00006450-198901000-00010. [DOI] [PubMed] [Google Scholar]
  41. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]
  42. Zhou Y. T., Shimabukuro M., Koyama K., Lee Y., Wang M. Y., Trieu F., Newgard C. B., Unger R. H. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6386–6390. doi: 10.1073/pnas.94.12.6386. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES