Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jul 15;102(2):412–420. doi: 10.1172/JCI3155

Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity.

C Guerra 1, R A Koza 1, H Yamashita 1, K Walsh 1, L P Kozak 1
PMCID: PMC508900  PMID: 9664083

Abstract

The mRNA levels for the mitochondrial uncoupling protein (UCP1) in fat tissues of A/J and C57BL/6J inbred strains of mice varied in a regional-specific manner after stimulation of adrenergic signaling by cold exposure or treatment with a beta3-adrenergic agonist. While the differences between strains were minimal in interscapular brown fat, large differences occurred in white fat tissues, particularly in retroperitoneal fat. Among the AXB recombinant inbred strains, the Ucp1 mRNA levels varied up to 130-fold. This large induction at the mRNA level was accompanied by a corresponding increase in brown adipocytes as revealed by immunohistology with anti-UCP1 antibodies. A high capacity to induce brown fat in areas of traditional white fat had no impact on the ability to gain weight in response to high fat and sucrose diets, but did correlate with the loss of weight in response to treatment with a beta3-adrenergic agonist (CL 316,243). This genetic variation in mice provides an experimental approach to identify genes controlling the induction of brown adipocytes in white fat tissues.

Full Text

The Full Text of this article is available as a PDF (904.1 KB).

Selected References

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

  1. Bailey D. W. Recombinant-inbred strains. An aid to finding identity, linkage, and function of histocompatibility and other genes. Transplantation. 1971 Mar;11(3):325–327. doi: 10.1097/00007890-197103000-00013. [DOI] [PubMed] [Google Scholar]
  2. Boss O., Samec S., Paoloni-Giacobino A., Rossier C., Dulloo A., Seydoux J., Muzzin P., Giacobino J. P. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 1997 May 12;408(1):39–42. doi: 10.1016/s0014-5793(97)00384-0. [DOI] [PubMed] [Google Scholar]
  3. Bronnikov G., Houstek J., Nedergaard J. Beta-adrenergic, cAMP-mediated stimulation of proliferation of brown fat cells in primary culture. Mediation via beta 1 but not via beta 3 adrenoceptors. J Biol Chem. 1992 Jan 25;267(3):2006–2013. [PubMed] [Google Scholar]
  4. Bukowiecki L. J., Géloën A., Collet A. J. Proliferation and differentiation of brown adipocytes from interstitial cells during cold acclimation. Am J Physiol. 1986 Jun;250(6 Pt 1):C880–C887. doi: 10.1152/ajpcell.1986.250.6.C880. [DOI] [PubMed] [Google Scholar]
  5. Champigny O., Ricquier D., Blondel O., Mayers R. M., Briscoe M. G., Holloway B. R. Beta 3-adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial uncoupling protein in adult dogs. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10774–10777. doi: 10.1073/pnas.88.23.10774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Champigny O., Ricquier D. Evidence from in vitro differentiating cells that adrenoceptor agonists can increase uncoupling protein mRNA level in adipocytes of adult humans: an RT-PCR study. J Lipid Res. 1996 Sep;37(9):1907–1914. [PubMed] [Google Scholar]
  7. 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]
  8. Collins S., Daniel K. W., Petro A. E., Surwit R. S. Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology. 1997 Jan;138(1):405–413. doi: 10.1210/endo.138.1.4829. [DOI] [PubMed] [Google Scholar]
  9. Cousin B., Cinti S., Morroni M., Raimbault S., Ricquier D., Pénicaud L., Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci. 1992 Dec;103(Pt 4):931–942. doi: 10.1242/jcs.103.4.931. [DOI] [PubMed] [Google Scholar]
  10. Cummings D. E., Brandon E. P., Planas J. V., Motamed K., Idzerda R. L., McKnight G. S. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature. 1996 Aug 15;382(6592):622–626. doi: 10.1038/382622a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  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. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  14. Fleury C., Neverova M., Collins S., Raimbault S., Champigny O., Levi-Meyrueis C., Bouillaud F., Seldin M. F., Surwit R. S., Ricquier D. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997 Mar;15(3):269–272. doi: 10.1038/ng0397-269. [DOI] [PubMed] [Google Scholar]
  15. Foster D. O., Frydman M. L. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmacol. 1979 Mar;57(3):257–270. doi: 10.1139/y79-039. [DOI] [PubMed] [Google Scholar]
  16. Ghorbani M., Claus T. H., Himms-Hagen J. Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a beta3-adrenoceptor agonist. Biochem Pharmacol. 1997 Jul 1;54(1):121–131. doi: 10.1016/s0006-2952(97)00162-7. [DOI] [PubMed] [Google Scholar]
  17. Ghorbani M., Himms-Hagen J. Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats. Int J Obes Relat Metab Disord. 1997 Jun;21(6):465–475. doi: 10.1038/sj.ijo.0800432. [DOI] [PubMed] [Google Scholar]
  18. Gimeno R. E., Dembski M., Weng X., Deng N., Shyjan A. W., Gimeno C. J., Iris F., Ellis S. J., Woolf E. A., Tartaglia L. A. Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. Diabetes. 1997 May;46(5):900–906. doi: 10.2337/diab.46.5.900. [DOI] [PubMed] [Google Scholar]
  19. Gong D. W., He Y., Karas M., Reitman M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem. 1997 Sep 26;272(39):24129–24132. doi: 10.1074/jbc.272.39.24129. [DOI] [PubMed] [Google Scholar]
  20. Himms-Hagen J., Cui J., Danforth E., Jr, Taatjes D. J., Lang S. S., Waters B. L., Claus T. H. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol. 1994 Apr;266(4 Pt 2):R1371–R1382. doi: 10.1152/ajpregu.1994.266.4.R1371. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Kopecky J., Clarke G., Enerbäck S., Spiegelman B., Kozak L. P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest. 1995 Dec;96(6):2914–2923. doi: 10.1172/JCI118363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kopecký J., Hodný Z., Rossmeisl M., Syrový I., Kozak L. P. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution. Am J Physiol. 1996 May;270(5 Pt 1):E768–E775. doi: 10.1152/ajpendo.1996.270.5.E768. [DOI] [PubMed] [Google Scholar]
  24. Kozak L. P., Britton J. H., Kozak U. C., Wells J. M. The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains. J Biol Chem. 1988 Sep 5;263(25):12274–12277. [PubMed] [Google Scholar]
  25. Krief S., Lönnqvist F., Raimbault S., Baude B., Van Spronsen A., Arner P., Strosberg A. D., Ricquier D., Emorine L. J. Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest. 1993 Jan;91(1):344–349. doi: 10.1172/JCI116191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Loncar D., Afzelius B. A., Cannon B. Epididymal white adipose tissue after cold stress in rats. I. Nonmitochondrial changes. J Ultrastruct Mol Struct Res. 1988 Nov-Dec;101(2-3):109–122. doi: 10.1016/0889-1605(88)90001-8. [DOI] [PubMed] [Google Scholar]
  27. Nagase I., Yoshida T., Kumamoto K., Umekawa T., Sakane N., Nikami H., Kawada T., Saito M. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. J Clin Invest. 1996 Jun 15;97(12):2898–2904. doi: 10.1172/JCI118748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rothwell N. J., Stock M. J. A role for brown adipose tissue in diet-induced thermogenesis. Nature. 1979 Sep 6;281(5726):31–35. doi: 10.1038/281031a0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Soloveva V., Graves R. A., Rasenick M. M., Spiegelman B. M., Ross S. R. Transgenic mice overexpressing the beta 1-adrenergic receptor in adipose tissue are resistant to obesity. Mol Endocrinol. 1997 Jan;11(1):27–38. doi: 10.1210/mend.11.1.9870. [DOI] [PubMed] [Google Scholar]
  31. Surwit R. S., Kuhn C. M., Cochrane C., McCubbin J. A., Feinglos M. N. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988 Sep;37(9):1163–1167. doi: 10.2337/diab.37.9.1163. [DOI] [PubMed] [Google Scholar]
  32. Surwit R. S., Seldin M. F., Kuhn C. M., Cochrane C., Feinglos M. N. Control of expression of insulin resistance and hyperglycemia by different genetic factors in diabetic C57BL/6J mice. Diabetes. 1991 Jan;40(1):82–87. doi: 10.2337/diab.40.1.82. [DOI] [PubMed] [Google Scholar]
  33. Susulic V. S., Frederich R. C., Lawitts J., Tozzo E., Kahn B. B., Harper M. E., Himms-Hagen J., Flier J. S., Lowell B. B. Targeted disruption of the beta 3-adrenergic receptor gene. J Biol Chem. 1995 Dec 8;270(49):29483–29492. doi: 10.1074/jbc.270.49.29483. [DOI] [PubMed] [Google Scholar]
  34. Tai T. A., Jennermann C., Brown K. K., Oliver B. B., MacGinnitie M. A., Wilkison W. O., Brown H. R., Lehmann J. M., Kliewer S. A., Morris D. C. Activation of the nuclear receptor peroxisome proliferator-activated receptor gamma promotes brown adipocyte differentiation. J Biol Chem. 1996 Nov 22;271(47):29909–29914. doi: 10.1074/jbc.271.47.29909. [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. 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]
  37. Young P., Arch J. R., Ashwell M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett. 1984 Feb 13;167(1):10–14. doi: 10.1016/0014-5793(84)80822-4. [DOI] [PubMed] [Google Scholar]

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

RESOURCES