Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 1;97(11):2553–2561. doi: 10.1172/JCI118703

Regulation of PPAR gamma gene expression by nutrition and obesity in rodents.

A Vidal-Puig 1, M Jimenez-Liñan 1, B B Lowell 1, A Hamann 1, E Hu 1, B Spiegelman 1, J S Flier 1, D E Moller 1
PMCID: PMC507341  PMID: 8647948

Abstract

The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.

Full Text

The Full Text of this article is available as a PDF (254.0 KB).

Selected References

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

  1. Ailhaud G., Grimaldi P., Négrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr. 1992;12:207–233. doi: 10.1146/annurev.nu.12.070192.001231. [DOI] [PubMed] [Google Scholar]
  2. Amri E. Z., Bonino F., Ailhaud G., Abumrad N. A., Grimaldi P. A. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem. 1995 Feb 3;270(5):2367–2371. doi: 10.1074/jbc.270.5.2367. [DOI] [PubMed] [Google Scholar]
  3. Chawla A., Schwarz E. J., Dimaculangan D. D., Lazar M. A. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology. 1994 Aug;135(2):798–800. doi: 10.1210/endo.135.2.8033830. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Christy R. J., Yang V. W., Ntambi J. M., Geiman D. E., Landschulz W. H., Friedman A. D., Nakabeppu Y., Kelly T. J., Lane M. D. Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. Genes Dev. 1989 Sep;3(9):1323–1335. doi: 10.1101/gad.3.9.1323. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Flier J. S. The adipocyte: storage depot or node on the energy information superhighway? Cell. 1995 Jan 13;80(1):15–18. doi: 10.1016/0092-8674(95)90445-x. [DOI] [PubMed] [Google Scholar]
  8. Frederich R. C., Löllmann B., Hamann A., Napolitano-Rosen A., Kahn B. B., Lowell B. B., Flier J. S. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest. 1995 Sep;96(3):1658–1663. doi: 10.1172/JCI118206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gearing K. L., Crickmore A., Gustafsson J. A. Structure of the mouse peroxisome proliferator activated receptor alpha gene. Biochem Biophys Res Commun. 1994 Feb 28;199(1):255–263. doi: 10.1006/bbrc.1994.1222. [DOI] [PubMed] [Google Scholar]
  10. Gulick T., Cresci S., Caira T., Moore D. D., Kelly D. P. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11012–11016. doi: 10.1073/pnas.91.23.11012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamann A., Flier J. S., Lowell B. B. Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. Endocrinology. 1996 Jan;137(1):21–29. doi: 10.1210/endo.137.1.8536614. [DOI] [PubMed] [Google Scholar]
  12. Hu E., Tontonoz P., Spiegelman B. M. Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9856–9860. doi: 10.1073/pnas.92.21.9856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990 Oct 18;347(6294):645–650. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar]
  14. Issemann I., Prince R. A., Tugwood J. D., Green S. The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol. 1993 Aug;11(1):37–47. doi: 10.1677/jme.0.0110037. [DOI] [PubMed] [Google Scholar]
  15. Lang C. H., Dobrescu C., Bagby G. J. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology. 1992 Jan;130(1):43–52. doi: 10.1210/endo.130.1.1727716. [DOI] [PubMed] [Google Scholar]
  16. Le Marchand-Brustel Y., Jeanrenaud B., Freychet P. Insulin binding and effects in isolated soleus muscle of lean and obese mice. Am J Physiol. 1978 Apr;234(4):E348–E358. doi: 10.1152/ajpendo.1978.234.4.E348. [DOI] [PubMed] [Google Scholar]
  17. Lehmann J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M., Kliewer S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. doi: 10.1074/jbc.270.22.12953. [DOI] [PubMed] [Google Scholar]
  18. Lin F. T., Lane M. D. CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8757–8761. doi: 10.1073/pnas.91.19.8757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lowell B. B., Flier J. S. Differentiation dependent biphasic regulation of adipsin gene expression by insulin and insulin-like growth factor-1 in 3T3-F442A adipocytes. Endocrinology. 1990 Dec;127(6):2898–2906. doi: 10.1210/endo-127-6-2898. [DOI] [PubMed] [Google Scholar]
  20. Lowell B. B., S-Susulic V., Hamann A., Lawitts J. A., Himms-Hagen J., Boyer B. B., Kozak L. P., Flier J. S. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature. 1993 Dec 23;366(6457):740–742. doi: 10.1038/366740a0. [DOI] [PubMed] [Google Scholar]
  21. MacDougald O. A., Cornelius P., Liu R., Lane M. D. Insulin regulates transcription of the CCAAT/enhancer binding protein (C/EBP) alpha, beta, and delta genes in fully-differentiated 3T3-L1 adipocytes. J Biol Chem. 1995 Jan 13;270(2):647–654. doi: 10.1074/jbc.270.2.647. [DOI] [PubMed] [Google Scholar]
  22. MacDougald O. A., Hwang C. S., Fan H., Lane M. D. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9034–9037. doi: 10.1073/pnas.92.20.9034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Manson J. E., Willett W. C., Stampfer M. J., Colditz G. A., Hunter D. J., Hankinson S. E., Hennekens C. H., Speizer F. E. Body weight and mortality among women. N Engl J Med. 1995 Sep 14;333(11):677–685. doi: 10.1056/NEJM199509143331101. [DOI] [PubMed] [Google Scholar]
  24. Rodríguez J. C., Gil-Gómez G., Hegardt F. G., Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem. 1994 Jul 22;269(29):18767–18772. [PubMed] [Google Scholar]
  25. Saladin R., De Vos P., Guerre-Millo M., Leturque A., Girard J., Staels B., Auwerx J. Transient increase in obese gene expression after food intake or insulin administration. Nature. 1995 Oct 12;377(6549):527–529. doi: 10.1038/377527a0. [DOI] [PubMed] [Google Scholar]
  26. Schmidt A., Endo N., Rutledge S. J., Vogel R., Shinar D., Rodan G. A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992 Oct;6(10):1634–1641. doi: 10.1210/mend.6.10.1333051. [DOI] [PubMed] [Google Scholar]
  27. Spiegelman B. M., Green H. Control of specific protein biosynthesis during the adipose conversion of 3T3 cells. J Biol Chem. 1980 Sep 25;255(18):8811–8818. [PubMed] [Google Scholar]
  28. Spiegelman B. M., Hotamisligil G. S. Through thick and thin: wasting, obesity, and TNF alpha. Cell. 1993 May 21;73(4):625–627. doi: 10.1016/0092-8674(93)90243-j. [DOI] [PubMed] [Google Scholar]
  29. Spiegelman B. M. Regulation of gene expression in the adipocyte: implications for obesity and proto-oncogene function. Trends Genet. 1988 Jul;4(7):203–207. doi: 10.1016/0168-9525(88)90077-7. [DOI] [PubMed] [Google Scholar]
  30. Steineger H. H., Sørensen H. N., Tugwood J. D., Skrede S., Spydevold O., Gautvik K. M. Dexamethasone and insulin demonstrate marked and opposite regulation of the steady-state mRNA level of the peroxisomal proliferator-activated receptor (PPAR) in hepatic cells. Hormonal modulation of fatty-acid-induced transcription. Eur J Biochem. 1994 Nov 1;225(3):967–974. doi: 10.1111/j.1432-1033.1994.0967b.x. [DOI] [PubMed] [Google Scholar]
  31. Tominaga M., Igarashi M., Daimon M., Eguchi H., Matsumoto M., Sekikawa A., Yamatani K., Sasaki H. Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocr J. 1993 Jun;40(3):343–349. doi: 10.1507/endocrj.40.343. [DOI] [PubMed] [Google Scholar]
  32. Tontonoz P., Graves R. A., Budavari A. I., Erdjument-Bromage H., Lui M., Hu E., Tempst P., Spiegelman B. M. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res. 1994 Dec 25;22(25):5628–5634. doi: 10.1093/nar/22.25.5628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tontonoz P., Hu E., Devine J., Beale E. G., Spiegelman B. M. PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol. 1995 Jan;15(1):351–357. doi: 10.1128/mcb.15.1.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Tontonoz P., Hu E., Spiegelman B. M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994 Dec 30;79(7):1147–1156. doi: 10.1016/0092-8674(94)90006-x. [DOI] [PubMed] [Google Scholar]
  36. Van Itallie T. B. Obesity: adverse effects on health and longevity. Am J Clin Nutr. 1979 Dec;32(12 Suppl):2723–2733. doi: 10.1093/ajcn/32.12.2723. [DOI] [PubMed] [Google Scholar]
  37. Weinstein S. P., Holand A., O'Boyle E., Haber R. S. Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle. Metabolism. 1993 Oct;42(10):1365–1369. doi: 10.1016/0026-0495(93)90139-f. [DOI] [PubMed] [Google Scholar]
  38. Yu K., Bayona W., Kallen C. B., Harding H. P., Ravera C. P., McMahon G., Brown M., Lazar M. A. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem. 1995 Oct 13;270(41):23975–23983. doi: 10.1074/jbc.270.41.23975. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Zhu Y., Alvares K., Huang Q., Rao M. S., Reddy J. K. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem. 1993 Dec 25;268(36):26817–26820. [PubMed] [Google Scholar]
  41. Zhu Y., Qi C., Korenberg J. R., Chen X. N., Noya D., Rao M. S., Reddy J. K. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7921–7925. doi: 10.1073/pnas.92.17.7921. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES