Research Article| Volume 33, ISSUE 5, P679-687, May 1992

Download started.


Genetic regulation of fatty acid synthetase expression in adipose tissue: overtranscription of the gene in genetically obese rats.

Open AccessPublished:May 01, 1992DOI:
      This paper is only available as a PDF. To read, Please Download here.
      We have investigated the molecular mechanism of the overactivity of fatty acid synthetase (FAS) in adipose tissue from the genetically obese Zucker rat. Purified FAS from lean and obese rat adipose tissues displayed kinetics constants, molecular weight, and immunological properties that were identical. Western blot analysis revealed that FAS overactivity in obese versus lean rat adipose tissue was paralleled by a proportionate increase in FAS mass, i.e., 4-fold increase in suckling normoinsulinemic 16-day-old pups and 25-fold in weaned hyperinsulinemic 30-day-old rats. The determination of absolute FAS mass disclosed that FAS was quantitatively a major protein in obese rat adipose tissue accounting for 13% of cytosolic proteins versus 2% in lean rat at 30 days of age. FAS hyperabundance could be ascribed to an increased relative rate of FAS synthesis that was 6-fold higher in obese than in lean rat adipose tissue. Northern blot analysis demonstrated that FAS mRNA levels in obese rats were increased 4- and 14-fold over those of lean rats at 16 and 30 days of age, respectively, in very close proportion to the 3- and 15-fold increases in FAS gene transcription rates revealed by nuclear run-on assays. Southern analysis of genomic DNA did not allow for detecting amplification or any major structural changes in the FAS gene. It is concluded that FAS overactivity, shown here to be a life-long and general feature of all adipose tissue sites in the obese rat, arises primarily from FAS gene overtranscription.


        • Zucker L.M.
        • Zucker T.F.
        Fatty, a new mutation in the rat.
        J. Hered. 1961; 62: 275-278
        • Stunkard A.J.
        • Sorensen T.I.A.
        • Harris G.
        • Teasdale T.N.
        An adoption study of human obesity.
        N. Engl. J. Med. 1986; 314: 193-198
        • Boulange A.
        • Planche E.
        • De Gasquet P.
        Onset of genetic obesity in the absence of hyperphagia during the first week of life in the Zucker rat.
        (fa/fa). J. Lipid Res. 1979; 20: 857-864
        • Bazin R.
        • Lavau M.
        Development of hepatic and adipose tissue lipogenic enzymes and insulinemia during suckling and weaning on to a high-fat diet in Zucker rats.
        J. Lipid Res. 1982; 23: 839-849
        • Lavau M.
        • Bazin R.
        • Guerre-Millo M.
        Increased capacity for fatty acid synthesis in white and brown adipose tissues from 7-day-old obese Zucker pups.
        Int. J. Obes. 1985; 9: 61-66
        • Volpe J.J.
        • Vagelos P.R.
        Mechanisms and regulation of biosynthesis of saturated fatty acids.
        Physiol. Rev. 1976; 56: 339-417
        • Guynn R.W.
        • Veloso D.
        • Veech R.L.
        The concentration of malonyl coenzyme A and the control of fatty acid synthesis in vivo.
        J. Biol. Chem. 1972; 247: 7325-7331
        • Lavau M.
        • Bazin R.
        Inguinal fat pad weight plotted versus body weight as a method of genotype identification in 16-day-old Zucker rat.
        J. Lipid Res. 1982; 23: 941-943
        • Halestrap A.P.
        • Denton R.M.
        Insulin and the regulation of acetyl coenzyme A carboxylase.
        Biochem. J. 1973; 132: 509-513
        • Bradford M.M.
        A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
        Anal. Biochem. 1976; 72: 248-254
        • Ramakrishna S.
        • Benjamin W.B.
        Rapid purification of enzymes of fatty acid biosynthesis from rat adipose tissue. Prep.
        Biochem. 1983; 13: 475-488
        • Laemli U.K.
        Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
        Nature. 1970; 227: 680-685
        • Cathala G.
        • Savouret J.F.
        • Mendez B.
        • West B.L.
        • Karin M.
        • Martial J.A.
        • Baxter J.D.
        A method for isolation of intact translationally active ribonucleic acid.
        DNA. 1983; 2: 329-335
        • Nepokroeff C.M.
        • Adachi K.
        • Yan C.
        • Porter J.W.
        Cloning of DNA complementary to rat liver fatty acid synthetase mRNA.
        Eur. J. Biochem. 1984; 140: 441-445
        • Dugail I.
        • Quignard-Boulange A.
        • Le Liepvre X.
        • Lavau M.
        Impairment of adipsin expression is secondary to the onset of obesity in.
        db/db mice. J. Biol. Chem. 1990; 265: 1831-1833
        • Zechner R.
        • Newman T.C.
        • Sherry B.
        • Cerami A.
        • Breslow J.L.
        Recombinant human cachectin/tumor necrosis factor but not interleukin-I down-regulates LPL gene expression.
        Mol. Cell. Biol. 1988; 8: 2394-2401
        • Sambrock J.
        • Fritsch E.F.
        • Maniatis T.
        Molecular Cloning, a Laboratory Manual. 2nd Ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1989
        • Hainault I.
        • Guerre-Millo M.
        • Guichard C.
        • Lavau M.
        Differential regulation of adipose tissue glucose transporters in genetic obesity (Fatty rat).
        J. Clin. Invest. 1991; 87: 1127-1131
        • Yan C
        • Wood E.A.
        • Porter J.W.
        Characterization of fatty acid synthase cDNA clone and its mRNA.
        Biochem. Biophys. Res. Commun. 1985; 126: 1235-1241
        • Paulauskis J.D
        • Sul H.S.
        Cloning and expression of mouse fatty acid synthase and other specific mRNAs.
        J. Biol. Chem. 1988; 263: 7049-7054
        • Dugail I.
        • Le Liepvre X.
        • Quignard-Boulange A.
        • Pairault J.
        • Lavau M.
        Adipsin mRNA amounts are not decreased in the genetically obese Zucker rat.
        Biochem. J. 1989; 257: 917-919
        • Bray G.A.
        • York D.A.
        • Swerloff R.S.
        Genetic obesity in the rat: the effect of food restriction on body composition and hypothalamic function.
        Metabolism. 1973; 22: 435-442
        • Cleary M.P.
        • Vasselli J.P.
        • Greenwood M.R.C.
        Development of obesity in Zucker obese ja/ja rat in absence of hyperphagia.
        Am. J. Physiol. 1980; 238: 284-292
        • Kameda K.
        • Goodridge A.G.
        Isolation and partial characterization of the gene for goose fatty acid synthetase.
        J. Biol. Chem. 1991; 266: 419-426
        • Amy C.M.
        • Williams-Ahlf B.
        • Naggert J.
        • Smith S.
        Molecular cloning of the mammalian fatty acid synthetase gene and identification of the promoter region.
        Biochem. J. 1990; 271: 675-679
        • Stapleton S.R.
        • Mitchell D.A.
        • Salati L.M.
        • Goodridge A.G.
        Triiodothyronine stimulates transcription of the fatty acid synthetase gene in chick embryo hepatocytes in culture.
        J. Biol. Chem. 1990; 265: 18442-18446
        • Moustaïd N.
        • Sul H.S.
        Regulation of expression of the fatty acid synthase gene in 3T3-L1 cells by differentiation and triiodothyronine.
        J. Biol. Chem. 1991; 266: 18550-18554
        • Beltramo J.L.
        • Chomard P.
        Glandular production of thyroid hormones in the developing genetically obese male Zucker rat.
        Int. J. Obes. 1991; 15 (abstract): 14
        • Paulauskis J.D
        • Sul H.S.
        Hormonal regulation of mouse fatty acid synthase gene transcription in liver.
        J. Biol. Chem. 1989; 264: 574-577
        • Shillabeer G.
        • Hornford J.
        • Forden J.M.
        • Wong N.C.W.
        • Lau D.C.W.
        Hepatic and adipose tissue lipogenic enzyme mRNA levels are suppressed by high fat diets in the rat.
        J. Lipid Res. 1990; 31: 623-631