Pharmacological Doses of Triiodothyronine Upregulate Lipogenic Enzyme Gene Expression in Rat White Adipose Tissue

Abstract

Triiodothyronine (T₃) is known to increase liver lipogenic enzyme gene expression both in vivo and in tissue culture. Conflicting results have been reported on the effect of T₃ on lipogenic enzyme gene expression in white adipose tissue. The results presented in this paper indicate that administration of pharmacological doses of T₃ in rats leads to increased fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), ATP-citrate lyase (ACL) and malic enzyme (ME) activity in white adipose tissue. The increase in lipogenic enzyme activity was associated with increased FAS, ACC, ACL and ME mRNA levels. The response was dose-dependent. Activity of lipogenic enzyme and the lipogenic enzyme mRNA levels were positively correlated to serum T₃ concentration. The in vivo effect of T₃ on lipogenic enzyme gene expression could be reproduced in primary white rat adipocyte culture. In conclusion, the results presented in this paper indicate that T₃ exerts a stimulatory effect on lipogenic enzyme gene expression in white adipose tissue both in vivo and in tissue culture. Significant effects of T₃ on lipogenic enzyme gene expression were only observed in the presence of relatively high (pharmacological) concentrations of the hormone.

Key words

Triiodothyronine - lipogenic enzyme activity - mRNA - white adipose tissue - rat adipocytes

References

• 1 Mariash C N, Kaiser F E, Oppenheimer J H. Comparison of the response characteristics of four lipogenic enzymes to 3,5,3’-triiodothyronine administration: evidence for variable degrees of amplification of the nuclear 3,5,3’-triiodothyronine signal.  Endocrinology. 1980;  106 22-27
• 2 Diamant S, Gorin E, Shafrir E. Enzyme activities related to fatty-acid synthesis in liver and adipose tissue of rats treated with triiodothyronine.  Eur J Biochem. 1972;  26 553-559
• 3 Wilson S B, Back D W, Morris S M Jr, Swierczynski J, Goodridge A G. Hormonal regulation of lipogenic enzymes in chick embryo hepatocytes in culture. Expression of the fatty acid synthase gene is regulated at both translational and pretranslational steps.  J Biol Chem. 1986;  261 15179-15182
• 4 Stapleton S R, Mitchell D A, Salati L M, Goodridge A G. Triiodothyronine stimulates transcription of the fatty acid synthase gene in chick embryo hepatocytes in culture. Insulin and insulin-like growth factor amplify that effect.  J Biol Chem. 1990;  265 18442-18446
• 5 Swierczynski J, Mitchell D A, Reinhold D S, Salati L M, Stapleton S R, Klautky S A, Struve A E, Goodridge A G. Triiodothyronine-induced accumulations of malic enzyme, fatty acid synthase, acetyl-coenzyme A carboxylase, and their mRNAs are blocked by protein kinase inhibitors. Transcription is the affected step.  J Biol Chem. 1991;  266 17459-17466
• 6 Hillgartner F B, Chen W, Goodridge A G. Overexpression of the alpha-thyroid hormone receptor in avian cell lines. Effects on expression of the malic gene are selective and cell-specific.  J Biol Chem. 1992;  267 12299-12306
• 7 Freake H C, Moon Y K. Hormonal and nutritional regulation of lipogenic enzyme mRNA levels in rat primary white and brown adipocytes.  J Nutr Sci Vitaminol (Tokyo). 2003;  49 40-46
• 8 Jiang W, Miyamoto T, Kakizawa T, Sakuma T, Nishio S-I, Takeda T. Expression of thyroid hormone receptor α in 3T₃-L1 adipocytes; triiodothyronine increases the expression of lipogenic enzyme and triglyceride accumulation.  J Endocrinol. 2004;  182 295-302
• 9 Moustaid 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
• 10 Gharbi-Chihi J, Facchinetti T, Berge-Lefranc J L, Bonne J, Torresani J. Triiodothyronine control of ATP-citrate lyase and malic enzyme during differentiation of a murine preadipocyte cell line.  Horm Metab Res. 1991;  23 423-427
• 11 Gharbi-Chihi J, Chabaud O, Torresani J. The role of triiodothyronine in the regulation of synthesis rate and translatable mRNA level of fatty acid synthase in a preadipocyte cell line.  Biochim Biophys Acta. 1984;  783 26-35
• 12 Flores-Delgado G, Marsch-Moreno M, Kuri-Harcuch W. Thyroid hormone stimulates adipocyte differentiation of 3T₃ cells.  Mol Cell Biochem. 1987;  76 35-43
• 13 Roncari D AK, Murthy V K. Effects of thyroid hormone on enzymes involved in fatty acid and glycerolipid synthesis.  J Biol Chem. 1975;  250 4134-4138
• 14 Llobera M, Muniesa A, Herrera E. Effects of hyperthyroidism on in vivo lipogenesis in fed and fasted rats.  Horm Metab Res. 1979;  11 628-634
• 15 Mooradian A D, Albert S G. The age-related changes in lipogenic enzymes: the role of dietary factors and thyroid hormone responsivness.  Mech Ageing Dev. 1999;  108 139-149
• 16 Freake H C, Schwartz H L, Oppenheimer J H. The regulation of lipogenesis by thyroid hormone and its contribution to thermogenesis.  Endocrinology. 1989;  125 2868-2874
• 17 Gnoni G V, Landriscina C, Quagliariello E. Fatty acid biosynthesis in adipose tissue and lung subcellular fractions of thyrotoxic rats.  FEBS Lett. 1980;  122 37-40
• 18 Blennemann B, Moon Y K, Freake H C. Tissue specific regulation of fatty acid synthesis by thyroid hormone.  Endocrinology. 1992;  130 637-643
• 19 Blennemann B, Leahy P, Kim T-S, Freake H C. Tissue specific regulation mRNAs by thyroid hormone.  Mol Cell Endocrinol. 1995;  110 1-8
• 20 Dugail I, Quignard-Boulange A, Le Liepvre X, Ardouin B, Lavau M. Gene expression of lipid storage-related enzymes in adipose tissue of the genetically obese Zucker rat co-ordinated increase in transcriptional activity and potentiation by hyperinsulinemia.  Biochem J. 1992;  281 607-611
• 21 Kochan Z, Karbowska J, Swierczynski J. Unusual increase of lipogenesis in rat white adipose tissue after multiple cycles of starvation-refeeding.  Metabolism. 1997;  46 10-17
• 22 Rodbell M. Localisation of lipoprotein lipase in fat cells of rat adipose tissue.  J Biol Chem. 1964;  239 753-755
• 23 Karbowska J, Kochan Z, Zelewski L, Swierczynski J. Tissue specific effect of clofibrate on rat lipogenic enzyme gene expression.  Eur J Pharmacol. 1999;  370 329-336
• 24 Karbowska J, Kochan Z, Swierczynski J. Differential effect of clofibrate on acetyl-CoA carboxylase mRNA level in rat white and brown adipose tissue.  Life Sci. 2000;  66 545-552
• 25 Trayhurn P, Duncan J S, Rayner D V. Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system.  Biochem J. 1995;  311 729-733
• 26 Chomczynski P, Sacchi N. Single-step method of RNA isolation by guanidinium thiocyanate-phenol-chloroform extraction.  Anal Biochem. 1987;  162 156-159
• 27 Kochan Z, Karbowska J, Swierczynski J. Effect of clofibrate on malic enzyme and leptin mRNA levels in rat brown and white adipose tissue.  Horm Metab Res. 1999;  31 538-542
• 28 Zelewski L, Swierczynski J. The effect of clofibrate feeding on the NADP-linked dehydrogenases activity in rat tissue.  Biochim Biophys Acta. 1983;  758 152-157
• 29 Korczynska J, Stelmanska E, Swierczynski J. Differential effect of long-term food restriction on fatty acid synthase and leptin gene expression in rat white adipose tissue.  Horm Metab Res. 2003;  35 593-597
• 30 Petty K J, Desvergne B, Mistuhashi T, Nikodem V M. Identification of a thyroid hormone response element in the malic enzyme gene.  J Biol Chem. 1990;  265 7395-7400
• 31 Xiong S, Chirala S S, Hsu M H, Wakil S J. Identification of thyroid hormone response elements in the human fatty acid synthase promoter.  Proc Nat Acad Sci USA. 1998;  95 12260-12265
• 32 Zhang Y, Yin L, Hillgartner F B. Thyroid hormone stimulates acetyl-CoA carboxylase-α transcription in hepatocytes by modulating the composition of nuclear receptor complex bound to a thyroid hormonr response element.  J Biol Chem. 2001;  276 974-983