0013.7227/92/1302-0637$03.00/0

Endocrinology Copyright 0 1992 by The Endocrine

Vol. 130, No. 2 Printed in U.S.A.

Society

Tissue-Specific Regulation Thyroid Hormone* BEATE Department

BLENNEMANN, of

Nutritional

YANGHA Sciences, University

K. MOON, of

of Fatty AND

Connecticut,

ABSTRACT. It is generally agreed that thyroid hormone stimulates the hepatic synthesis of long chain fatty acids in the rat. However, there are conflicting data about its effects in white adipose tissue, while in brown adipose tissue, lipogenic rates are highest in hypothyroid animals. We have systematically examined the effect of thyroid state on lipogenesis in different rat tissues. Fatty acid sythesis was assessed in uiuo, using the incorporation of tritiated water. Hepatic lipogenesis was induced Is-fold between hypothyroid (4.1 + 0.6 pm H incorporated/g. h) and hyperthyroid rats (66.5 + 13.2 pm H/g. h). Kidney and heart were much less lipogenically active, but also responded positively to thyroid hormone. Both hyperand hypothyroidism diminished fatty acid synthesis in retroperitoneal fat and had similar, although not significant, effects in epididymal fat. However, epididymal adipocytes, taken from hyperthyroid rats and cul-

T

HE SYNTHESIS of long chain fatty acids is an essential metabolic pathway for the storage of energy and the provision of subcellular structural components. The pathway is under both hormonal and dietary control to adjust the supply of fatty acids to the requirements of the animal and the necessity of storing dietary energy. Fatty acid synthesis is active when the animal eats, and substrate is abundant and relatively inactive at times of fasting, when lipolysis occurs and fatty acids are withdrawn from stores. Regulation is effected by both short term (allosteric modification of preexisting enzymes, substrate flux) and long term (new enzyme synthesis) mechanisms (1, 2). Thyroid hormone is a well established stimulator of fatty acid synthesis, at least in liver (3-5). Although earlier investigators reported relatively modest effects, we recently showed an 18-fold difference in lipogenic rates per g liver between hypo- and hyperthyroid rats (6). In white adipose tissue, the situation is rather confused. Roncari and Murthy (5) and Llobera et al. (7) Received July 29, 1991. Address all correspondence and requests for reprints to: Dr. Hedley Freake, Department of Nutritional Sciences, University of Connecticut U17,3624 Horse Barn Road, Storrs, Connecticut 06268. * This work was supported by a NIH FIRST Award (DK-41705; to H.C.F.). A preliminary and partial account of these studies was reported at the Annual Meeting of the Federation of American Societies for Experimental Biology, Washington, D.C., April 1990.

HEDLEY

Acid

Synthesis

by

C. FREAKE

Storrs, Connecticut

06269-4017

tured in uitro, were 3 times more lipogenically active than cells from either hypo- or euthyroid animals. Lipogenesis in SC fat from hyperthyroid rats was enhanced when calculated per g tissue, but was not different when expressed per whole tissue. In brown adipose tissue, lipogenesis was inversely related to thyroid hormone status. Fatty acid synthesis in brain, lung, skin, and bone and muscle did not respond to changes in thyroid state. TLC confirmed that greater than 90% of the incorporated tritium was in fatty acids. Thus, in hypothyroid animals, lipogenesis primarily occurs in skin, bone, muscle, and other nonresponsive organs, whereas in hyperthyroid rats, the liver alone constitutes almost half of all fatty acid synthesis. The fatty acid synthetic pathway provides an excellent model for examining the tissue-specific regulation of gene expression by thyroid hormone. (Endocrinology 130: 637-643, 1992)

reported that thyroid hormone treatment of either euthyroid or hypothyroid rats decreased the synthesis of fatty acids in white adipose tissue, whereas Diamant et al. (4) and Gnoni et al. (8) observed the opposite effect. We found that the effects of thyroid hormone in epididymal fat appeared to parallel those in liver, although large variations were seen (6). Little is known about T3 regulation of fatty acid synthesis in white adipose depots other than epididymal fat. In brown adipose tissue, fatty acid synthesis is uniquely stimulated in the hypothyroid state (9, 10). The only other tissue to be examined for thyroid hormone responsiveness is lung, where little if any effect of alterations in thyroid state was seen (8). We have also observed that thyroid hormone dramatically affects the extent to which the liver contributes to total lipogenesis in the rat. This contribution ranges from 5% in the hypothyroid animal to 34% in the hyperthyroid animal (6). Taken together with the data cited above, this clearly demonstrates that the effects of thyroid hormone on the fatty acid synthetic pathway are tissue specific. The effects of thyroid hormone on fatty acid synthesis operate via its regulation of the lipogenic enzymes. These enzymes include acetyl coenzyme-A carboxylase and fatty acid synthase, which are directly involved in pro-

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638

THYROID

HORMONE

REGULATION

ducing the carbon backbone, as well as malic enzyme and the enzymes of the pentose phosphate pathway, which are responsible for synthesis of the necessary reducing equivalents. At least in liver, thyroid hormone stimulates fatty acid synthesis by increasing enzyme mass, and this, in turn, is a pretranslational effect (5, 11-13). We are interested in using the fatty acid synthetic pathway as a model of the tissue-specific regulation of gene expression by thyroid hormone. As a first step, we report here a systematic examination of the effects of thyroid state on lipogenesis in different rat tissues.

Materials

and Methods

Animals Male Sprague-Dawley rats (Holtzman, Madison, WI), initially weighing 150-175 g, were used in all experiments. The rats were housed individually in stainless steel wire mesh cages on a 12-h light, 12-h dark cycle at 20-22 C. The animals were fed laboratory rodent chow (Purina Mills, St. Louis, MO) ad libitum. Hypothyroidism was induced by the addition of 0.025% methimazole to the drinking water for 3 weeks. This treatment results in cessation of growth after the second week, and plasma Ta levels are undetectable at the time of death. Animals were made hyperthyroid by daily ip injections of 15 pg T&00 g BW for the final 7 days. To minimize the stress experienced during assay of lipogenesis, the animals were handled daily and mock injected for 3 days before death. The rats were 10 weeks old when fatty acid synthesis was measured. They were maintained according to the NIH Guide, and all procedures were approved by the Institutional Animal Care and Use Committee. Labeling

of fatty acids in uivo

The rats were injected with 2 mCi “HZ0 (New England Nuclear, Boston, MA; original SA, 100 mCi/ml; diluted to 10 mCi/ml in saline), ip, between 0800-1000 h. Exactly 30 min later, the animals were anesthetized with ether, and blood was collected from the abdominal aorta. Incorporation of “HZ0 into lipids is linear over this time period, and plasma labeled fatty acids are negligible, indicating that lipid radioactivity within a tissue represents synthesis at that site. Liver, heart, lung, kidney, brain, epididymal fat, retroperitoneal fat, and interscapular brown adipose tissue were removed separately. Other internal organs were removed as a group. The peritoneal cavity was cleaned of any remaining adipose tissue, which was pooled with fat trimmed from tissues to constitute other inner fat. The animal was skinned, and SC fat isolated, leaving bone and muscle. The tissues were rinsed in ice-cold saline, weighed, and frozen immediately on dry ice. They were stored at -20 C. Extraction

of lipids

Tritium incorporation into fatty acids was assessed as described by Stansbie et al. (14). Briefly, tissues were digested, and lipids were saponified by heating in ethanolic KOH. After acidification with H2S04, lipids were extracted with petroleum ether, and the pooled extracts were back-washed with water. They were evaporated to dryness and quantitated by liquid

OF LIPOGENESIS

Endo. 1992 Vol 130. No 2

scintillation counting. The bone and muscle fractions were first homogenized using a Waring blender. Duplicate aliquots were taken from each homogenate and processed as described above. Blood was centrifuged to remove serum and precipitated with 20% trichloroacetic acid, and an aliquot of the supernatant was counted to determine the specific activity of water in each animal. Data were calculated as micromoles of H incorporated per g wet wt tissue/h. Analysis

of the lipid class of the labeled materials

Labeled tissue extracts were analyzed using TLC to assess the relative contributions of different lipid classes to total H incorporation. The extracts were dissolved in 1 ml methylene chloride, and 800 ~1 of the sample were plated, while the remaining 200 ~1 were directly quantitated by liquid scintillation counting. The plates were run in petroleum ether, ethyl ether, and acetic acid at a 70:30:1 ratio. Cholesterol, phospholipid, fatty acid, and triglyceride standards were included on each plate. The lipid fractions were visualized with rhodamine dye and illuminated by UV light, the bands were scraped from the plates, and the radioactivity within them was measured by liquid scintillation counting. Pairfeeding A pairfeeding study was also performed to determine to what extent any changes seen in lipogenesis were secondary to hormonally induced alterations in food consumption. Thus, for the week before measurement of lipogenesis, hyperthyroid animals were pairfed with euthyroid controls, and euthyroid rats were pairfed with hypothyroid animals. The diet fed was calculated on a body weight basis. Lipogenesis was then assessed as before. Adipocyte

lipogenesis

in vitro

Fatty acid synthesis was also measured in freshly isolated cells from epididymal fat pads. Pads were removed from animals as described above, except that pentobarbital, rather than ethyl ether, was used as the anesthetic. Fat cells were isolated by collagenase digestion, using a modified Rodbell method (15, 16). Epididymal fat pads were minced with scissors and then digested for 1 h at 37 C in collagenase (1 mg/ml in Dulbecco’s Modified Eagle’s Medium, pH 7.4, containing 3% BSA and 25 mM HEPES). The cells were filtered through nylon mesh, and floating cells were collected after centrifugation at 600 x g for 15 sec. After washing in the same medium without collagenase, the cells were diluted 1:lO in Dulbecco’s Modified Eagle’s Medium with 3% BSA, 4 rig/ml porcine insulin, 20 U/ml penicillin, and 20 mg/ml streptomycin. One milliliter of diluted cells was incubated with 0.5 mCi “HZ0 for 2 h at 37 C, with constant shaking. The labeled lipids were extracted from cells and media as described above for tissues. The DNA content of each cell preparation was estimated after removal of lipid, using diphenylamine (17). Statistical

analysis

One-way analysis of variance, followed by Fisher’s protected least squares difference test, and Student’s t test were used to determine statistical differences between the treatment groups.

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THYROID

HORMONE

REGULATION

Results

Lipogenesis was assessed in a total of 13 tissues or groups of tissues in rats in differing thyroid states (Table 1). Of these, 6 showed a statistically significant difference between one state and another when expressed on a per g tissue basis. Liver was clearly the most responsive organ, with a 4-fold increase observed between both the hypo- to euthyroid and eu- to hyperthyroid states. In retroperitoneal fat, lipogenesis was significantly reduced in both the hype- and hyperthyroid states compared to that in euthyroid rats. Similar, although not significant, changes were observed in epididymal fat pads. However, in SC fat, lipogenesis was enhanced about 75% in the hyperthyroid state relative to that in euthyroid animals. Brown adipose tissue was unique, in that 100% more fatty acids were synthesized in the hypothyroid than in the euthyroid state. A further decrease in brown fat lipogenesis was evident in hyperthyroid animals. Brown adipose tissue was also notable as the most lipogenically active tissue on a per g basis in hypo- and euthyroid animals. The other two tissues found to be responsive were kidney and heart. Lipogenic rates were relatively low at these sites, particularly in heart (Table l), but were stimulated by thyroid hormone treatment. In kidney, a decrease was also observed in hypothyroid rats. No alterations in lipogenesis were detected in brain, lung, skin, bone, muscle, or other organs. TABLE 1. Effect of thyroid expressed per g tissue

state on lipogenesis

Hypothyroid (5) Liver Adipose tissues Epididymal Retroperitoneal Other inner SC Brown Kidney Heart Lung Brain Other organs Skin Bone and muscle

in different

Euthyroid (4)

Hyperthyroid (5)

4.1 t 0.6”

16.7 f 1.5

6.7 k 0.9 3.2 + 0.7b

9.2 t 8.2 + 7.7 + 4.7 f 54.9 + 5.3 f 1.3 + 5.1 + 4.2 + 8.4 + 5.1 + 2.6 +

7.2 + 0.8 4.2 + 0.5

118.1 + 11.9’ 2.9 + 0.2" 1.8 + 0.5 5.6 + 0.9 3.6 + 0.3 6.7 + 1.8 5.6 + 0.9 2.4 + 0.2

rat tissues,

6.3 + 0.7 5.4 f 0.9"

1.1

6.8 + 1.0 8.2 + 0.9"

3.9 1.1 0.1 0.4 1.3 0.7 0.3 0.5

Variations in thyroid state also affect body size in general and some tissue weights more specifically. These changes have to be taken into account when comparing fatty acid synthetic rates expressed on a per tissue basis. Tissue weights, expressed as a percentage of body weight, are shown in Table 2. Removal or addition of thyroid hormone decreased the relative weight of all white adipose tissues and increased the weight of brown adipose tissue. Kidney size was reduced in hypothyroid animals, and the sizes of both kidney and heart were increased with hyperthyroidism. Brain is notable, in that its size was relatively increased in the hypothyroid rats. To compare relative lipogenic rates per tissue between rats in different thyroid states and, therefore, of different body sizes, values have been corrected on the basis of body weight and are expressed per 200 g rat (Table 3). Since, for the most part, alterations in relative tissue weight with thyroid state parallel those in lipogenic rate, the effects on lipogenesis are exaggerated when considered on a tissue basis. This is particularly evident in retroperitoneal and epididymal fat, in which significant decreases were observed in both hypo- and hyperthyroid animals. Similarly, the elevations in fatty acid synthesis found in hypothyroid brown adipose tissue and hyperthyroid kidney and heart compared to those in euthyroid tissues are greater when expressed in this way. Liver lipogenesis remains proportionately the same, since relative liver weight was unaffected by changes in thyroid hormone status. In SCfat, the hyperthyroid stimulation of fatty acid synthesis is not seen when the data are expressed per total tissue, since the tissue size is smaller in the hyperthyroid animals. This may be a more accuTABLE

2. Effect

66.5 + 13.2*

2.1 0.6 0.2

OF LIPOGENESIS

31.0 + 8.4 + 2.7 f 4.8 + 4.6 + 5.6 f 5.3 f 2.2 +

0.5” 0.8" 0.2" 0.3 0.4 0.6 0.4 0.2

Lipogenesis, assessed in uiuo using the incorporation of tritiated water, is expressed as micromoles of H incorporated per g tissue/h. The number of animals in each group is indicated in parentheses, and values given are the mean + SE. Other inner adipose tissue is all fat within the peritoneal cavity, excepting the epididymal and retroperitoneal depots. Subcutaneous fat includes all fat located between the skin and the musculature. Similar results were observed in two additional experiments. n P < 0.05 us. euthyroid. b P < 0.01 US. euthyroid.

of thyroid

status

on relative

Hypothyroid

Euthyroid

(5)

Liver Adipose tissues Epididymal Retroperitoneal Other inner

SC Brown Kidney Heart Lung Brain Other organs Skin Bone and muscle

tissue

weights Hyperthyroid

(4)

4.30

f

0.12

4.22

+ 0.15

0.84 0.50 0.74

f k

0.07" 0.08"

1.33 0.82

+ 0.11

4.14

k

0.76 4.57

+ 0.33 k 0.06 + 0.17 f 0.47

0.32

0.17 + 0.03” 0.63

k 0.02"

0.36 0.58 0.68

+ 0.02 k 0.07 + 0.06"

0.10 + 0.01 0.71 0.38 0.51

+ 0.02

0.49

+ 0.02

+ 0.02 + 0.03

(5) 4.34

+ 0.20

0.61 0.38

+ O.lO*

0.75 1.82

f 0.08 + 0.32'

f

0.07'

0.19 f 0.02” 0.93 0.56 0.58

f 0.04* f 0.03* + 0.03

0.59

+ 0.05

13.22 + 0.62 15.81 + 1.46

12.93 + 0.74 14.78 + 0.50

13.82 + 1.49 16.08 + 0.27

52.67

53.14

52.65

+ 2.11

+ 1.36

+ 1.42

Tissue weights are expressed as a percentage of body weight. The animals were age matched, with final body weights of 253 + 17 g (hypothyroid), 383 + 24 g (euthyroid), and 321 +- 31 g (hyperthyroid). The number of rats in each group is given in parentheses. Similar values were seen in two additional experiments. ’ P < 0.05 us. euthyroid. b P < 0.01 us. euthyroid.

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640

THYROID

TABLE 3. Effect of thyroid expressed per whole tissue

state on lipogenesis

Hypothyroid (5)

11.4 3.1 10.2 35.5 38.1 3.7 1.4 5.9 4.8 178.4 166.5 257.6

* + + + + + + + f + + +

2.1* 1.0* 0.9 6.5 6.5b 0.2" 0.5 0.6 0.5 22.2 23.3 22.5

751.9

Total

in different

Euthyroid (4)

35.3 f 5.5"

Liver Adipose tissues Epididymal Retroperitoneal Other inner SC Brown Kidney Heart Lung Brain Other organs Skin Bone and muscle

HORMONE

REGULATION

rat tissues,

Hyperthyroid (5)

141.1 f 15.9

599.5 + 133.3*

24.3 13.2 11.2 39.5 11.5 7.8 0.9 5.1 3.9 216.9 151.4 269.3

7.7 3.2 10.5 29.4 11.9 15.9 3.1 5.6 5.3 177.9 178.5 227.8

k + f + + rf: + + + + + +

3.8 0.4 3.9 0.8 0.8 1.6 0.1 0.2 0.4 14.2 9.0 51.5

896.0

+ + + + + + + + + + + f

1.1” 0.9" 1.9 6.9 1.3 1.5* 0.4* 0.3 0.4 15.2 7.3 7.4

1276.3

These data are derived from those in Table 1 by multiplying the per g values by the tissue weights. The values are then standardized to a 200-g body weight rat, so that effects of treatment on overall body size are excluded. They are, therefore, expressed as micromoles of H incorporated per tissue/h.200 g rat. The number of animals is given in parentheses. a P < 0.05 VS. euthyroid. b P < 0.01 US. euthyroid. TABLE tissues

4. Effect of thyroid to total lipogenesis

state

Hypothyroid (5) Liver Adipose tissues Inner Outer Brown Kidney Heart Skin Bone and muscle Other organs The number

4.7 + 0.7 3.2 3.8 5.1 0.49 0.18 21.8 33.8 27.0 of animals

+ + rt + + f + +

0.3 0.3 0.7 0.03 0.06 2.7 3.0 2.7

is given

on percent

contribution

Euthyroid (4)

of different

Hyperthyroid (5)

15.9 I? 2.0

47.0 + 9.0

4.5 4.4 1.3 0.87 0.10 17.1 30.4 25.4

1.6 2.3 0.92 1.24 0.24 14.0 17.8 14.8

t + + k f f k f

0.7 0.1 0.1 0.17 0.01 1.2 6.6 1.7

+ + + + + + + +

0.1 0.6 0.11 0.12 0.03 0.6 2.1 1.2

in parentheses.

rate reflection of thyroid hormone action on lipogenesis in this tissue, since the drop in size probably reflects TXstimulated lipolysis, rather than a change in other components of the cell. Total lipogenesis increased from 752 pmol H/200 g rat. h in hypothyroid animals to 1276 pmol H/200 g rat. h in hyperthyroid animals. The percent contribution of different tissues to these totals varied with thyroid state (Table 4). Most notable was liver, which constituted only 5% of hypothyroid lipogenesis but almost half of the total in hyperthyroid rats. Thus, in the hypothyroid animal, lipogenesis largely occurs in skin, bone and muscle, and the rest of the internal organs. Lipogenesis at these sites does not change with increasing levels of thyroid hormone, and consequently, their percent con-

Endo. Vol 130.No2

OF LIPOGENESIS

tribution drops in eu- and hyperthyroid animals. The experimental procedure used here extracts all tissue lipids. It has been established, under euthyroid conditions, that at least 95% of lipids labeled in liver using this technique are fatty acids (14). However, it was necessary to confirm the nature of the labeled material in other tissues, and that the changes observed with thyroid hormone treatment were, indeed, changes in fatty acid synthesis. Consequently, labeled extracts from selected tissues were analyzed by TLC. In all cases, greater than 90% of the labeled lipids were fatty acids (Table 5), with the balance being in the cholesterol fraction. Thus, any changes in labeling could be attributed to alterations in fatty acid synthesis. We also sought to confirm that any effects on fatty acid synthesis were not due to the effects of thyroid hormone on food consumption. Thus, hyperthyoid animals were pairfed to euthyroid controls, and euthyroid animals were pairfed to hypothyroid rats. Pairfed animals experienced very minor food restriction (9-417 2. Geelen MJ. Harris RJ. Bevnen AC. McCune SA 1980 Short term hormonal control of hepatic lipogenesis. Diabetes 29:1006-1022 3. Spirtes MA, Medes G, Weinhouse S 1953 A study of acetate metabolism and fatty acid synthesis in liver slices of hyperthyroid rats. J Biol Chem 195:705-713 4. Diamant S, Gorin E, Shafrir E 1972 Enzyme activities related to fatty acid synthesis in liver and adipose tissue of rats treated with triiodothyronine. Eur J Biochem 26:553-559 DAK, Murthy VK 1975 Effects of thyroid hormones on 5. Roncari enzymes involved in fatty acid and glycerolipid synthesis. J Biol Chem 250:4134-4138 6. Freake HC, Schwartz HL, Oppenheimer JH 1989 The regulation of lipogenesis by thyroid hormone and its contribution to thermogenesis. Endocrinology 125:2868-2874 7. Llobera M, Muniesa A, Herrera E 1979 Effects of hyperthyroidism on in viuo lipogenesis in fed and fasted rats. Horm Metab Res 11:628-634 a. Gnoni GV, Landriscina C, Quagliariello E 1980 Fatty acid biosynthesis in adipose tissue and lung subcellular fractions of thyrotoxic rats. FEBS Lett 122:37-40 9. Freake HC, Oppenheimer JH 1987 Stimulation of S14 mRNA in brown fat by hypothyroidism cold exposure and cafeteria feeding: evidence supporting a general role for S14 in lipogenesis and lipogenesis in the maintenance of thermogenesis. Proc Nat1 Acad Sci USA 84:3070-3074 10. Baht HS, Saggerson ED 1988 A tissue specific increase in lipogenesis in rat brown adipose tissue in hypothyroidism. Biochem J 251:553-557 11. Towle HC, Mariash CN, Schwartz HL, Oppenheimer JH 1981 Quantitation of rat liver messenger ribonucleic acid for malic enzyme during induction by thyroid hormone. Biochemistry 20:3486-3492 B, Magnuson MA, Nikodem VM 1986 Thyroid hormone 12. Dozin regulation of malic enzyme synthesis. J Biol Chem 261:1029010292 13. Goodridge AG, Back DW, Wilson SB, Goldman MJ 1986 Regulation of genes for enzymes involved in fatty acid synthesis. Ann NY Acad Sci 478:46-62 D, Brownsey RW, Crettaz M, Denton RM 1976 Acute 14. Stansbie effects in uiuo of anti-insulin serum on rates of fatty acid synthesis and activities of acetyl-coenzyme A carboxylase and pyruvate dehydrogenase in liver and epididymal adipose tissue of fed rats. Biochem J 160:413-416 15. Marshall S, Garvey WT, Geller M 1984 Primary culture of isolated adipocytes. J Biol Chem 259:6376-6384 16. Rodbell M 1964 Metabolism of isolated fat cells. J Biol Chem 239:375-380 17. Livingston JN, Cuatrecasas P, Lockwood DH 1974 Studies of glucagon resistance in large rat adipocytes: iz51-labeled glucagon binding and lipolytic capacity. J Lipid Res 15:26-32 18. Correze C, Berriche S, Tamayo L, Nunez J 1982 Effect of thyroid hormones and cyclic AMP on some lipogenic enzymes of the fat cell. Eur J Biochem 122:387-392 19. Levacher C, Sztalryd C, Kinebanyan M-F, Picon L 1988 Hepatic and adipose tissue lipogenesis as related to age and thyroid status in the rat. Horm Metab Res 20:395-399 20. Gandemer G, Pascal G, Durand G 1982 In uiuo changes in the rates of total fatty acid synthesis in liver and white adipose tissues of male rats during postweaning growth. Int J Biochem 14:797-804 21. Debons AF, Schwartz IL 1961 Dependence of the lipolytic action of epinephrine in vitro upon thyroid hormone. J Lipid Res 2:86-89 22. Fisher JN, Ball EG 1967 Studies on the metabolism of adipose

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THYROID

23.

24.

25. 26.

21.

28.

HORMONE

REGULATION

tissue: the effect of thyroid status upon oxygen consumption and lipolysis. Biochemistry 6:637-647 Van Inwegen RG, Robinson GA, Thompson WJ, Armstrong KJ, Stouffer KE 1975 Cyclic nucleotide phosphodiesterases and thyroid hormones. J Biol Chem 250:2452-2456 Rapiejko PJ, Watkins DC, Ros M, Malbon CC 1989 Thyroid hormones regulate G-protein P-subunit mRNA expression in uiuo. J Biol Chem 264:16183-16189 Paulauskis JD, Sul HS 1989 Hormonal regulation of mouse fatty acid synthase gene transcription in liver. J Biol Chem 264:574-577 Yeh W-J, Freake HC 1991 A sympathetic nerve supply is required for the hypothyroid stimulation of brown adipose tissue lipogenesis. FASEB J 5:A1132 Gandemer G, Durand G, Pascal G 1983 Relative contributions of the main tissues and organs to body fatty acid synthesis in the rat. Lipids 18223-228 Oppenheimer JH, Schwartz HL, Mariash CN, Kinlaw WB, Wong NCW, Freake HC 1987 Advances in our understanding of thyroid hormone action at the cellular level. Endocr Rev 8:288-308

OF LIPOGENESIS

29. Song M-KH, Dozin B, Grieco D, Rall JE. Nikodem VM 1988 Transcriptional activation and stabilization of malic enzyme mRNA precursor by- thvroid hormone. J Biol Chem 263:17970_ 17974 30. Oppenheimer JH, Schwartz HL, Surks MI 1974 Tissue differences in the concentration of triiodothyronine nuclear binding sites in the rat: liver, kidney, pituitary, heart, brain, spleen and testis. Endocrinology 95:897-903 31. Sap J, Muno; A, Damm K, Goldberg Y, Ghsydael J, Leutz A, Beug H, Vennstrom B 1986 The c-erb-A protein is a high affinity receptor for thyroid hormone. Nature 324:635-640 32. Weinberaer C. Thomnson CC. Ona ES. Lebo R. Gruol DJ. Evans RM 1986 The c-erb-A gene encodes athyroid hormone receptor. Nature 324:641-646 33. Murray MB, Zilz ND, McCreary NL, MacDonald MJ, Towle HC 1988 Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors. J Biol Chem 263:12770-12777 34. Lazar MA: Hodin RA, Darling DS, Chin WW 1988 Identification of a rat c-erbAol related protein which binds DNA but does not bind thyroid hormone. Mb1 Endocrinol2:893-901

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Tissue-specific regulation of fatty acid synthesis by thyroid hormone.

It is generally agreed that thyroid hormone stimulates the hepatic synthesis of long chain fatty acids in the rat. However, there are conflicting data...
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