Nonlinear (amplified) relationship between nuclear occupancy by triiodothyronine and the appearance rate of hepatic alpha-glycerophosphate dehydrogenase and malic enzyme in the rat.

Oppenheimer, Jack H.; Schwartz, Harold L.; Gutfeld, Nicholas W.

doi:10.1172/jci109024

Cited by 95 publications

(41 citation statements)

References 33 publications

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“…would approximate previouis valtues on a regular diet (14). On the other hand, if the high CHO diet prodtuces maximal (juantities of 0 indepenident of(T3N), then Eq.…”

Section: Resultsmentioning

confidence: 94%

“…An increase in activity and mass of lipogenic enzymes also follows administration of thyroid hormone (9)(10)(11)(12). Moreover, previous studies from our laboratory have shown that the rate of lipogenic enzyme induction is related to nuclear occupancy in a nonlinear and highly amplified fashion (13)(14)(15). Thus, in the euthyroid state when approximately one half of the nuclear sites are occupied, the rate of ME induction is less than one-tenth of that which characterizes the response when the sites are fully occupied by triiodothyronine (T3).…”

Section: Introductionmentioning

confidence: 99%

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Synergism of thyroid hormone and high carbohydrate diet in the induction of lipogenic enzymes in the rat. Mechanisms and implications.

Mariash¹,

Kaiser²,

Schwartz³

et al. 1980

J. Clin. Invest.

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A B S T R A C T We have investigated the relationship between the administration of triiodothyronine (T3) and a high carbohydrate (CHO) fat-free diet in the induction of lipogenic enzymes in two rat tissues, liver, and fat. Male thyroidectomized rats were treated with graded daily doses of T3 and either supplemented with a high CHO diet or left on a regular diet. Enzymes studied included malic enzyme (ME), fatty acid synthetase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase. In the liver, all four lipogenic enzymes showed a synergistic response between T3 administration and high CHO feeding. In fat, ME also responded synergistically. The interaction was reflected in ani increased sensitivity to T3. The dose of T3 required to achieve 50% Y maximal response was reduced three-to seven-fold by the high CHO diet. This phenomenon could not be attributed to a dietary-induced alteration either in T3 metabolism or in number or affinity of the T3-nuclear receptors. Moreover, studies of the relative rate of synthesis of ME suggested a simultaneous time of onset in the induction of ME, within 2 h after the application of either T3 or CHO. Thus, it is unlikely that either stimulus is secondary to the other. Since parallel experiments from this laboratory (Towle, Mariash, and Oppenheimer. 1980. Changes in hepatic levels of messenger ribonucleic acid for malic enzylme during induction by thyroid hormone or diet. show that ME induction both by CHO and T3 is mediated by an increase in specific messenger RNA for ME, the interaction of T3 and the dietary factor occurs at a pretranslational level.Dr.

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“…would approximate previouis valtues on a regular diet (14). On the other hand, if the high CHO diet prodtuces maximal (juantities of 0 indepenident of(T3N), then Eq.…”

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Synergism of thyroid hormone and high carbohydrate diet in the induction of lipogenic enzymes in the rat. Mechanisms and implications.

Mariash¹,

Kaiser²,

Schwartz³

et al. 1980

J. Clin. Invest.

Self Cite

150

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“…This relationship, however, differed markedly from what we had observed in studies of the induction by T3 of hepatic mitochondrial a-glycerophosphate dehydrogenase (a-GPD) and cytosolic malic enzyme (decarboxylating) (ME) in the intact rat. In our studies, the number of detectable T3 nuclear-binding sites appeared to be independent of the level of T3 occupation (12), and the rate of enzyme induction was shown to become increasingly amplified with progressive nuclear occupancy by hormone (13). Thus, with full saturation of the nuclear sites, the rate of induction of a-GPD and ME was 10-18 times that observed under physiological conditions at which approximately one-half ofthe sites are normally occupied.…”

Section: Introductionmentioning

confidence: 43%

“…Because of the marked discrepancy between the occupancy-response relationships reported by Samuels et al (11) and by us (13), and because of the intrinsic biologic importance ofthe induction of pituitary GH by T3, we undertook a series of studies to analyze the kinetics of accumulation of pituitary GH in the intact hypothyroid rat. The mathematical model used in our analysis ofhepatic enzyme induction was applied to the pituitary GH data generated.…”

Section: Introductionmentioning

confidence: 94%

“…Thus, with full saturation of the nuclear sites, the rate of induction of a-GPD and ME was 10-18 times that observed under physiological conditions at which approximately one-half ofthe sites are normally occupied. The relationship between hepatic nuclear occupancy and responsivity was calculated by application of a mathematical model in which the assumption was made that the rate offormation ofa T3-inducible protein could be related to the level of T3 nuclear occupancy attained (13).…”

Section: Introductionmentioning

confidence: 99%

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Relationship between the Accumulation of Pituitary Growth Hormone and Nuclear Occupancy by Triiodothyronine in the Rat

Schwartz¹,

Oppenheimer²

1978

J. Clin. Invest.

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A B S T R A C T Studies were undertaken in hypothyroid rats in an effort to define the kinetics of growth hormone (GH) accumulation in response to i.v. pulse injections of triiodothyronine (T3) and to calculate the relationship between nuclear occupancy by T3 and the instantaneous rate of accumulation of pituitary GH. Results were contrasted to the findings in previous studies of the induction of hepatic mitochondrial a-glycerophosphate dehydrogenase (a-GPD) and malic enzyme (ME) by T3. The dose of T3 required to achieve halfmaximal accumulation of GH in 24 h was 0.6 ,ug/100 g body wt, a value 15-fold less than the half-maximal dose for a-GPD and ME induction at a comparable time after injection. Although significant increases in pituitary GH were evident as early as 3 h after injection of maximally effective doses of T3, the rate of increase became linear only 12 h after injection. After achievement of peak values, the pituitary content of GH decayed with a similar terminal tl2 of3.9 days and 4.1 days in two groups of animals injected with a single dose of 1.0 and 50 ,ug TJ100 g body wt, respectively. In vivo isotopic displacement studies carried out at the equilibrium time point indicated that the pituitary nuclear binding capacity was 5.5 ng T3/g tissue and that the plasma concentration at which one-half of the nuclear sites are occupied is 1.0 ng/ml. Nuclear occupancy as a function of time was calculated from the estimated plasma T3 concentration after injection of the dose and the half-occupancy plasma concentration. These data were then analyzed by application of the mathematical model previously developed to ascertain the relation- 1020 ship between nuclear occupancy and the rate of hepatic enzyme induction. Results indicated that the pituitary nuclear occupancy-response relationship was generally linear, in marked contrast to the highly amplified relationship between nuclear occupancy and the response of ME and a-GPD to T3 in the liver. In supplementary experiments, euthyroid rats received daily injections of 200 ,ug of T3 for 7 days to keep nuclear sites nearly saturated for the duration of the experiment. No significant increase in the pituitary GH content above euthyroid base-line levels was noted. This also contrasts with the marked increase above euthyroid levels in a-GPD and ME observed in previous studies. Our findings suggest the existence of major differences between the specific mechanisms which lead to the induction of pituitary GH and the hepatic enzymes by T3.

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Overnutrition in spiny mice (Acomys cahirinus): ?-cell expansion leading to rupture and overt diabetes on fat-rich diet and protective energy-wasting elevation in thyroid hormone on sucrose-rich diet

Shafrir

2000

Diabetes Metab. Res. Rev.

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Previous studies The investigation of diabetes propensity in spiny mice, performed in Geneva and Jerusalem colonies, is reviewed. Spiny mice live in semi‐desert regions of the eastern Mediterranean countries. Those transferred to Geneva in the 1950s were maintained on a rodent diet supplemented by fat‐rich seeds. They became obese, exhibited pancreatic islet hyperplasia and hypertrophy. Low insulin secretion response was characteristic of this species, despite ample pancreatic content of insulin. After a few months, diabetes with ketosis occurred, often suddenly, in association with islet cell disintegration. In Jerusalem the spiny mice were collected from their native habitat and placed on diets containing 50% sucrose or fat‐rich seed diets. On a sucrose‐rich diet, spiny mice developed hepatomegaly, lipogenic enzyme hyperactivity, and elevation in very low density lipoproteins as a result of metabolism of the fructose component mainly in the liver. No overt diabetes or pancreatic islet disintegration were observed, although insulin content and β‐cell hypertrophy and hyperplasia were apparent. On a fat‐rich diet, spiny mice exhibited marked weight gain, adipose tissue growth and low hepatic lipogenesis. The obesity was accompanied by mild hyperglycemia and hyperinsulinemia with glucose intolerance leading to an occasional glucosuria after several months on the diet. Novel experiments The sucrose diet induced an extrathyroidal elevation of triiodothyronine (T3). Serum T3 level and hepatic T4–T3 conversion were increased, while serum T4 levels tended to decrease. The activity of the T3‐inducible hepatic mitochondrial FAD‐glycerophosphate oxidase and K+/Na+‐ATPase, as well as body temperature were increased, indicating that the sucrose diet was associated with enhanced thermogenesis and energy‐wasting metabolic cycling. The sucrose‐rich diet might exert an adaptive thermogenesis‐mediated defense mechanism, protecting against excessive weight gain and disruptive pancreatic islet lesion. After 18 months maintenance on sucrose‐rich versus fat‐rich diets the number of animals surviving was significantly higher on the sucrose diet whereas on the fat diet a significant number of animals succumbed to expansive islet cell disruption and diabetes. Copyright © 2000 John Wiley & Sons, Ltd.

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Nonlinear (amplified) relationship between nuclear occupancy by triiodothyronine and the appearance rate of hepatic alpha-glycerophosphate dehydrogenase and malic enzyme in the rat.

Cited by 95 publications

References 33 publications

Synergism of thyroid hormone and high carbohydrate diet in the induction of lipogenic enzymes in the rat. Mechanisms and implications.

Synergism of thyroid hormone and high carbohydrate diet in the induction of lipogenic enzymes in the rat. Mechanisms and implications.

Relationship between the Accumulation of Pituitary Growth Hormone and Nuclear Occupancy by Triiodothyronine in the Rat

Overnutrition in spiny mice (Acomys cahirinus): ?-cell expansion leading to rupture and overt diabetes on fat-rich diet and protective energy-wasting elevation in thyroid hormone on sucrose-rich diet

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