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Thyroid hormones affect reactions in almost all pathways of lipid metabolism. It has been reported that plasma free fatty acid (FFA) concentration in hypothyroidism is generally within the normal range. In this study, however, we show that plasma FFA concentration in some hypothyroid patients is higher than the normal range. Symptoms of thyroid dysfunction in these individuals were less severe than those of patients with lower plasma FFA concentrations. From these findings we hypothesized that the change in FFA concentration must correlate with thyroid function. Using an animal model, we then examined the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E), a n-3 polyunsaturated fatty acid derived from fish oil, on thyroid function in 1-methyl-2-imidazolethiol (MMI)-induced hypothyroid rats. Oral administration of EPA-E inhibited reduction of thyroid hormone levels and the change of thyroid follicles in MMI-induced hypothyroid rats. These findings suggest that FFA may affect thyroid functions and EPA-E may prevent MMI-induced hypothyroidism.
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Abstract
The adrenal steroid dehydroepiandrosterone (DHEA) stimulates a dramatic increase in both the size and the number of peroxisomes present in liver when given at pharmacological doses to rodents. Structurally diverse chemicals including many fatty acids, hypolipidemic drugs and other foreign chemicals, can also induce such a peroxisome proliferative response. This response is associated with a dramatic induction of peroxisomal fatty acid β-oxidation enzymes and microsomal cytochrome P450 4A fatty acid hydroxylases and, long-term, can lead to induction of hepatocellular carcinoma. This review examines the underlying mechanisms by which DHEA induces peroxisome proliferation and evaluates the possible role of peroxisome proliferator-activated receptor (PPAR) in this process. Like DHEA, the 17β-reduced metabolite 5-androstene-3β, 17β-diol (ADIOL) is an active peroxisome proliferator when administered in vivo, whereas androgenic and estrogenic metabolites of DHEA are inactive. In primary rat hepatocytes, however, DHEA and ADIOL are inactive as inducers of P450 4A and peroxisomal enzymes unless first metabolized by steroid sulfotransferase to the 3β-sulfates, DHEA-S and ADIOL-S. Investigations as to whether DHEA utilizes the same induction mechanism employed by classic, foreign chemical peroxisome proliferators, namely, activation of the intracellular receptor molecule PPAR, have shown that DHEA-S and ADIOL-S are ineffective with respect to PPAR activation in transient transfection/trans-activation assays. This inactivity of DHEA-S in vitro suggests a requirement for specific cellular transport or for further metabolism of the steroid which is only met in liver cells. Alternatively, the action of DHEA-S may require accessory proteins or other nuclear factors that modulate the activity of PPAR, such as retinoid X receptor (RXR), hepatocyte nuclear factor-4 (HNF-4) or chick ovalbumin upstream promoter transcription factor (COUP-TF). Investigations using Ca2+-channel blockers such as nicardipine suggest that there are important mechanistic similarities between the foreign chemical- and DHEA-S-stimulated induction responses, and support the hypothesis that these two classes of peroxisome proliferators both activate Ca2+-dependent signaling pathways. Further studies are required to ascertain whether this potential of DHEA and its sulfated metabolites to serve as physiological modulators of fatty acid metabolism and peroxisome enzyme expression contributes to the striking anticarcinogenic and other useful chemoprotective properties that DHEA is known to possess.
Journal of Endocrinology (1996) 150, S129–S147
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ABSTRACT
To elucidate the hypolipacidaemic effect of insulin in ducks, its action on the uptake of free fatty acids (FFA) by duck hepatocytes was determined. At low doses (10 mu./l) insulin stimulated FFA uptake. This effect was not observed with higher doses of insulin (20, 30 and 50 mu./l). Growth hormone at physiological concentrations and corticosterone (14·4 nmol/l) decreased basal activity, probably by reducing glucose metabolism and consequently α-glycerophosphate (α-GP) supply. Insulin was able to reverse the inhibition induced by GH and corticosterone on both FFA uptake and α-GP production. These results therefore suggest that the hypolipacidaemic effect of insulin may be partly mediated by its action on hepatic FFA uptake.
J. Endocr. (1984) 102, 381–386
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Abnormal glucose tolerance is known to occur in the obese (Butterfield, Hanley & Whichelow, 1965) and Karam, Grodsky & Forsham (1963) have demonstrated increased insulin levels to be a feature of the response to a glucose load in overweight subjects. There has been no previous published work on the effects of prolonged starvation (over 14 days) on the carbohydrate metabolism of obese patients and this paper reports our findings in the first 12 subjects studied.
Twelve obese subjects (11F, 1M; aged 16–55 yr., 125–245% standard weight) were admitted to hospital and treated by complete starvation for 2½–18 weeks (mean 7). None were known to be diabetic. Before fasting an oral glucose tolerance test (50 g.) was performed and venous blood was removed for the determination of blood sugar, plasma insulin and free fatty acid (FFA) levels at 0, 30, 60, 90 and 120 min. The fast was terminated by administering
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SUMMARY
Thyroidectomy decreased the body weight and the height of the cells lining the sex-segment of the kidney of the Chequered Water-snake, Natrix piscator maintained at 30 °C; at 40 °C the liver, kidney and gonad were also affected. At the higher temperature, thyroidectomy influenced significantly protein, carbohydrate and lipid metabolism. At 30 °C, only a decrease in the rate of esterification of the free fatty acids in the liver and of their release from the adipose tissue was observed. The difference in the effect of thyroidectomy at 30 and 40 °C is explained by suggesting that thyroid activity was low in animals maintained at the lower temperature and high in those kept at the higher temperature.
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CONTENTS
Introduction
Effect on the foetus of diabetic diathesis in the mother
Size
Energy metabolism and hormonal status
Normal newborn infant
Infant of diabetic mother:
Blood glucose and free fatty acids
Hyperinsulinism
Hyperglycaemia
Growth hormone
Synalbumin antagonist
Adrenal cortex
Adrenal medulla
High perinatal mortality
Congenital abnormalities
Later incidence of clinical diabetes
The diabetogenic effect of pregnancy on the mother
Changes in glucose tolerance in normal pregnancy; criteria of normality; diagnosis of prediabetes
Plasma insulin in normal pregnancy
Glucose tolerance and plasma insulin in gestational diabetes
Parity and the development of diabetes
INTRODUCTION
The subject of pregnancy and diabetes can be considered from two main points of view: that of the baby and that of the mother.
There is no doubt that the children born to diabetic mothers (both before and after the development of clinical diabetes) commonly exceed the mean body weight for their gestational age, have a characteristic appearance,
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Impaired oral (OGTT) and i.v. glucose tolerance (IVGTT) has been found in some women receiving oral contraceptives (Wynn & Doar, 1966). The precise cause is not known but it has been suggested that elevated plasma growth hormone (GH) levels may be responsible (Spellacy, Carlson & Schade, 1967). Striking increases of OGTT and IVGTT blood pyruvate levels have also been found during oral contraceptive therapy (Wynn & Doar, 1966). The present study was undertaken to investigate the acute effects of GH on carbohydrate and intermediary metabolism.
Two IVGTT's were carried out by methods previously described (Wynn & Doar, 1966) in 12 normal ambulatory subjects (aged 20–49), six of whom were women. The first test served as a control. The second test was carried out 120 min. after i.v. administration of 5 mg. human GH (HGH, MRC R. 10 Batch). Blood samples were analysed for plasma glucose (Cramp, 1967), non-esterified fatty acid
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The effects of injections of cortisol, corticosterone and ACTH on indices of carbohydrate, fat and protein metabolism were investigated in the conscious echidna, Tachyglossus aculeatus.
Intravenous infusion of cortisol and corticosterone for 2 h at rates of 3 and 30 μg/kg/h respectively did not cause significant changes in the plasma concentrations of glucose, urea or amino acids during a 12·5 h observation period. In contrast, a dose-related increase in plasma free fatty acid (FFA) concentration was observed. Infusion of synthetic ACTH at 2 i.u./kg/h for 2 h caused a minor, short-lived increase in FFA concentration.
Daily i.m. injections of 0·2 mg cortisol or corticosterone acetates/kg, which raised plasma total corticosteroid concentrations to levels characteristic of maximal ACTH stimulation, did not cause glycosuria nor was there any change in body weight, nitrogen intake or urinary nitrogen excretion. However, there was a minor, but significant, increase in plasma glucose concentration. The liver glycogen content of 24 h fasted, corticosteroid-treated animals was similar to that of fasted control animals.
It is concluded that cortisol, corticosterone and ACTH have only minor effects on carbohydrate and protein metabolism and that the main action of these hormones may be to mobilize fat reserves.
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Dairy cows suffer from an intense energy deficit at parturition due to the onset of copious milk synthesis and depressed appetite. Despite this deficit, maternal metabolism is almost completely devoted to the support of mammary metabolism. Evidence from rodents suggests that, during periods of nutritional insufficiency, a reduction in plasma leptin serves to co-ordinate energy metabolism. As an initial step to determine if leptin plays this role in periparturient dairy cows, changes in the plasma concentration of leptin were measured during the period from 35 days before to 56 days after parturition. The plasma concentration of leptin was reduced by approximately 50% after parturition and remained depressed during lactation despite a gradual improvement in energy balance; corresponding changes occurred in the abundance of leptin mRNA in white adipose tissue. To determine whether negative energy balance caused this reduction in circulating leptin, cows were either milked or not milked after parturition. Absence of milk removal eliminated the energy deficit of early lactation, and doubled the plasma concentration of leptin. The plasma concentration of leptin was positively correlated with plasma concentrations of insulin and glucose, and negatively correlated with plasma concentrations of growth hormone and non-esterified fatty acids. In conclusion, the energy deficit of periparturient cows causes a sustained reduction in plasma leptin. This reduction could benefit early lactating dairy cows by promoting a faster increase in feed intake and by diverting energy from non-vital functions such as reproduction.
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SUMMARY
An investigation was made of the interactions between insulin and cortisol on carbohydrate, fat and protein metabolism in the marsupial brush-tailed opossum Trichosurus vulpecula (Kerr).
Intravenous injection of 0·15 i.u. regular insulin/kg caused a prompt fall in plasma glucose concentration to 33–54% of the control value, in the first 30 min, with complete recovery within 4 h. This was associated with a slow fall in plasma amino acid concentration and a moderate rise in plasma free fatty acid (FFA) concentration. Plasma cortisol concentration was increased 1·5 h after insulin injection to maximum values of 1·24–4·44 μg/100 ml, which were approximately proportional to the degree of hypoglycaemia.
Pretreatment with five daily i.m. injections of 1 mg cortisol acetate/kg caused a marked reduction in insulin sensitivity of three out of four opossums, and increasing the dose to 5 mg/kg caused a similar reduction in insulin sensitivity of the remaining opossum. Cortisol pretreatment raised the control plasma amino acid and FFA concentrations and enhanced the effect of insulin injection on these variables. There was a linear relationship between the control plasma cortisol concentration, within the physiological range, and sensitivity to insulin.
It is concluded that, in contrast to the red kangaroo, the interactions between insulin and glucocorticoids in Trichosurus resemble those reported for eutherian mammals. However, the unusual increase in plasma FFA after insulin injection is unexplained.
