A Differential Effect of Thyroxine and Glucocorticoids on Fetal Brain and Heart Insulin Receptor

Devaskar, Sherin U.; Grim, P.; Devaskar, Uday

doi:10.1203/00006450-198502000-00009

Cited by 13 publications

(20 citation statements)

References 27 publications

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“…The decrease in circulating insulin concentrations during the suckling phase is associated with an increase in insulin receptors (9,10,29) and total insulin-responsive GLUT 4 concentrations suggestive of improved insulin sensitivity, glucose transport, and utilization by the skeletal muscle. Increased insulin sensitivity at 70 days of age was confirmed by the hyperinsulinemic euglycemic clamp technique after postnatal glucocorticoid administration (35).…”

Section: Discussionmentioning

confidence: 99%

Postnatal glucocorticoid exposure alters the adult phenotype

He¹,

Varma²,

Weissfeld³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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He, Jing, Amit Varma, Lisa A. Weissfeld, and Sherin U. Devaskar. Postnatal glucocorticoid exposure alters the adult phenotype. Am J Physiol Regul Integr Comp Physiol 287: R198 -R208, 2004. First published March 4, 2004 10.1152/ajpregu.00349.2003We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in ␣-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume). development; food intake; neuropeptide Y; glucose transporters POSTNATAL GLUCOCORTICOID THERAPY constituted a standard intervention to combat chronic lung disease in the newborn premature infant (18,40). Recent reports of adverse outcomes such as cerebral palsy have cautioned the clinicians into judicious use of this drug (2, 17, 50). However, there still continue to be certain infants with chronic lung changes who are resilient to conventional modes of therapy warranting the use of postnatal glucocorticoids as a life-saving intervention (19,42). Furthermore, despite the absence of well-controlled trials, glucocorticoids are still used in term infants for differing indications other than prevention of chronic lung disease. While the adverse effects of antenatal glucocorticoid therapy have been examined and long-term changes reported in animals (13,20,33,37,38), limited studies exist in resp...

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Section: Discussionmentioning

confidence: 99%

Postnatal glucocorticoid exposure alters the adult phenotype

He¹,

Varma²,

Weissfeld³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In previous studies in fetal rat, rabbit, and human lung, the actions of glucocorticoid and thyroid hormones were generally reported to be additive when indices of surfactant production were measured (8-13). Betamethasone and thyroxine also had a marked additive effect on depletion of fetal heart glycogen when administered to the pregnant rabbit (40). Thyroxine, however, was reported to antagonize the stimulatory effect of cortisol on incorporation of glucose and acetate into phosphatidylcholine and phosphatidylglycerol in cultured adult rat type I1 pneumocytes (41), the cellular source of surfactant within the lung (I).…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Opposes Some Glucocorticoid Effects on Glycogen Content and Lipid Synthesis in Developing Fetal Rat Lung

1986

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ABSTRACT. Because of current interest in use of a com-used prophylactically to accelerate fetal lung maturation and bination of glucocorticoid and thyroid hormones for pre-prevent RDS in human newborns (2, 3) and in at least one vention of respiratory distress syndrome we examined the clinical study (4) thyroxine was also reported to be effective in effects of dexamethasone and triiodothyronine (T3), alone this regard. However, the findings in a recent multicenter study and in combination, on glycogen content and rates of fatty that glucocorticoids are not as efficacious in preventing RDS as acid and phosphatidylcholine synthesis in fetal rat lung. earlier believed and that its effects may be largely confined to The hormones were administered to the mothers on the 2 female infants (5) has led to interest in use of a combination of days before delivery on days 17-22 of gestation. Both glucocorticoids and thyroid hormone for prevention of RDS (6).hormones increased the rate of choline incorporation into Prior to such clinical use, however, it is desirable to have inforphosphatidylcholine, an index of surfactant synthesis, on mation on the interaction of these hormones in the acceleration day 20 just prior to the normal developmental surge but of lung maturation in animals. had no effect on this parameter on days 19, 21, or 22.Previous studies in animals have shown that a combination of There is a developmental increase in lung glycogen on days glucocorticoid and thyroid hormones is more effective than either 17-20 with a decrease thereafter and a developmental hormone alone in accelerating fetal lung maturation and stimuincrease in the rate of fatty acid synthesis between days 20 lating surfactant production. In a morphological study in the and 21. The increases in glycogen content and fatty acid fetal rat, Hitchcock (7) reported maximal acceleration of lung synthesis were accelerated by dexamethasone and pre-maturation when glucocorticoids and thyroxine were both presvented by T3 and when the hormones were administered ent. Similarly, a synergistic interaction between glucocorticoids together T3 antagonized the stimulatory effects of dexa-and thyroid hormone in stimulating synthesis of phosphatidylmethasone on these parameters. Both dexamethasone and choline and disaturated phosphatidylcholine, the major compo-T3 accelerated the normal developmental decrease in lung nent of pulmonary surfactant (I), was demonstrated in fetal rat glycogen later in gestation and the effects of the two lung in vivo (8,9) and in fetal rat (10, 1 I), rabbit (12), and hormones on this parameter were additive. The combina-human (1 3) lung in culture. tion of dexamethasone and T3 led to significantly smaller In addition to morphology and synthesis of surfactant phosfetuses and increased mortality late in gestation. These pholipids, lung maturation may also be assessed by other criteria. data show that glucocorticoid and thyroid hormones have An increase followed by a decrease in glycogen content is a opposite as well as common effects on...

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“…Plasma was sepa rated at 4 °C. Plasma glucose was measured by the glucose oxidase method using the Yellow Springs In strument (YS1 27A) [9], Plasma insulin was measured by radioimmunoassay as described previously [7],…”

Section: Blood Assaysmentioning

confidence: 99%

“…Insulin by interacting with specific recep tors, influences growth, and metabolism of various organs [1,2] including the brain [3,4], The existence of insulin receptors has been demonstrated in a wide variety of fetal/neonatal peripheral tissues [5][6][7] and the brain [8,9], Recent studies demonstrated varying patterns of ontogenetic changes in the concentration of insulin receptors among different organs during the perinatal period [5][6][7], As the degree of biological response from insulin stimulation can be influenced by the number and affinity of these receptors along with postreceptor events [10]. we delin eated the ontogeny of rabbit brain insulin binding and receptors using plasma mem branes.…”

Section: Introductionmentioning

confidence: 99%

Ontogenesis of the Insulin Receptor in the Rabbit Brain

Devaskar¹,

Holekamp²,

Karycki³

et al. 1986

Horm Res

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We delineated the ontogeny of the brain insulin binding, insulin receptor number and affinity using plasma membranes isolated from the rabbit. Specific ¹²⁵I-insulin binding and receptor number expressed per milligram of protein increased from the 20 day gestation fetus to the 1-day-old newborn, declining thereafter to attain adult values by day 6 of postnatal life. Specific ¹²⁵I-insulin binding and the receptor number in the adult brain was less than the fetal and neonatal (1 day) brain receptors. Although a similar trend was observed specifically during fetal development, the changes in receptor number expressed per microgram DNA were not significant in the neonatal period. The adult brain insulin receptor number was higher than the 20- to 27-day fetus and similar to that of the 30-day fetus and the 1- to 5-day newborns. The total receptor number correlated linearly with the brain plasma membrane protein increment velocity. The affinity of the receptors increased during early fetal development (20–27 days) and remained constant thereafter in the postnatal period. We conclude that the ontogenic changes of the brain insulin receptors are similar to the ontogenic changes of brain plasma membrane protein. The developmental changes are more pronounced when the receptor number is expressed per milligram protein versus microgram DNA.

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A Differential Effect of Thyroxine and Glucocorticoids on Fetal Brain and Heart Insulin Receptor

Cited by 13 publications

References 27 publications

Postnatal glucocorticoid exposure alters the adult phenotype

Postnatal glucocorticoid exposure alters the adult phenotype

Thyroid Hormone Opposes Some Glucocorticoid Effects on Glycogen Content and Lipid Synthesis in Developing Fetal Rat Lung

Ontogenesis of the Insulin Receptor in the Rabbit Brain

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