Biomedical subjects

J A Majzoub

Publications and source records attributed to J A Majzoub.

At least 19 recordsLinked to original sources

PubMed2000

Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency.

The hypothalamic-pituitary-adrenal (HPA) axis, including hypothalamic corticotropin-releasing hormone (CRH) and pituitary corticotropin, is one of the first endocrine systems to develop during fetal life, probably because glucocorticoid secretion is necessary for the maturation of many essential fetal organs. Consistent with this, pregnant mice with an inactivating mutation in the Crh gene deliver CRH-deficient offspring that die at birth with dysplastic lungs, which can be prevented by prenatal maternal glucocorticoid treatment. But children lacking the ability to synthesize cortisol (because of various genetic defects in adrenal gland development or steroidogenesis) are not born with respiratory insufficiency or abnormal lung development, suggesting that the transfer of maternal glucocorticoid across the placenta might promote fetal organ maturation in the absence of fetal glucocorticoid production. We used pregnant mice with a normal HPA axis carrying fetuses with CRH deficiency to characterize the relative contributions of the fetal and maternal adrenal to the activity of the fetal HPA axis, and related these findings to fetal lung development. We found that in the presence of fetal adrenal insufficiency, normal fetal lung development is maintained by the transfer of maternal glucocorticoid to the fetus, specifically during the circadian peak in maternal glucocorticoid secretion.

Adrenal Insufficiency↗

PubMed2000

Neuroanatomy of human appetitive function: A positron emission tomography investigation.

OBJECTIVE: The mediating neuroanatomy of human appetitive function is poorly understood. A state induction paradigm was employed, in conjunction with positron emission tomography, to test the hypothesis that limbic/paralimbic regions respond to the desirability of food stimuli. METHODS: Eight normal subjects were studied during each of three conditions, involving visual exposure to high-caloric food, low-caloric food, and nonfood stimuli. Subjective indices of hunger were measured via analog scales. RESULTS: Planned contrasts demonstrated significant increases in desire to eat and decreases in left temporoinsular cortical blood flow during the high-caloric versus control conditions. DISCUSSION: Results implicate the temporo-insular cortex in normal appetitive function, suggesting that activity within this region is associated with the desirability or valence of food stimuli, prior to ingestion. These data will provide a broad foundation for future studies of patients with eating disorders.

Adult↗

PubMed2000

CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors.

We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress.

Adrenocorticotropic Hormone↗

PubMed2000

Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.

Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.

Adrenal Insufficiency↗

PubMed2000

Urocortin expression in the Edinger-Westphal nucleus is up-regulated by stress and corticotropin-releasing hormone deficiency.

Urocortin is a 40-amino acid mammalian peptide related to CRH and urotensin. The physiological role of urocortin is unknown, but it has been postulated to serve some of the functions previously attributed to CRH. We had earlier found that urocortin messenger RNA (mRNA) expression within the mouse brain is confined to the region of the Edinger-Westphal (EW) nucleus of the midbrain. To further characterize the regulation of the urocortin gene, we first cloned and sequenced the mouse gene, confirming the presence of a single gene in the murine genome. A general survey of mouse tissues using Northern blot analysis revealed the presence of urocortin mRNA only within the midbrain. By in situ hybridization analysis, we found that urocortin mRNA expression in the EW nucleus is responsive to stress, as mRNA levels increased approximately 3-fold after 3 h of restraint. Chronic glucocorticoid treatment, although not affecting basal levels, blocked the stress-induced rise in urocortin mRNA. Using CRH-deficient [knockout (KO)] mice, we examined the effect of combined CRH and glucocorticoid deficiency upon urocortin mRNA expression. As in wild-type (WT) mice, we had previously found that urocortin expression in CRHKO mouse brain was not detected outside of the EW nucleus. However, we found that urocortin expression within the EW of CRHKO mice is up-regulated 2- to 3-fold compared with that in WT mice. This up-regulation is not due to a lack of inhibition by glucocorticoids, as urocortin mRNA levels in the EW nucleus of CRHKO mice did not change after glucocorticoid supplementation. As the EW does not project to any brain regions known to be involved in the behavioral responses to stress, urocortin expressed in this site is unlikely to mediate stress-induced behaviors. On the other hand, as the EW nucleus may play a role in the regulation of the autonomic nervous system and projects to various brain stem nuclei that express the CRH receptor, urocortin originating in the EW may play a role in the regulation of the autonomic nervous system during stress.

Animals↗

PubMed2000

Impaired basal and restraint-induced epinephrine secretion in corticotropin-releasing hormone-deficient mice.

CRH is thought to play a role in responses of the adrenocortical and adrenomedullary systems during stress. To investigate the role of CRH in stress-induced secretions of corticosterone and epinephrine, we subjected wild-type (WT) and CRH-deficient (knockout, KO) mice to restraint, and analyzed plasma corticosterone, plasma catecholamines, and adrenal phenylethanolamine N-methyltransferase (PNMT) gene expression and activity before and during 3 h of restraint. Plasma corticosterone increased over 40-fold in WT mice, but minimally in CRH KO mice. Adrenal corticosterone content tended to increase in CRH KO mice, although to levels 5-fold lower than that in WT mice. CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint. Adrenal PNMT messenger RNA content in CRH KO mice tended to be lower than that in WT mice, though the degree of induction was similar in both genotypes. PNMT enzyme activity was significantly lower in CRH KO mice. Pharmacological adrenalectomy abolished restraint-induced corticosterone secretion and PNMT gene expression in WT mice, consistent with an absolute requirement of glucocorticoids for PNMT gene expression. We conclude that glucocorticoid insufficiency in CRH KO mice leads to decreased basal and restraint-induced plasma epinephrine and adrenal PNMT gene expression and enzyme activity.

Adrenalectomy↗

PubMed1999

CRH-deficient mice have a normal anorectic response to chronic stress.

Many studies have implicated corticotropin-releasing hormone (CRH) as a mediator of stress-induced decreases in food intake. However, urocortin, sauvagine, and urotensin, other members of the family of CRH-like molecules, have also been shown to be potent inhibitors of food intake. This raises the possibility that a CRH-related molecule might also be responsible for stress-induced anorexia. We therefore examined the effects of three chronic stressors, repetitive daily restraint, turpentine abscess, and surgical stress, upon food intake in wildtype and CRH-deficient mice created by targeted inactivation of the CRH gene. We have found that both genotypes have similar basal food intake which initially decreases to the same degree following initiation of each stress paradigm. Food intake also recovers following the same time course and to the same degree in both genotypes. Therefore, CRH is not necessary for decreases in food-intake induced by the chronic stressors examined in this study.

Animals↗

PubMed1999

Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH.

Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response, causing stimulation of corticotropin and glucocorticoid secretion. CRH is also widely believed to mediate stress-induced behaviors, implying a broader, integrative role for the hormone in the psychological stress response. Mice lacking the CRH gene exhibit normal stress-induced behavior that is specifically blocked by a CRH type 1 receptor antagonist. The other known mammalian ligand for CRH receptors is urocortin. Normal and CRH-deficient mice have an identical distribution of urocortin mRNA, which is confined to the region of the Edinger-Westphal nucleus, and is absent from regions known to mediate stress-related behaviors. Since the Edinger-Westphal nucleus is not known to project to any brain regions believed to play a role in anxiety-like behavior, an entirely different pathway must be postulated for urocortin in the Edinger-Westphal nucleus to mediate these behaviors in CRH-deficient mice. Alternatively, an unidentified CRH-like molecule other than CRH or urocortin, acting through the CRH receptors in brain regions believed to mediate stress-induced behaviors, may mediate the behavioral response to stress, either alone or in concert with CRH.

Animals↗

PubMed1999

Corticotropin-releasing hormone deficiency unmasks the proinflammatory effect of epinephrine.

Traditionally, the adrenal gland has been considered an important endocrine component of the pathway to inhibit acute inflammation via hypothalamic corticotropin-releasing hormone (CRH)-mediated secretion of glucocorticoid. Immunoreactive CRH found in inflamed tissues is a potent proinflammatory factor. Using genetic and pharmacological models of CRH deficiency, we now show that CRH deficiency unmasks a major proinflammatory effect of epinephrine secreted from the adrenal medulla. Together, epinephrine and peripheral CRH stimulate inflammation, and glucocorticoid acts as a counterbalancing force in this regard. Our findings suggest that stimulation of the acute inflammatory response should be included with the other "fight-or-flight" actions of epinephrine.

Adrenal Glands↗

PubMed1999

Animal models of CRH deficiency.

Corticotropin-releasing hormone (CRH), the major regulator of hypothalamic-pituitary-adrenal (HPA) axis, was first isolated due to its ability to stimulate the release of adrenocorticotropic hormone from the anterior pituitary. Later, it was also found to have also a wide spectrum of actions within the central nervous system and the periphery. Studies with pharmacological administration of this peptide and/or antagonists and antibody neutralization techniques have yielded important information concerning the physiological relevance of CRH. The development of CRH knockout mice (CRH KO) has been an important tool for addressing the physiologic and pathologic roles of CRH. This review describes the phenotype of CRH-deficient mice, as well as the use of this model to study the roles of CRH on fetal development and postnatal life. The role of CRH in prenatal development and postnatal regulation of the HPA axis, in activation of the reproductive system during stress, and in modulation of the immune function will be discussed. The review concludes with a comparison of CRH KO mice with other models of CRH deficiency.

Animals↗

PubMed1999

A central theory of preterm and term labor: putative role for corticotropin-releasing hormone.

Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releasing hormone and its duration through time have been linked to the time of onset of labor. Paradoxically, although glucocorticoids are known to inhibit corticotropin-releasing hormone production within the hypothalamic-pituitary-adrenal axis, cortisol actually increases corticotropin-releasing hormone levels in several areas outside the hypothalamus, including the placenta. Placental corticotropin-releasing hormone may be an important component of a system that controls the normal maturation of the fetus and signals the initiation of labor. Abnormal elevations in corticotropin-releasing hormone, which may be a hormonal response to stressors arising in either the mother, placenta, or fetus, may prove to participate in the premature onset of parturition.

Corticotropin-Releasing Hormone↗

PubMed1999

Placental corticotropin-releasing hormone: function and regulation.

Corticotropin-releasing hormone is a neuropeptide placentally expressed among mammals only in primates. Its expression increases as much as 100 times during the last 6 to 8 weeks of pregnancy and is paradoxically stimulated by glucocorticoids. Increasing evidence suggests that placental corticotropin-releasing hormone may have evolved in primates to stimulate fetal adrenocorticotropin release and adrenal steroidogenesis, thus satisfying the high demand for synthesis of dehydroepiandrosterone, the predominant source of placental estradiol. Concomitant stimulation by placental corticotropin-releasing hormone of fetal cortisol and dehydroepiandrosterone would couple the glucocorticoid effects on fetal organ maturation with the timing of parturition, an obvious benefit in postnatal survival.

Animals↗

PubMed1999

Corticotropin-releasing hormone stimulates angiogenesis and epithelial tumor growth in the skin.

The hypothalamic neuropeptide corticotropin-releasing hormone is the major hypothalamic regulator of the endocrine pituitary-adrenal axis. Corticotropin-releasing hormone is also expressed in many peripheral sites, where its functions are unclear. It is also secreted by diverse neoplasms, where it may be associated with malignant behavior. To provide information regarding the function of corticotropin-releasing hormone in peripheral sites and in tumors, we asked whether corticotropin-releasing hormone has angiogenic properties. In vitro, we found that human corticotropin-releasing hormone specifically stimulates endothelial chemotaxis via a corticotropin-releasing hormone receptor-dependent mechanism. In vivo, subcutaneous inoculation of nude mice with human epithelial tumor cells engineered to secrete corticotropin-releasing hormone was associated with significantly enhanced angiogenesis (2.3-fold over control) and tumor growth (5-fold over control). Peripheral corticotropin-releasing hormone may thus enhance local angiogenesis, which may provide clues to its function outside of the nervous system.

Animals↗

PubMed1999

Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice.

Corticotropin-releasing hormone-deficient (CRH-KO) mice, which as a consequence are also glucocorticoid-insufficient, exhibit neonatal lethality when derived from CRH-KO mothers. Death is due to respiratory insufficiency as a result of abnormal pulmonary development, and can be prevented by prenatal administration of glucocorticoids. In the study described here, we used CRH-KO mice as a model of genetically altered in utero glucocorticoid action to elucidate the role of endogenous glucocorticoids in lung maturation. The histologic appearance of the lungs of these mice is normal until Day 17.5 of gestation, at which point failure of septal thinning and air-space formation is observed. These morphologic alterations in the CRH-KO mouse lung are the result of continued cell division in cellular compartments that by this time in gestation have ceased proliferating in wild-type mice, rather than the result of a failure of apoptosis. In accord with this observation, the CRH-KO lung exhibits delayed induction of type II pneumocyte biochemical parameters, such as messenger RNAs (mRNAs) for surfactant protein-A (SP-A) and SP-B, and fatty acid synthase, as well as delayed Clara cell maturation. In contrast, surfactant phospholipid synthesis is not impaired during CRH-KO lung development. Our findings indicate that an essential role of endogenous glucocorticoids in pulmonary maturation in utero is to stimulate a developmental program in late gestation that affects epithelial and mesenchymal cell proliferation and differentiation throughout the parenchyma.

Animals↗

PubMed1999

Regulation of hepatic glycogen in the insulin-like growth factor II-deficient mouse.

Insulin-like growth factor II (IGF-II), a polypeptide hormone with structural homologies to insulin-like growth factor I (IGF-I) and insulin, regulates the metabolism and growth of many tissues. In this study, we examined the role of IGF-II in hepatic glycogen metabolism in normal and growth-retarded IGF-II-deficient (knockout) mice. Liver glycogen content was significantly lower in the IGF-II knockout than in control livers during embryonic day 18 and postnatal day 0. Biochemical results were verified histologically using a glycogen-specific stain. The enzymatic activity of glycogen synthase, the rate-limiting enzyme for glycogen synthesis, was significantly lower in livers of knockout mice than in livers from wild-type controls on embryonic day 18 and postnatal day 0. The levels of glycogen synthase messenger RNA were not different between the two groups at any age studied, indicating that IGF-II acts posttranscriptionally. Hepatic glycogen content, measured in newborns after food withdrawal, was significantly lower in knockout mice compared with that in wild-type mice after 0, 3, and 6 h of fasting. Blood glucose was significantly lower in knockouts vs. wild-type newborn mice before fasting and was similar in both genotypes after 6 h of fasting. Consistent with this, only 23% of IGF-II knockout newborn mice survived fasting for 12 h, whereas 93% of wild-type mice survived this treatment. These results indicate that IGF-II is required for the regulation of glycogen metabolism of the mouse in the perinatal period, possibly via stimulation of glycogen synthase activity. IGF-II, via perinatal regulation of glycogen synthesis, may regulate fetal growth as well as play an important role in the transition from fetal to postnatal life by protecting the neonate against hypoglycemia during periods of fasting.

Animals↗

PubMed1999

Normal suppression of the reproductive axis following stress in corticotropin-releasing hormone-deficient mice.

The hypothalamic neuropeptide CRH has been postulated to inhibit LH secretion by a central action within the brain. To characterize the physiological significance of CRH in stressor-induced inhibition of LH secretion, CRH-deficient and wild-type mice were subjected to restraint or food withdrawal, and plasma LH levels were determined. The proestrus LH surge of female mice was equally suppressed by restraint in both genotypes, and central administration of a CRH antagonist did not alleviate this suppression in either genotype. Male mice of both genotypes also demonstrated suppression of both LH and testosterone secretion following restraint. Furthermore, food withdrawal caused similar suppression of LH secretion in both female and male mice regardless of CRH status. These data demonstrate that CRH is not necessary to inhibit LH secretion following either restraint or food withdrawal and that other molecules are able to suppress LH secretion during the response to stress in the context of CRH deficiency.

Animals↗

PubMed1999

Inducible binding of cyclic adenosine 3',5'-monophosphate (cAMP)-responsive element binding protein (CREB) to a cAMP-responsive promoter in vivo.

In general, DNA-binding factors that activate gene transcription are thought to do so via reversible interaction with DNA. However, most studies, largely performed in vitro, suggest that the transcriptional activator, cAMP response element-binding protein (CREB), is exceptional in that it is constitutively bound to the promoter, where its phosphorylation leads to the recruitment of CREB-binding protein (CBP) to form a CREB/CBP/promoter complex. We have studied how CREB interacts with DNA in vivo to regulate the cAMP-responsive gene encoding human CRH (hCRH). Protein-DNA complexes were cross-linked in cells expressing the endogenous hCRH gene by exposure to a 10 nsec pulse of high-energy UV-laser light, followed by immunoaffinity purification of CREB-DNA complexes. Binding of CREB to a fragment of the hCRH promoter containing a canonical, functional cAMP response element was absent in untreated cells, but was specifically induced after activation of the protein kinase A pathway with forskolin. These data indicate that, in vivo, CREB, like the majority of other DNA-binding transcriptional activators, undergoes signal-mediated promoter interaction.

Binding Sites↗

PubMed1999

High glycemic index foods, overeating, and obesity.

OBJECTIVE: The prevalence of obesity has increased dramatically in recent years. However, the role of dietary composition in body weight regulation remains unclear. The purpose of this work was to investigate the acute effects of dietary glycemic index (GI) on energy metabolism and voluntary food intake in obese subjects. METHODS: Twelve obese teenage boys were evaluated on three separate occasions using a crossover study protocol. During each evaluation, subjects consumed identical test meals at breakfast and lunch that had a low, medium, or high GI. The high- and medium-GI meals were designed to have similar macronutrient composition, fiber content, and palatability, and all meals for each subject had equal energy content. After breakfast, plasma and serum concentrations of metabolic fuels and hormones were measured. Ad libitum food intake was determined in the 5-hour period after lunch. RESULTS: Voluntary energy intake after the high-GI meal (5.8 megajoule [mJ]) was 53% greater than after the medium-GI meal (3.8 mJ), and 81% greater than after the low-GI meal (3.2 mJ). In addition, compared with the low-GI meal, the high-GI meal resulted in higher serum insulin levels, lower plasma glucagon levels, lower postabsorptive plasma glucose and serum fatty acids levels, and elevation in plasma epinephrine. The area under the glycemic response curve for each test meal accounted for 53% of the variance in food intake within subjects. CONCLUSIONS: The rapid absorption of glucose after consumption of high-GI meals induces a sequence of hormonal and metabolic changes that promote excessive food intake in obese subjects. Additional studies are needed to examine the relationship between dietary GI and long-term body weight regulation.

Adolescent↗