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Partial leptin deficiency in heterozygotes

We studied the heterozygous relatives of our leptin deficient subjects (Farooqi et al., 2001). Serum leptin levels in the heterozygous subjects were found to be significantly lower than expected for body fat and they had a higher prevalence of obesity than seen in a control population of similar age, sex and ethnicity (Farooqi et al., 2001). Additionally, percentage body fat was higher than predicted from their height and weight in the heterozygous subjects compared to control subjects of the same ethnicity. These findings closely parallel those in heterozygous ob- and db -mice (Chung et al., 1998). These data provide further support for the possibility that leptin can produce a graded response in terms of body composition across a broad range of plasma concentrations.

Congenital leptin deficiency

Mice Leptin Deficiency

The role of leptin was first discovered in studies of severely obese ob ob mice, which harbour mutations in the ob gene resulting in a complete lack of its protein product leptin which is derived from adipose tissue (Zhang et al., 1994). Administration of recombinant leptin reduces the food intake and body weight of leptin-deficient ob ob mice and corrects all their neuroendocrine and metabolic abnormalities (Halaas et al., 1995). In 1997, we reported two severely obese cousins from a highly consanguineous family of Pakistani origin who had undetectable levels of serum leptin and were found to be homozygous for a frameshift mutation in the ob gene (AG133), which resulted in a truncated protein that was not secreted (Montague et al., 1997). We have since identified four further affected individuals from three other families who are also homozygous for the same mutation in the leptin gene. All the families are of Pakistani origin but not known to be related over five generations. A...

Leptin receptor deficiency

The signalling form of the leptin receptor is deleted in db db mice (and disrupted in the fatty Zucker and Koletsky rat models) which are consequently unresponsive to endogenous or exogenous leptin (Tartaglia, 1997). In rodents, the phenotype is comparable to ob ob, with earlier development of hyperglycemia on some backgrounds. A mutation in the leptin receptor has been reported in several obese subjects from a consanguineous family of Kabilian origin (Clement et al., 1998). Affected individuals were homozygous for a mutation that truncates the receptor before the transmembrane domain and the mutated receptor circulates bound to leptin. Although this mutation does not result in a complete null phenotype, there are a number of phenotypic similarities with the leptin-deficient subjects. Leptin receptor deficient subjects were also born of normal birth weight, exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behaviour when denied food....

Response to leptin therapy

Recently we reported the dramatic and beneficial effects of daily subcutaneous injections of leptin reducing body weight and fat mass in three congenitally leptin-deficient children (Farooqi et al., 1999 2002). The major effect of leptin was on appetite with normalisation of hyperphagia. Leptin therapy reduced energy intake during an 18MJ ad libitum test meal by up to 84 (Farooqi et al., 2002). We were unable to demonstrate a major effect of leptin on basal metabolic rate or free-living energy expenditure, but, as weight loss by other means is associated with a decrease in (BMR) basal metabolic rate, the fact that energy expenditure did not fall in our leptin-deficient subjects is notable. The administration of leptin-permitted progression of appropriately timed pubertal development in the single child of appropriate age and did not cause the early onset of puberty in the younger children (Farooqi et al., 2002). Leptin also reversed the T cell dysfunction and caused a switch from a...


Cortisol (hydrocortisone) is a glucocorticoid, which means it affects glucose metabolism. It is produced in the middle zone (zona fasciculata) of the adrenal cortex and has a molecular structure similar to aldosterone (fig. 13.30). In addition to affecting glucose, cortisol influences protein and fat metabolism. Among the more important actions of cortisol are the following The set point of the feedback loop controlling cortisol secretion changes from time to time, altering hormone output to meet the demands of changing conditions. For example, under stress injury, disease, extreme temperature, or emotional upset nerve impulses send the brain information concerning the stressful condition. In response, brain centers signal the hypothalamus to release more CRH, leading to a higher concentration of cortisol until the stress subsides (fig. 13.31).

Plasma Leptin

Perirenal Fat Rat

Plasma leptin concentrations are known to reflect body fat content (Niswender and Schwartz, 2003). At the age between 6 and 8 months, plasma concentrations did not significantly differ among rat groups, although the fat content was slightly lower in (tg tg) rats compared with Figure 31.5. (A) Body fat content, and (B) plasma leptin and (C) adiponectin concentrations. The body fat content represents the combined wet weights of perirenal and epididymal fat normalized by body weight (g 100 g body weight (BW)). Fat content did not significantly differ between the CR1 and CR2 phase rats thus data were combined into the CR group. Plasma samples were prepared from trunk blood collected at decapitation. Plasma leptin and adiponectin data was unavailable for (tg tg) rats. ''Young'' represents an age of 6 to 8 months, while ''Old'' represents an age of 24 to 25 months. The numbers of rats examined were 7 to 24 for body fat content, 3 to 8 for plasma leptin, and 3 to 7 for plasma adiponectin....

Preface to the Second Edition

Biochemically characterized over the past decade (including leptin, interleukins 3-13, inhibins, activins, en-dothelins, lipoxins, leukemia inhibitory factor, and stem cell factor). It also has an increased page size (from 6 X 9 to 8.5 X 11 inches). Also, this second edition has a total of 449 figures, 270 of which are either new or significantly changed.

Formation of Corticosteroids

In contrast to the mineralocorticoid pathway, the glucocorticoid pathway, leading to formation of cortisol, begins with 17-hydroxyprogesterone. The latter compound is converted to 11-deoxy-cortisol, which is then transformed to cortisol through the action of 21-hydroxylase and 11jS-hydroxylase, respectively. These reactions are analagous to the formation of corticosterone from progesterone. Cortisol has high glucocor-ticoid activity, in contrast to 11-deoxycortisol, which lacks significant amounts of this activity.

Physiological Stimuli For Gh Release In Search Of An Endogenous Ligand For Gh Secretagogues

It seems possible that an endogenous GH secretagogue ligand could be synthesized in some discrete population of neurons within the CNS, possibly even synthesized in neuroendocrine cells controlling GH secretion. However, it is equally possible that it is produced peripherally in response to physiological stimuli. Under what physiological circumstances are plasma levels of GH higher than normal, possibly reflecting the release of an endogenous GH secretagogue ligand Interestingly, the endocrine response to GHRP-6 is in some respects similar to that observed in response to exercise. In humans, infusion of GHRP-6 results in an initial rapid increase in plasma levels of GH, followed by long-lasting elevated fluctuations (25) this profile is in marked contrast to the profile of GH release in response to GHRH infusion, which elicits a rapidly desensitizing response. However, the pituitary response to GHRP-6 desensitizes even more rapidly than that to GHRH, hence the profile of the in vivo...

Lipid Receptors Peroxisome Proliferator Activated Receptors

The observations that the thiazolidinedione class of Type 2 diabetic non-insulin-dependent diabetes mellitus insulin sensitizers act as direct PPARy ligands implicates PPARy as a NR involved in glucose as well as lipid homeostasis.400 Although adipose tissue and obesity contribute to insulin resistance, the molecular details concerning this relationship remain unclear.401 Several possibilities for the involvement of PPARy activity in insulin and glucose resistance have been suggested, such as regulation of adipocyte size, glucose transporters, and circulating leptin and free fatty acid levels.402-405 Since PPARy activity may directly or indirectly contribute to regulation of several of these parameters, it is likely that this receptor will continue to be targeted in the pharmacological intervention of Type 2 diabetes and obesity.406 Additionally, several studies have implicated PPARy as a regulator of macrophage foam cell generation, a process directly correlated to the incidence of...

Growth Suppression of Prostate Cancer Cells in Culture by Androgen

The cellular level of AR mRNA was 2-3 fold higher in the LNCaP 104-R1 and 104-R2 cells than in LNCaP 104-S cells. AR protein level increased 10-20 fold during this transition from A-dependent 104-S cells to A-independent 104-R1 or 104-R2 cells. The growth of both 104-R1 and 104-R2 cells, as well as CDXR cells in culture was suppressed by physiological concentrations (

Discovery Of The Benzolactam Secretagogues

L-692,429 (3) was shown to release endogenous GH in rats, pigs, sheep, dogs, and rhesus monkeys when administered intravenously. In dogs the release of GH was shown to be dose-dependent with a minimum effective dose of 0.1 mg kg (30). L692,429 had little effect on other hormones except for slight elevation in Cortisol. Unfortunately, 3 showed poor oral efficacy in dogs ( 30 mg kg) owing to poor oral bioavailability (2 ) (31). Even though excellent clinical efficacy with GHRP-6 had been demonstrated, L-692,429 was tested intravenously in humans in order to validate our peptidomimetic approach to GH release in humans. In healthy young males L692,429 (t1 2 3.8 h) was found to release GH in a dose-dependent fashion with a minimum effective dose of 0.2 mg kg (32). As observed with all the GHRPs, there were small transient increases in cortisol and prolactin after L-692,429 administration. No significant changes in other pituitary hormones or changes in insulin-like growth factor (IGF)-1,...

Biomedical Importance

Acylglycerols constitute the majority of lipids in the body. Triacylglycerols are the major lipids in fat deposits and in food, and their roles in lipid transport and storage and in various diseases such as obesity, diabetes, and hyperlipoproteinemia will be described in subsequent chapters. The amphipathic nature of phospholipids and sphingolipids makes them ideally suitable as the main lipid component of cell membranes. Phos-pholipids also take part in the metabolism of many other lipids. Some phospholipids have specialized functions eg, dipalmitoyl lecithin is a major component of lung surfactant, which is lacking in respiratory distress syndrome of the newborn. Inositol phospholipids in the cell membrane act as precursors of hormone second messengers, and platelet-activating factor is an alkyl-phospholipid. Glycosphingolipids, containing sphingo-sine and sugar residues as well as fatty acid and found in the outer leaflet of the plasma membrane with their oligosaccharide chains...

Changes in the skeleton and internal organs

Fat Quadriplegic

Striking changes occurred in the skull for example, there was a shortening of the snout and jaws and at the same time a reduction of the number of teeth (dog, cat, cattle, pig). The shortened snout and accentuated rounded eyes induced the juvenile appearance of the eternal cub. It also resulted in lower brainpower and smaller brain volume. The skeleton became less resistant than that of wild animals as a consequence of the comfortable life with its lack of movement. For the same reasons, the size of some of the physical organs decreased, for example, the heart (35 lower by weight in the domestic rabbit when compared to its wild ancestor). Of course there are exceptions. The English thoroughbred, trained for several centuries for racing, has a heart about one fifth heavier than that of other horses of the same size. The fat storage mechanism has also been modified by domestication. In wild animals, fat is stored in the surroundings of the

Prolifer f Prolifer

FIGURE 8.9 The selective estrogen enzyme modulator (SEEM) concept in human hormone-dependent breast cancer cells. The SEEM can control the enzymatic mechanisms involved in the formation and transformation of estrogens in breast cancer cells, where the sulfatase pathway is quantitatively higher than the aromatase. SEEM-I inhibits the estrone sulfatase SEEM-II the 17p-hydroxysteroid dehydrogenase type 1 SEEM-III the aromatase activities and SEEM-IV stimulates the estrone SULT activity. It is suggested that E1S is present in the tumor outside the cell and reaches the cell membrane where it is in contact with the intra-cellular estrone sulfatase. ANDR androgens E1 estrone E2 estradiol E1S estrone sulfate. Quoted from Chetrite G, Pasqualini JR, J Steroid Biochem Molec Biol 76 95-104, 2001. With permission. FIGURE 8.9 The selective estrogen enzyme modulator (SEEM) concept in human hormone-dependent breast cancer cells. The SEEM can control the enzymatic mechanisms involved in the formation...

Transduction of the Liver

Leptin is a potent modulator of weight and food intake. Leptin deficient ob ob mice gain considerable weight ( 70 g) compared with lean littermates ( 28 g) at 8 to 12 weeks of age. Morsy et al. (62) compared HDAd with FGAd, with respect to safety and efficacy, for leptin gene therapy in ob ob mice. Intravenous injection of 1-2 X 1011 particles of a FG vector encoding murine leptin (Ad-leptin) into ob ob mice resulted in an increase in serum leptin levels for only the first 4 days, returning to baseline levels 10 days postinjection (Fig. 5A). Increased leptin levels were associated with transient weight loss of 25 followed by weight gain 2 weeks after treatment (Fig. 5B). In contrast, ob ob mice injected with an HDAd-encoding leptin (HD-leptin) resulted in about 2-fold higher serum levels of leptin up to 15 days postinjection (Fig. 5A). However, expression was transient and gradually returned to baseline levels 40 days postinjection. Rapid weight loss to levels approaching that of...

Interactions Between Fetal Growth And Adult Body Mass

A mechanism other than insulin resistance by which the effects of birth weight and body mass index may interact is through their effects on plasma cortisol concentrations. A recent study showed that fasting plasma cortisol concentrations in adult men and women fell by 23.9 nmol (95 CI 9.6-8.2) with each kilogram increase in birth weight (49). This is thought to reflect persistingly increased cortisol secretion in people who grew slowly in utero, and who may have enhanced their glucocorticoid secretion in order to accelerate maturation of key organs including, importantly, the lung (50). Although obesity is associated with a reduction in plasma cortisol concentrations (51), Table 4, which combines studies in the United Kingdom and Australia (49), shows that the association between high plasma cortisol and raised blood pressure is stronger in people who are overweight or obese. This suggests the existence of a group of men and women who, while becoming overweight, paradoxically maintain...

Obesity as a disease state or adiposity as a continuous variable

Obesity as a clinical condition is currently defined as an excess accumulation of adipose tissue resulting in a BMI greater than 30kg m2. While the diagnosis of obesity by this criterion has clinical relevance with regards to intervention, management, and treatment, from an epidemiological perspective, it may hamper the study of the genetics underlying variation in body fat mass and distribution. For example, BMI exhibits a normal distribution with no clear division between the ''clinically obese (BMI 30) and the non-obese. Such a pattern of continuous distribution is not restricted to merely BMI but is found in all obesity-related phenotypes, including anthropo-metric measures (e.g. skin folds, and waist circumference), measures of body composition (e.g. percentage body fat, fat mass), and associated biochemical markers (e.g. leptin). Therefore the division of individuals into ''obese'' versus ''non-obese'' categories has a certain degree of arbitrariness that does not appear to...

Recent Advances in Treatment

Pathogenic mechanism of diabetes type 2 has provided a strong rationale for the introduction of thiazolidinedione (TZDs), which are PPARy agonists and which target insulin resistance in part through improvement of postprandial fat storage in adipose tissues (Miles et al., 2003 Boden et al., 2005). Large clinical trials are currently ongoing to test whether these drugs can prevent the progression of beta cell dysfunction in the natural history of diabetes and whether their beneficial effects on cardiovascular function observed in small-scale studies can translate into significant benefits in terms of hard cardiovascular end-points (Kanaya et al., 2003).

Linkage studies in common obesity

At present, the strongest evidence for a QTL influencing obesity-related phenotypes in humans comes from the San Antonio Family Heart Study (SAFHS) with a Log Odds Ratio (LOD) score of 7.5 for serum leptin levels on chromosome 2 (Comuzzie et al., 1997). This study used a sample of 459 Mexican-Americans distributed in ten families. In addition, in this population significant linkage has also been detected on chromosome 8 with both leptin (LOD 3.1) (Martin et al., 2002) and BMI (LOD 3.2) (Mitchell etal., 1999), as well as on chromosome 17 (LOD 3.2) for BMI (Comuzzie, 2002). The chromosome 2 QTL localizes very near the POMC locus, which encodes pro-opiomelanocor-tin. Hixson and colleagues detected significant association (P 0.001) between molecular variation in the POMC locus and variation in serum leptin levels among Mexican-Americans (Hixson et al., 1999). The region containing the QTL on chromosome 8 contains the b-3-adrenergic receptor (ADRB3 gene), a strong candidate previously...

Neuroendocrine Theories

Hypercortisolemia associated with late-life depression has been found to be associated with neuronal degeneration in the rat as well as human hippocampus (Sapolsky, 2000 Sheline, Wang, Gado, Csernansky, & Vannier, 1996). Thus, a neuroendocrine hypothesis for depression as a risk factor for dementia holds that late-life depression-induced cortisolemia could cause hippocampal degeneration and eventual cognitive decline. Lupien et al. (1994) found that aged subjects showing significantly increased cortisol levels with age and with high basal cortisol levels had impaired cognitive performance compared to aged controls without those abnormalities. Katona and Aldridge (1985) found failure of suppression on the Dexam-ethasone Suppression Test (DST) in 10 of 20 patients with dementia non-suppressors had significantly higher depression scores on the Depressive Signs Scale (DSS) than suppressors. Following antidepressant treatment, three of eight nonsuppressors reverted to normal suppression,...

Environmental adversity and reproductive development

Low birth weight (birth weight that is less than expected for gestational age) followed by a postnatal period of adequate nutritional resources is commonly associated with a period of catch-up growth over the first 3 years of life. As predicted by Chisholm and Burbank (2001), it is precisely this population of children that show an advanced age of sexual maturation. This same population shows an increased risk for obesity and metabolic diseases (Barker et al., 1989, 2002 Gluckman and Hanson, 2004a Hales and Barker, 2001 Phillips, 1998). Compared with controls (i.e., children born at weights that are average for gestational age) children showing low birth weight and postnatal catch-up growth reveal evidence for hyperinsulinemia, dyslipidemia, and increased body fat with reduced lean body mass. This condition is also associated with increased leptin levels (Ong et al., 1999 Pulzer et al., 2001). Increased insulin activity is thought to advance adrenarche by stimulating the activity of...

And Parasympathetic Cardiac Controls

Heart Contractility Spread

The suprarenal glands can also contribute to vasomotion. Because norepinephrine is released directly into the bloodstream from these endocrine glands, arteriolar constriction in the systemic organs can result. The human fight-or-flight response elicited under stressful or exciting circumstances originates within the hypothalamus and via hormones travels to the pituitary gland and later the adrenal cortex, where the agent cortisol is released into the bloodstream and adrenal medulla. It is in the medulla that cortisol activates the enzyme necessary to convert norepinephrine to epinephrine, which is released into the bloodstream to amplify increased sympathetic activity (2,3). Blood flow to the skin and other internal organs (like the stomach and intestines) is greatly decreased by increasing sympathetic (and decreasing parasympathetic) tonic activity flow to skeletal muscles and the heart increases considerably. This process can be thought of as simply delivering blood to the areas of...

Hormone Action And Biochemistry

Preganglionic Neuron

The relationship of the adrenal cortex to the medulla is shown in Figure 11-4. In Figure 11-4A, the vascular relationships are evident. The secretions from the cortex bathe the medulla on their way to the general circulation. Since unique environmental signals similar to those that cause epinephrine secretion from the medulla also stimulate glucocorticoid synthesis in the cortex, a ready supply of Cortisol is available to the medulla for enhancement in the rate of conversion of norepinephrine to epinephrine. The availability of glucocorticoid is demonstrated in Figure 11-4B. Here it is shown that the initial signals resulting in ACTH stimulation of the zona fasciculata of the cortex also stimulate the release of neurosecretory granules by way of the limbic system, hypothalamus, and autonomic nervous system via a cholinergic neuron, which is shown to release acetylcholine synapsing with a receptor on the membrane of a chromaffin cell. Some rearrangement of macromolecules in the cell...

The choice between Thl and Th2 responses in humans nature versus nurture

Nature Nurture Human Development

Neuroendocrine factors have a powerful effect on immune responses. Populations stressed by war or natural disasters have an increased incidence of infections such as tuberculosis and typhus, but under these circumstances it is difficult to estimate the relative contributions of defective public health and of increased host susceptibility to infection. Bernton et al (1995) studied the immunological and endocrine changes in military recruits under conditions of 'mental and physical stress approaching that found in combat', and found raised cortisol levels and reduced DHEA cortisol ratios in these recruits. Testosterone levels, delayed-type hypersensitive responses and T cell mitogenic responses decreased, while IgE levels increased. The authors suggested that stress induced a Th1 to Th2 shift.

Cortical collecting duct cell

FIGURE 15-9 Cellular model of the actions of aldosterone on Na+ and K+ transport processes in the mucosal cells of the collecting duct of the kidney. In the absence of aldosterone, there is only basal update of Na+ from the lumen by the Na+ permease and a basal rate of translocation of the Na+ across the cell so as to exit the peritubular side of the cell via the action of a Na+ K+ ATPase. The figure illustrates the five steps which are believed to be operative in the presence of aldosterone. Step (J), aldosterone enters the cell and in (2) binds to a high-affinity receptor by a reaction similar to that described for Cortisol in the liver cell (see Chapter 10). The complex of aldosterone-receptor presumably is activated and translocated to the nucleus ((3)) where it stimulates the rate of transcription of certain mRNAs which generate several aldosterone-induced proteins indicated as new proteins ( ). These include the a- and 3-subunits of the Na+ permease pump (step 4A), which is...

Aldosterone Receptor

Like the glucocorticoid receptor, the mineralocorti-coid receptor resides in the cytoplasm in the unoccupied (by ligand) form and also appears to contain hsp 90 in a heteromeric structure. Different from the glucocorticoid receptor, it appears that aldosterone binds in the binding pocket of the mineralocorticoid receptor D ring first, as contrasted with A ring first in the case of the glucocorticoid receptor (Figure 10-28). In addition, there seem to be three possible configurations of aldosterone, as shown in Figure 10-29. There may be a preponderance of the C-ll hemiacetal form, and this may be the major form binding to the mineralocorticoid receptor. Presumably the mineralocorticoid receptor undergoes activation-transformation in the cytoplasm and is transported into the nucleus by mechanisms similar to those described for the glucocorticoid receptor. An important issue is the crossover of ligand binding, and the mineralocorticoid receptor is an effective binder of Cortisol. Thus,...

The Psychobiology Of Stress

Ship Breasting Dolphins

Like the terms motivation and emotion, periodically there are calls to strike stress from the scientific lexicon (e.g., Engle, 1985). Stress variously refers to objective events (stressors), subjective psychological states (being stressed), and physiological responses (e.g., increases in cortisol). Following Selye (1975), in this chapter we refer to the events that precipitate stress reactions as Contemporary formulations of stress describe a loosely integrated system consisting of neuroanatomical and functional subsystems. Below the neck, stress biology centers on the regulation of glucocorticoids or CORT (cortisol in primates, corticosterone in rodents) and catecholamines, primarily norepinephrine and epinephrine (NE and EPI) (e.g., Johnson et al., 1992). In the periphery, CORT and cate-cholamines operate to increase the energy available for action through inhibiting glucose uptake into storage sites and liberating energy from fat and protein stores....

Hormones Regulate Fat Mobilization

Fat Mobilization

The hormones that act rapidly in promoting lipoly-sis, ie, catecholamines, do so by stimulating the activity of adenylyl cyclase, the enzyme that converts ATP to cAMP. The mechanism is analogous to that responsible for hormonal stimulation of glycogenolysis (Chapter 18). cAMP, by stimulating cAMP-dependent protein kinase, activates hormone-sensitive lipase. Thus, processes which destroy or preserve cAMP influence lipolysis. cAMP is degraded to 5'-AMP by the enzyme cyclic 3',5'-nucleotide phosphodiesterase. This enzyme is inhibited by methylxanthines such as caffeine and theophylline. Insulin antagonizes the effect of the lipolytic hormones. Lipolysis appears to be more sensitive to changes in concentration of insulin than are glucose utilization and esterification. The antilipolytic effects of insulin, nicotinic acid, and prostaglandin E1 are accounted for by inhibition of the synthesis of cAMP at the adenylyl cyclase site, acting through a Gi protein. Insulin also stimulates...

Mineralocorticoid Effect

The GA constituent in licorice (and its metabolite 3-monoglucuronyl-glycyrrhetinic acid) inhibits the enzyme 11 HSD (Kato et al 1995), which catalyses the conversion of Cortisol into its inactive metabolite, cortisone. This results in delayed excretion and prolonged activity of Cortisol. Additionally, GL and GA bind to mineralocorticoid and glucocorticoid receptors and may displace Cortisol from its carrier molecule, transcortin (Nissen 2003). Pseudohyperaldosteronism As Cortisol levels rise, they stimulate mineralocorticoid receptors in the distal renal tubule (Walker et al 1992). This creates pseudohyperaldosteronism, which has the same clinical features as primary aldosteronism, including sodium retention, fluid retention and oedema, hypertension, hypokalemia and metabolic alkalosis (Armanini et al 1996, Heldal & Midtvedt 2002, Kato et al 1995, vanUum et al 1998, Walker & Edwards 1994). A case report suggests that the symptoms occur despite low plasma levels of aldosterone (Nobata...

Ocular Use Of Steroids

The actions of the synthetic steroids used therapeutically are similar to those of cortisol. They bind to the specific intracellular receptor proteins and produce the same effects but have different ratios of glucocorticoid to mineralocorticoid potency. The anti-inflammatory and immunosuppressive effects of glucocorticoids are used for a variety of ocular conditions, such as postoperative inflammation, uveitis, macular edema, hyphema, and ocular trauma. The most common route of administration is topical as solution, suspension, or ointment. Other routes of administration include subconjunctival, subtenon, intraocular, or intravitreal injection. Occasionally, glucocorticoids are administered systemically in ocular-related diseases such as optic neuritis and giant cell arteritis.

End Organ Androgen Sensitivity

However, androgen metabolism has been investigated in normal human apocrine glands and in those isolated from age-matched patients with HS 2 . No increased activity of 3 3-hy-droxysteroid dehydrogenase, A4-5 isomerase, or 17 p-hydroxysteroid dehydrogenase was found and 5a-reductase activity was similar. These results suggest that HS cannot be attributed to exaggerated activities of androgen-interconvert-ing enzymes within apocrine gland cells.

Postpartum depression

The cause of postpartum depression has been extensively studied. Alterations of hormone levels for pro-lactin, progesterone, estrogen, and cortisol are not significantly different from those of patients who do not suffer from postpartum depression. However, some research indicates a change in a brain chemical that controls the release of cortisol.

Plate 80 Adrenal Gland I

The cortex is divided into three zones according to the type and arrangement of its parenchymal cells. These are designated zona glomerulosa, zona fasciculata, and zona reticularis. The zona glomerulosa constitutes 15 of the cortical volume. It secretes mineralocorticoids (aldosterone and deoxycorticosterone). The zona fasciculata constitutes nearly 80 of the cortical volume. It secretes the glucocorticoids (Cortisol, cortisone, and corticosterone) and a small amount of adrenal androgens. The zona reticularis (5 to 7 of cortical volume) produces most of the adrenal androgens.

Long vs Short Acting Compounds GH Secretory Pattern and Hormonal Specificity

Growth Hormone Adaptive Demands

In clinical studies, single doses of growth hormone secretagogues, given intravenously, intranasally, or orally have resulted in a dramatic elevation in serum GH levels (to approx 40-70 ng mL) (38-45) accompanied by modest post-dose increases in serum cortisol (mediated by ACTH) and prolactin (46,47). Since growth hormone and prolactin secreting cells are derived from the same embryonic lineage, stimulation of prolactin can frequency, but not in amount of GH secreted, was observed. Chapman et al. (37) performed a double-blind placebo controlled study with the same compound in healthy elderly men and women with somewhat different results. Subjects were dosed daily with MK-0677 (or placebo). GH was measured every 20 min for 24 h prior to treatment and after two weeks. In the MK-0677 treated subjects, increases in GH peak amplitude, peak area, and interpeak nadir were observed, but no difference in peak number was detected (Figs. 4 and 5). Serial samples were also collected for...

Pharmacological Toxicological Effects

Hyperforin (4.5 ) were shown to have dose-dependent enhanced 5-HT levels in all brain regions. Norepinephrine levels were increased in the dien-cephalon and brain stem, but not in the cortex, and higher levels of hypericum were needed. Dopamine levels were only increased in the diencephalon region with doses similar to those required for increased levels of norepinephrine (12). Cott demonstrated that hypericum extracts had affinity for adenosine, y-aminobutyric acid (GABA)-A, GABA-B, benzodiazapine, and monoamine oxidase (MAO) types A and B receptors (3). However, with the exception of GABA-A and GABA-B receptors, it is unlikely that the concentrations required to produce a physiological effect can be reached (3). Other studies have shown that hypericum extracts do not have high affinity for GABA-A and -B (5). Additionally, H. perforatum extracts downregulate P receptors and upregulate 5-HT2 receptors in the frontal cortex when given to rats (3,11). Hypericum extract standardized to...

Clinical Classification

Liposarcoma Lump

Obesity is a disease whose pathology lies in the increased size and number of fat cells. An anatomic classification of obesity from which a pathologic classification arises is based on the number of adipocytes, on the regional distribution of body fat, or on the characteristics of localized fat deposits (1,2). Weber-Christian disease and Dercum's disease are idiopathic accumulations of fat. Dercum's disease, also called adiposis dolorosa, is named after the painful nodules in the subcutaneous fat of middle-aged women. Weber-Christian disease, on the other hand, is a relapsing febrile disease occurring in younger women. All of these forms of localized fat deposits are relatively rare (2). Hypothalamic obesity is rare in humans (21). It can be regularly produced in animals by injuring the ven-tromedial or paraventricular region of the hypothalamus or the amygdala (22). These brain regions are responsible for integrating metabolic information on nutrient stores provided by leptin with...

Experimental Animal Models

Currently there exist several experimental animal models for the study of diabetes (Mathews, 2002). The most currently used are from rodents. All these animal models mainly reproduce by genetic engineering single specific alterations found in type 2 diabetes. These models try to elucidate one particular pathological aspect of the disease. The most widely used are the leptin-deficient ob ob_ mice, db db+ + mice, KATp-channel mutated, ApoE deficient mice with other deficiencies, several knock-out mice including for RAGE, for specific signaling molecules for IR, for PTP1B.

The Mechanism Of Stress Reaction

The hypothalamus receives signals from higher centres of the brain indicating a stress situation such stimulation causes release of chemical messengers called peptide neurohormones into the blood stream prompting the activation of the pituitary gland with the release of signals to the adrenal glands via the adrenocorticotrophin hormone (ACTH). Responding to ACTH stimulation the adrenal cortex, the outer area of the adrenal gland, secretes corticosteroids (glucocorticoids e.g. hydrocortisone or cortisol) which rapidly mobilise the body's carbohydrate, protein and fat reserves. In man hydrocortisone forms 95 per cent of the total glucosteroids formed in the adrenal cortex. Production and distribution of glucosteroid stress hormones is increased under stress although limited in the body at rest even when ginseng is administered. Ginseng encourages adrenal gland response in stress situations and also facilitates a rapid shutdown when the stress is removed. If the stress is prolonged the...

Glucocorticoid and Mineralocorticoid Receptors

Mineralocorticoid receptors are primarily involved in the regulation of salt balance. In addition to being activated by the mineralocorti-coid aldosterone, MR binds to and is activated by glucocorticoids. Since MRs are expressed in many tissues that also express GRs, it is probable that MR also activates transcription through GREs.316,317 However, in tissues where MR function is critical, such as in the gut and kidney, glucocorticoids are metabolized via the action of 11jS-hydroxysteroid dehydrogenase, ensuring MR-aldosterone sensitivity.318 Currently, little is known about bona fide MR target genes, other than that loss of the receptor through gene knockout results in severely impaired regulation of salt balance.319 In any event, it is clear that the CNS-related activities of these two receptors ensure appropriate regulation of peptide and steroid hormone production and response from the hypothala-mic-pituitary-adrenal axis.

Sheep Ovis ammon f aries

Almost 14,000-year-old paintings from the La Pileta cave in Spain show sheep and goats in a corral. It takes a long time for wild sheep, which were kept in simple corrals, to become truly domestic animals. The oldest findings of domestic sheep come from the north Iran mountains (Zawi Chemi Shanidar) and date from 9000 B.C. However, there were certainly more areas of domestication in western Asia at that time. In 4000 B.C., domestic sheep were bred throughout the civilized world. At first they gave only meat, milk, and leather, and only later did wool sheep appear, though only with short and rough wool (in Mesopotamia around 3000 B.C.). In the first millenium, sheep spread all over Europe, Africa (except in primeval forest areas), and Asia (to Sulawesi). At that time sheep with white, longer wool were common, with four horns or without horns (known from ancient Egyptian frescos). Sheep from antique Greece and Rome resembled modern breeds. The number of sheep breeds today ranges between...

Night Eating Syndrome

A characteristic circadian neuroendocrine pattern has been observed in a study of the night eating syndrome (7). The presence of elevated 24-hr levels of cortisol provides a biological marker of the stress under which patients are laboring. Blunting of the expected nighttime rise in melatonin and leptin was also found, in intriguing association with the impaired sleep and nighttime snacking of the night eating syndrome.

Adaptogenic And Tonic Effects

Ginseng Is used by many athletes to Improve stamina and to facilitate rapid recovery from Injuries. To examine the effects of ginseng supplements on hormonal status following acute resistance exercise, eight male college students were randomly given water (control group) or 20 g ginseng root extract treatment Immediately after a standardised training exercise. Human growth hormone, testosterone, Cortisol, and Insulln-IIke growth factor 1 levels were determined by radioimmunoassay. The responses of plasma hormones following ginseng consumption were not significant between the control and the ginseng groups during the 2-hour recovery period (YouI et al 2002).

Regulation of Cholesterol to Pregnenolone Conversion

Following the conversion of cholesterol to pregnenolone by the mitochondrial side-chain cleavage system, the adrenals and gonads can transform pregnenolone to either progesterone or 17a-hydroxypregnenolone. The formation of progesterone from pregnenolone is catalyzed by the enzyme 3jS-hydroxysteroid oxidoreductase commonly referred to as 3j6-hydroxysteroid dehydrogenase (3jS-HSD) in combination with A5,4-iso-merase, in the presence of the cofactor (NAD + ). In addition, 3jS-HSD catalyzes the formation of other A4-3-ketosteroids from corresponding A5-3j6-hydroxysteroids, which leads to the formation of androgens, estrogens, mineralocorticoids, and glucocorticoids. Thus, the reactions involving 3jS-HSD represent an obligatory step in the formation of highly biologically active steroids.

Many Hormones Are Made From Cholesterol

All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or endoplas-mic reticulum of the adrenal cell. Hydroxylases that require molecular oxygen and NADPH are essential, and dehydrogenases, an isomerase, and a lyase reaction are also necessary for certain steps. There is cellular specificity in adrenal steroidogenesis. For instance, 18-hydroxylase and 19-hydroxysteroid dehydrogenase, which are required for aldosterone synthesis, are found only in the zona glomerulosa cells (the outer region of the adrenal cortex), so that the biosynthesis of this min-eralocorticoid is confined to this region. A schematic representation of the pathways involved in the synthesis of the three major classes of adrenal steroids is presented in Figure 42-4. The enzymes are shown in the rectangular boxes, and the modifications at each step are shaded. Synthesis of aldosterone follows the mineralocorticoid pathway and...

Mutants Polymorphisms Transgenic and Gene Targeted Mutations Collectively Known as Mutants

The nomenclature of mutants is reasonably straightforward. However, there are some complications, because gene symbols are changed frequently as a result of genetic advances. Thus, mutants such as obese were given a symbol, in this case ob, which indicated the allele and the locus. The wild type at the ob locus was then designated +ob or, when the context was clear, just +. However, when the gene was mapped and cloned, it was found to code for a protein named leptin, which was given the locus symbol, Lep, so the obese allele has now been renamed Lep b. Now the wild type is designated +Lep or Lep+. Many mutants are undergoing such changes in their designations, with old symbols such as c for the albino locus now being redesignated Tyrc. The nude mutation has been redesignated Foxn1nu, because it is a mutation at a locus first described in Drosophila, which causes a forked head in that insect. As far as possible gene symbols for loci that are recognizable as identical in different...

Formation of 5Androstene317Diol and Testosterone

5-Androstene-3j6,17jS-diol and testosterone are formed from DHEA and androstenedione, respectively, through the action of 17 -hydroxys-teroid oxidoreductase, which is commonly referred to as 17j6-hydroxysteroid dehydrogenase (17jS-HSD) the reactions are reversible. Five isoforms of the enzyme, encoded by the 17fi-HSD gene, have been described in humans, each having cell-specific expression, substrate specificity, regulatory mechanisms, and reductase or oxidative catalytic activities. They are designated types 1-5 in the chronological order of their isolation. Chromosomal locations, enzymatic activities, and cellular distributions of the human 17fi-HSD isoenzymes vary (see review by An-dersson and Moghrabi38).

Reconnect to chapter 11 Sympathetic Division page 438

What Hormone Stimulates Adrenal Medulla

The cells of the adrenal cortex produce more than thirty different steroids, including several hormones (cortico-steroids). Unlike the adrenal medullary hormones, without which a person can survive, some of those released by the cortex are vital. In fact, in the absence of adrenal cortical secretions, a person usually dies within a week if he or she does not receive extensive electrolyte therapy. The most important adrenal cortical hormones are aldo-sterone, cortisol, and certain sex hormones.

Clinical Aspects

Glucocorticoids, the limbic system of the brain, the hypothalamus, the blood portal system connecting the hypothalamus with the anterior pituitary, and the adrenal gland are parts of the system. The normal values of steroidal hormones produced by the adrenal are presented in Table 10-2. When Cortisol is overproduced, often by a pituitary tumor causing high levels of circulating ACTH, the resulting disease is known as Cushing's disease. When Cortisol is underproduced, the resulting disease is known as Addison's disease, which is most frequently the result of adrenal destruction. The effects of Cushing's disease are summarized in Table 10-4. Hyperproduction of Cortisol from the adrenal gland would be expected to occur if there is a tumor of the adrenal producing abnormal amounts of the steroid or if there is a pituitary tumor producing high levels of ACTH (also if there is overproduction of CRH at the hypothalamic level, which apparently has not been documented so far). Adrenalectomy is...

Personality and the NHP Model

Recently, this also has been found to be an indicator, or by-product, of psychological well-being in humans in that higher levels of psychological well-being have also been associated with lower levels of cortisol release (Lindfors and Lundberg, 2002). Environmental enrichment is often used to alleviate stress and promote psychological well-being in captive nonhuman primates. This is particularly important as stress has been clearly associated with a variety of undesirable physiological effects, mostly as the result of compromised immune system functioning (Kelly, 1985 Shapiro et al., 1998).

Pharmacological Toxicological Effects 51 Endocrine Effects

Ginseng appears to have a modulating effect on the hypothalamic-pitu-itary-adrenal axis by inducing secretion of adrenocorticotropic hormone from the anterior pituitary to increase plasma cortisol (29,30), perhaps accounting for improvement in 11 quality of life measurements in a large double-blind study using ginseng extract G115 (31). Maternal ingestion of 650 mg of Siberian ginseng (Jamieson Natural Sources, Toronto) twice daily was associated with androgenization in a neonate (67). The product had been taken for the previous 18 months, including the pregnancy. During pregnancy, the mother noted increased and thicker hair growth on her head, face, and pubic area, and had experienced repeated premature uterine contractions during late pregnancy. At birth, the Caucasian child weighed 3.3 kg, had thick black pubic hair, hair over the entire forehead, and swollen red nipples. The woman continued to take the ginseng product for 2 weeks after the baby's birth, during which time she...

Reproductive biology

Humans mature slowly, so that the onset of puberty is delayed relative to pongids and other catarrhines. In females, the onset of puberty is signaled by menarche, or first menstruation. This is triggered by a critical amount of body fat. The hormone leptin, released by fat, appears to trigger menarche. Reduction of body fat in a cycling female suppresses menstruation.

Ectopic Production Of Hormones By Tumor Cells

Various tumors have been shown to secrete ACTH and to cause hypercortisolism, even when the tumor is undetectably small for many years. The secretion of this hormone ectopically occurs mainly with bronchial carcinoid tumors and to a smaller degree with pheo-chromocytomas, thymic carcinoids, and islet cell tumors. The carcinoid tumors can be very difficult to locate. This condition can lead to Cushing's syndrome, characterized by overproduction of Cortisol from the adrenal gland as a result of the uncontrolled levels of ACTH or its stimulating hormone, CRH, derived directly from ectopic production of the hormone. These tumors can also secrete proopiomelanocortin-related peptides.

Anatomical And Morphological Relationships

Medieval Knights Clothing Diagram

The endocrine changes accompanying pregnancy are remarkable. A pregnant woman in the late phase of the third trimester produces, on a daily basis, some 250-300 mg of progesterone, 15-20 mg of 17 3-estradiol, 50-100 mg of estriol, 75-100 mg of Cortisol, 3-8 mg of deoxycorticosterone (DOC), and 1-2 mg of aldosterone. In addition, there is a massive production of human chorionic somatomammotropin (in excess of 1 g day), human chorionic gonadotropin, human cho

GHD in the Newborn Period

Hypopituitarism may present in the newborn in a nonspecific fashion. Signs and symptoms include apnea, cyanosis, pallor, lethargy, jitteriness, and seizures. The differential diagnosis of hypogylcemia includes GHD and hypopituitarism, which could include cortisol deficiency. Prolonged hyperbilirubinemia may be owing to TRH or TSH deficiency, causing hypothyroidism in a neonate with multiple hormone deficiency. Patients with congenital hypopituitarism may have a turbulent neonatal course, generally more characteristic of a full-term infant because of the frequency of neonatal problems in preterm infants. Neonatal glucocorticoid deficiency can present as hyponatremia.

Endocrine Aberrations

During recent years of investigation abdominal visceral distribution of adipose tissue has been found to be associated with endocrine disturbances, confirming the original observation by Vague (6). These disturbances include an increased cortisol activity and a blunted secretion of growth hormone (GH) and sex steroids in both men and women (29-34). These endocrine perturbations can theoretically be a consequence of the obese condition but it has also been suggested that the endocrine aberrations can have causal effects (33,35). Cortisol is of interest as it causes accumulation of abdominal visceral adipose tissue (39) and an increased release of FFA. The latter will, in turn, cause reduced insulin binding in the liver and thereby higher circulating levels of insulin, glucose, and blood lipids by the mechanisms discussed above. The role of cortisol in obesity has been controversial during many years. Several authors have found decreased plasma cortisol levels in obese subjects while...

Management of anesthesia

Postoperative most serious postoperative problem is thyroid storm, which is characterized by hyperpyrexia, tachycardia, altered consciousness, and hypotension. Most commonly occurs 6-24 hours postoperatively. Treatment includes hydration and cooling, propranolol (0.5 mg increments until heart rate is below 100 beats min) or esmolol. Consider cortisol (100-200 mg IV every 8 hours), propylthiouracil (250 mg every 6 hours orally) followed by sodium iodide (1 gm IV over 12 hours), and correction of any precipitating cause.

Empiric regimen for perioperative supplementation

For major surgery give usual daily dose with premedications, cortisol 25 mg IV on induction, then 100 mg IV by infusion over the next 24 hours. Resume daily dose postoperatively. 2. For minor surgery give usual daily dose with premedications and cortisol 25 mg IV on induction. Resume daily dose postoperatively.

Drug Delivery System Complications

To increase gastrointestinal motility, stimulant laxatives, such as bisacodyl, are beneficial. Increased retention time allows for greater fluid extraction and stool softeners, such as docusate, or bulk-forming laxatives, such as psyllium, counteract these effects. Sexual dysfunction is another adverse effect that should be monitored in both men and women. Levels of thyroid functioning, cortisol, and testosterone or estrogen should be obtained and followed if loss of libido, difficulty achieving or maintaining an erection, or amenorrhea develops. Some patients may require hormone replacement and the use of steroids.

Physiological Biological Methods Reactivity and Regulation

Developmental psychologists often use physiological measures to assess variables such as stress, hormones, heart rate, and skin conductance (Berntson & Cacioppo, chap. 12, this volume). Typically, these variables are measured along with observations or self-reports of a similar construct (e.g., a stress index is taken before or while Cortisol levels are measured). In terms of their advantages, physiological and biological methods are extremely useful for measuring psychological processes that individuals are unable to report (e.g., emotional reactivity in young children). They also are relatively free from social desirability biases. Disadvantages of these methods include the cost of instruments and time spent editing and interpreting the data. Additionally, carryover effects may threaten internal validity because of previous stimuli responses affecting subsequent reactions and not accurately reflecting the individual's homeostatic state (Rothbart, Chew, & Gartstein, 2001). Moreover,...

PTPs and Human Disease

Even then, PTEN is unusual within the PTP family, displaying specificity for phos-phatidylinositol phospholipids 23,24 . More recently, the RPTP DEP-1 has been identified as a tumor suppressor associated with cancers of colon, breast, and lung 79 . Although PTP1B has been implicated in the dephosphorylation of several growth factor receptor PTKs, mice in which the gene for PTP1B has been ablated display disruption of signaling in response to insulin and leptin but no increased incidence of tumors 59,80-82 . Recent studies have shown that disruption of the PTP1B gene does lead to hyperphosphorylation of the EGF and PDGF receptors, but with only minimal changes in signaling 83 . Thus, it would appear that mechanisms exist within the cell to compensate for disruption in PTP expression. Such mechanisms may apply broadly across the PTP family, explaining why so few tumor suppressor PTPs have been identified.

Functional Aspects of PTPs in Health and Disease Bioinformatics

In the field of protein tyrosine phosphatase, PTP1B has received particular attention, and an understanding of its function is emerging from the above combined approaches. Thus, it seems likely that PTP1B is a key regulator of leptin signaling 54-56 and potentially an important drug target in obesity and type 2 diabetes (see Chapter 118). In the current bioinformatics context, it is of particular interest that PTP1B maps to 20q13.1-q13.2 (Table 2), a region linked to obesity and diabetes 57-60 , and recently a rare P387L variant of the PTP-1B gene was found to be associated with relative risk of type 2 diabetes in a Danish study 61 . 55. Cheng, A., Uetani, N., Simoncic, P. D., Chaubey, V. P., Lee-Loy, A., Mcglade, C. J., Kennedy, B. P., and Tremblay, M. L. (2002). Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497-503. 56. Zabolotny, J. M. et al. (2002). PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489-495.

Ligand Entry Loop Interactions

Figure 9.3 (a) Schematic diagram of the active site of the 17 -hydroxysteroid dehydrogenase 1 (17HSD1)-equilin-oxidized nicotinamide adenine dinucleotide phosphate (NADP+) ternary complex. Residues belonging to the hydrophilic catalytic and recognition ends, as well as residues lining the hy- Figure 9.3 (a) Schematic diagram of the active site of the 17 -hydroxysteroid dehydrogenase 1 (17HSD1)-equilin-oxidized nicotinamide adenine dinucleotide phosphate (NADP+) ternary complex. Residues belonging to the hydrophilic catalytic and recognition ends, as well as residues lining the hy- Figure 9.4 Superposition of the backbones of structures of 17 -hydroxysteroid dehydrogenase 1 (17HSD1) apoenzyme and ternary complex with equilin and oxidized nicotinamide adenine dinucleotide phosphate (NADP+). Substrate-entry loops (residues 286-201) in open and closed forms are shown in thicker cross-sections.

Nuclear Receptor Ligands

Specificity and are capable of binding to identical ligands. Examples of this cross-specificity include mineralocorticoid receptor high-affinity binding to cortisol and the ability of both GRs and PRs to bind the synthetic glucocorti-coid antagonist RU486 with relatively high

How Ovarian Steroids Affect Mammographic Density

The association between ovarian steroids and mammographic density parallels what is known about the effects of ovarian steroids and breast cell proliferation.43 Breast cell proliferation is higher in pre- than postmenopausal women and higher in women in the luteal than in the follicular phase of the menstrual cycle. In short, high estrogen progesterone levels are associated with high amounts of breast cell proliferation.

Cardiovascular Effects

Studies have been conducted to examine the effects on GB administration on blood pressure and blood flow. In one study, either GB or placebo was administered in a double-blind, placebo-controlled crossover design to healthy volunteers and forearm blood flow was measured (29). Forearm blood flow was significantly higher during GB therapy than with placebo and mean arterial pressure remained unchanged, thus rendering the forearm vascular resistance significantly lower during active treatment. In a related study, Jezova and colleagues studied the effect of GB (EGb 761) treatment on changes in blood pressure and cortisol release following exposure to stress stimuli (30). The rise in systolic blood pressure following stress stimuli was significantly lower ( 20 mmHg rise in subjects receiving EGb 761 vs an 30 mmHg rise in subjects receiving placebo) in the GB group. Differences in diastolic pressure rise were similar ( 10 mmHg difference between GB and placebo) between the two groups. GB...

Causes and symptoms

The human body was designed for life forty thousand years ago, when the ability to store energy in times of plenty meant the difference between life and death during famine. This protective mechanism is a source of trouble when food, in unlimited quantities, is readily available,. This is evident in the increasing prevalence of obesity in modern times, particularly in Western cultures. While obesity is just an exaggeration of a normal body, the storage of energy for future is properly classified as a health problem. This is because excessive amounts of storage fat may interfere with the normal physiology of the body. Obesity is directly related to the increasing Because obesity reflects an imbalance between the amount of energy taken into the body in the form of food and the amount of energy expended in metabolism and physical activity, and because eating is an activity that involves choice and volition, obesity is classified by the Health Care Financing Administration (HCFA) as a...

Drugs For Dyskinesia Sarizotan

64 dyskinetic PD subjects, sarizotan, at doses ranging from 2 mg BID to 10 mg BID, prolonged the amount of on time without dyskinesia (55). PD symptoms were not worsened, as assessed by amount of off time or UPDRS scores, although some patients did report worsening of parkinsonism as an adverse event. Additional adverse events reported included sedation and nausea. Higher doses have been associated with suppression of the cortisol response to ACTH challenge, but this was not seen in PD. A large multicenter Phase III trial did not demonstrate a difference between sarizotan and placebo and consequently the development of this compound for PD has been abandoned (56).

Antihypertensive Renal Effects

The release of substance P, or whether PGE merely changes the properties of the nociceptor membrane, which results in increased firing. The elevated cyclic AMP, if involved, somehow produces pain, which, if persistent, results in a stress response via the hypothalamus (CRH) to release ACTH and then Cortisol from the adrenal gland. In addition to ACTH, (i-lipotropin is formed in equivalent amounts, which is processed to enkephalin via -endorphin, and enkephalin binds to a cell membrane receptor, which may compete with the PGE receptor in some way or produce a second messenger opposing the action of cyclic AMP. Elevated levels of circulating Cortisol may produce a polypeptide, called lipocortin or annexin I ( 40,000 Da), in the same cells that originally produced the elevated PGEs. This polypeptide is an inhibitor of phospholipase A2 and thus quenches the production of PGEs leading to pain in the first place. This is expected to be a slower process than the analgesia produced by...

Pathogenic Mechanisms

The lipolytic process is mainly regulated by catecholamines in human adipose tissue (18). Furthermore, visceral adipocytes have a higher density of lipolytic -adrenergic receptors than other fat cells, mediating lipolysis by the action of norepinephrine (19). The density of glucocorticoid as well as androgen receptors is also higher (12,20). The effect of cortisol is mainly to increase visceral fat mass by increasing the expression of LPL (21,22), while testosterone has the capacity to decrease fat accumulation by inhibiting LPL (23,24) and enhancing lipolysis by the increasing the expression of P-adren-ergic receptors (25,26). In addition to these intrinsic characteristics of the visceral adipocytes the surroundings of these cells are different from other adipocytes. Blood flow is higher than in other adipose tissues (27), which is of fundamental importance for both lipid uptake and mobilization, and in addition visceral adipose tissue contains more catecholamines and...

Melanin Concentrating Hormone Receptors

Melanin-concentrating hormone (MCH) is a 19-amino acid cyclic, orexigenic neuropeptide, expressed predominantly in the lateral hypothalamus where it binds a cognate GPCR, MCHR1, and signals through complex neural networks to promote feeding and reduce energy expenditure.42-46 Infusion of MCH into rodents stimulates feeding and, on a chronic level, causes moderate weight gain.47-52 Increased expression of MCH in genetic models of obesity and the finding that MCH neurons express the leptin receptor suggest that leptin regulates MCH expression. Results of confirmatory in vitro and in vivo studies continue to emerge.53 56

Nutrient Sensing Receptors

GPR40 is expressed most highly in brain and in pancreatic beta cells. It has been shown that long-chain free fatty acids enhance glucose-dependent insulin secretion from beta cells through activation of GPR40.173 Some selectivity for specific fatty acids was found, with saturated free fatty acids of chain length C12-16 and unsaturated free fatty acids of chain length C18-20 preferred. Some eicosanoids also showed receptor stimulatory activities comparable to those of the long-chain fatty acids. GPR41 is expressed in a number of tissues including white fat. Activation of this receptor in fat cells and in intact animals by short-chain fatty acids (C2-C6) led to stimulation of leptin production.171 Because circulating leptin levels are reflective of both adipose mass and nutritional status, an involvement of GPR41 in leptin secretion identifies a signaling role for short-chain fatty acids from the diet in this nutrient-sensing pathway. GPR43 has a limited distribution, and its selective...

Avian migration and navigation

Inertial Navigation Illustration

Once in flight, the migrant's fat deposits are depleted. Fuel stores must be replenished during a migratory stop-over before the bird will be able to execute another flight segment. The rate of fuel recovery will depend upon the quality of the habitat in which the bird lands and lays over. Typically, songbirds are able to deposit fat at rates of 2-3 per day and under optimal conditions the rate may reach 10 of fat-free body mass. Given the obvious importance of stored fat to the success of a continuing migration, finding stop-over habitat in which fuel supplies can be quickly replenished is critical to a migrant's success.

Behavior And Reproduction

During the nonbreeding season, many sandpiper species feed and rest in large flocks. Sandpipers also migrate in large flocks of just one species. Some sandpipers migrate distances as great as several thousand miles, having built up large fat deposits to sustain them during the trip.

Materials and Methods

Tissue Sample, RT-PCR, and AR Yeast-based Functional Assay. The patient was diagnosed with T3NxMo PCA at age 76, and was first treated with leuprorelin and flutamide. The patient responded to this complete androgen blockade for 17 months, and relapsed thereafter. Using bone scanning, diffuse bone marrow metastases including bilateral posterior iliac metastases were revealed at that time. He was later treated by alternative hormonal (cyproterone acetate, cortisol, medroxyprogesterone) and chemotherapy. The bone marrow sample was aspirated at the site of a hyperfixation area on the right posterior iliac crest, five years after the initial diagnosis, and cytologic examination showed the presence of numerous metastatic PCA cells. Total RNAs were isolated from the bone marrow sample, and an AR fragment (1786 bp, 2311 - 4097) was amplified by RT-PCR, and cloned into a yeast expression plasmid. The AR functional assay has been described (7).

Multigenic Models Of Susceptibility

The steroid pathways), the genes originally proposed included three of interest the 17jS-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P450c17a (CYP17) gene, and the estrogen receptor a (ESR1) gene (Fig. 5.3). These genes were selected not only because of their known function but also because polymorphisms had already been identified that could be functionally relevant. Data have been published on the role of CYP17 and HSD17B1 and breast cancer risk.119 Huang and col-leagues120 have published findings of a similar model with the estrogen-metabolizing genes CYP17, CYP1A1 (which participates in estrogen hydroxylation), and catechol-O-methyltrans-ferase (COMT), which encodes the enzyme responsible for O-methylation, leading to inactiva-tion of catechol estrogen. Several candidate genes for such a model are described in subsequent chapters, and the numerous studies of other polymorphisms are reviewed else-where.121

In Vivo Expression of Recombinant Adenoviral Encoded Proteins

Systemically administered Ad vectors can also provide high-level temporary expression of a protein that is secreted into the bloodstream. Much of this work has focused on preclinical applications, as in expression of factor VIII for the treatment of hemophilia A (Connelly et al., 1996) or of erythropoietin to stimulate erythro-poiesis (Setoguchi et al., 1994a), but this property can also be useful in understanding the in vivo roles of secreted proteins. For example, rats treated intravenously with a viral vector directing expression of the rat leptin protein exhibited reduced food intake and weight gain, as well as a disappearance of fat deposits (Chen et al., 1996). Intraperitoneal administration of an Ad vector containing the gene encoding HST-l FGF-4 to mice stimulated platelet production (Sakamoto et al., 1994). This group then used the same viral vector in an in vitro study to demonstrate that the increased platelet count was due to FGF-4 stimulation of megakaryocyte maturation...

Using a Combination of Self Reports and Other Methods for Construct Validation Purposes

Logical indicators or observational data in combination with social and psychological variables may allow a researcher to overcome the limitations of self-report measures by combining it with methods that more objectively quantify the construct in question (e.g., blood pressure, heart rate, serum cholesterol, Cortisol, lipids, or insulin function).

Aging and the Hypothalamic PituitaryGonadal HPG Axis

Both males and females experience an age-related decline in the HPG axis. However, aging in the male system is a more gradual process in humans and in other species. Nonetheless, data show an age-related decline in testis function and decreased circulating androgen levels (for review, see Ottinger 1998). A recent study showed that circadian patterns in adrenal steroids were maintained in aging males for cortisol (Urbanski et al., 2004). Similarly, levels of dehydroepiandrosterone sulfate (DHEAS) also had a circadian pattern and did show an age-related decline.

Etiology and Pathogenesis

Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) may play a role in the pathogenesis and course of depression and anxiety (Hariri et al., 2003 Sen et al., 2004 Taylor et al., 2005). Geneotype has been related to hippocampal volumes (Taylor et al., 2005) and to amygdala reactivity to environmental stimuli (Hariri et al., 2005). These findings may be related to interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses and may bias an individual's reactivity to stressful life experiences (Hariri et al., 2005 Taylor et al., 2005). Some studies report that genotype significantly predicts the development of depression after stressful life events (Lenze et al., 2005), although others did not find an association (Gillespie et al., 2005). Several studies have suggested that response to antidepressant therapy may be related to serotonin transporter genotype (Murphy et al., 2004). The short (S) allele was associated...

Zebrafish For A Model Of Nutritionrelated And Agedependent Chronic Diseases With Oxidative Stress

The increasing prevalence of obesity and other nutrition-related chronic diseases, which usually accompany aging, has prompted considerable efforts to understand their pathogenesis and treatment. One experimental approach is to overexpress, inactivate, or manipulate specific genes that regulate energy metabolism and fat storage. Many such techniques are fully amenable and have been established as routine tools in zebrafish, as well as in Drosophila and C. elegans. In the future, these elegant models will be complementarily helpful in dissecting endocrine problems and metabolic pathways, associated with aging and senescence. Particularly, once zebrafish counterparts of essential signaling molecules, such as Sir2 and FoxOs, involved in regulation of energy metabolism are available, development of model systems appear to be within of our current technologies and fat storage, are obtained, development of new vertebrate aging models appears to be within the scope of our current...

The Neuroendocrine Dysfunction

As described earlier, aging is associated with a low-grade inflammation. This manifests itself also at the neuro-endocrine level by a relative sustained increase of cortisol and adrenergic hormone levels in elderly subjects (Valenti, 2004). The stress hormones such as cortisol may contribute to the development of insulin resistance. In case of acute events, such as illnesses, the effect of these stress hormones may be accentuated, contributing to the occurrence of type 2 diabetes. The contributing effect of cortisol on impaired glucose tolerance or type 2 diabetes could be through its ill-defined age-dependent effects on the innate immune response or direct interference with insulin-mediated glucose disposal. The -adrenergic effect of catechol-amines by inhibiting insulin secretion further accentuates the contribution of age-related hormonal changes to insulin resistance in diabetes mellitus. The activation of serine kinase via the catecholamine-mediated cAMP dependent kinase inhibits...

The Hypothalamic PituitaryGonadal HPG Axis and Agerelated Changes

Figure 43.1 A summary of the hypothalamic-pituitary-gonadal axis of females. GnRH stimulates gonadatropin release (LH and FSH), which then stimulates ovarian steroid hormone release (estrogen and progesterone). Estrogen either has positive (just prior to ovulation) or negative feedback actions on the hypothalamus and pituitary. Inhibin is also released by the ovary and inhibits FSH release. In rats, the estropause is characterized by continued high estrogen levels and a persistent estrus vaginal cytology until much later in life. On the arrows, the circle refers to the initiator of the signal, and arrows indicate the termination of the signal. Figure 43.1 A summary of the hypothalamic-pituitary-gonadal axis of females. GnRH stimulates gonadatropin release (LH and FSH), which then stimulates ovarian steroid hormone release (estrogen and progesterone). Estrogen either has positive (just prior to ovulation) or negative feedback actions on the hypothalamus and pituitary. Inhibin is also...

Body Composition Changes And Obesity

Most dramatically, not only is there an increase in the fat cell mass but also its distribution is changing, because this enhancement is due to an enrichment at the abdominal site (central distribution). This central redistribution of the fat cell mass has dramatic consequences for the metabolic environment and is a risk factor for several obesity and age-related metabolic abnormalities. Thus, the frontier between aging and obesity is very thin (Harris, 1999). Interestingly, the normal relationship between total body fat mass and circulating leptin levels appears to be disrupted in the elderly, suggesting that abnormal secretion of this adipostat may play a role in body fat changes with aging (Moller et al., 1998). The increase in visceral and central fat cell mass with or without reduction of peripheral fat mass has dramatic consequences for the metabolic environment and is a risk factor for several obesity and age-related metabolic abnormalities, such as hypertension and...

Inhibitory Effects Associated with Awakenings

In a study where GH secretion was stimulated by the injection of growth hormone releasing hormone (GHRH) at the beginning of the sleep period, it was found that whenever sleep was interrupted by a spontaneous awakening, the ongoing GH secretion was abruptly suppressed (41). This inhibitory effect of awakenings on the GH response to GHRH was further demonstrated in a detailed study where sleeping subjects who had received a GHRH injection were awakened 30 min after the injection and then allowed to re-initiate sleep 30 min later (42). The subjects who were able to resume sleep rapidly showed a secondary smaller GH pulse. A near complete inhibition of the GH response to GHRH was also observed when the injection was given 20 min after a forced awakening around the end of the first third of nocturnal sleep (42). It has been suggested that this inhibitory effect of nocturnal awakenings on the GH secretory response to GHRH could be mediated by an increase in somatostatin release (42). This...

Other Steroid Hormone Bacterial Conversions

Studies have shown that fecal organisms can modify corticosteroids. The corticosteroids undergo reduction in ring A, and undergo side-chain dehydroxylation separately or sequentially with the reduction (48). Cortisol is converted to 21 -deoxycortisol, tetrahydrocortisol, and tetrahyro-21-deoxycortisol (48). Corticosterone is metabolized to tetrahydrocorticosterone, 21-deoxycorticosterone, and 3-alpha-hydroxy or 3-beta-hydroxy epimers of tetrahydro-21-deoxycorticosterone (48).

Growth Hormone Gh And Somatomedins Igfs

Here it is shown that GH is released through the action of hypothalamic growth hormone-releasing hormone (GRH), as described earlier in Chapter 3. The GH released into circulation has two effects One effect is to directly act on lipid and fat metabolism, analogously to Cortisol action, in a manner to oppose the actions of insulin and IGF-I, as shown by its ability to directly increase blood sugar (Figure 19-1). The other action of GH is on liver and other organs to generate IGF-I, which, like insulin, produces skeletal growth as well as tissue growth. IGF-I is active as a negative feedback agent on the hypothalamus and causes the production of somatostatin (GIH), which inhibits the release of GH from the anterior pituitary, and it also acts at the level of the pituitary to inhibit expression of the GH gene in response to GRH. When GH causes IGF-I to be produced, IGF-I-binding proteins are also synthesized in the liver and other tissues, and both IGF-I and binding proteins are secreted...

Biological And Molecular Actions

While clinical treatment with pharmacological doses of glucocorticoids represents one end of the spectrum, the physiological rise in circulating levels of Cortisol following stress represents the other. Some workers believe that there is a close link between stress, elevated glucocorticoids resulting from it, and injury to the immunological apparatus, which may leave the individual vulnerable to the action of latent oncogenic viruses, newly transformed cancer cells, or other disease processes that are normally held in control by the immunological apparatus. On the other hand, some believe that, in stress, elevated levels of glucocorticoids serve to suppress the body's normal defenses against stress, preventing them from overshooting and causing damage to the organism. A more detailed discussion of the immune system and the effects of various factors on its function is found in Chapter 17 on thymus hormones. Thus, the negative effects of glucocortiocids are to be weighed against their...

Oral Properties of MK0677 in the Clinic

Based on the indications of potency, duration of action, oral bioavailability, and selectivity, which are summarized above, compound 44 (L-163,191) as its crystalline mesylate salt was selected for safety assessment studies. Subsequently it entered clinical testing and was given the designation MK-0677 as a potential product candidate. In confirmation of the animal data, MK-0677 was found to raise IGF-1 in man following oral administration. The first published account was by Copinischi et al. (62) who treated nine healthy young men daily for seven days in a crossover comparison of placebo and 5- and 25-mg doses of MK-0677. IGF-1 levels were increased in a dose dependent manner without detectable elevations of GH. Nor was any evidence observed of induced hypercortisolism. Chapman et al. (63) reported results shortly thereafter of a study in which 32 healthy elderly men and women received placebo, or 2, 10, or 25 mg MK-0677 orally, once daily for two separate study periods of 14 and 28...

Detail Of Liver Lobule

Amounts of Cortisol circulating in the bloodstream than the unstressed person. The steroid acts on many of the tissues of the body to an extent determined by the number of glucocorticoid receptors present in the cell of a particular tissue. The liver, which contains about 65,000 receptor molecules per cell in an experimental animal (rat), predominates as a major target of cortico-sterone, the principal glucocorticoid in rat. Other important targets are the lymphoid cells, thymus gland, and kidney. Many other tissues seem to have enough receptor molecules to provide a response to stress, especially if it is long-term. In fact, most tissues of animals or of cells in culture seem to contain measurable amounts of receptor, making it theoretically possible for nearly all tissues of the body to be affected by stress.

Proopiomelanocortin deficiency

The first-order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro-opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide-Y Agouti-related protein (NPY AgRP) neurons in the hypothalamic arcuate nucleus, where the signalling isoform of the leptin receptor is highly expressed (Schwartz et al., 2000). Forty percent of POMC neurons in the arcuate nucleus express the mRNA for the long form of the leptin receptor and POMC expression is regulated positively by leptin. POMC is sequentially cleaved by prohormone convertases to yield peptides including a-MSH that have been shown to play a role in feeding behavior.

Simultaneous Measurement of Other Variables to Enhance Understanding of Neuroimaging Data

Unfortunately, a problem arises in trying to integrate fMRI data with simultaneous collection of other types of data. Specifically, fMRI is both sensitive to artifacts caused by psychophysiological recording devices and causes interference in those same devices. Nevertheless, it is possible to implement psychophysiological recordings such as galvanic skin response, heart rate, blood pressure, and eye tracking within the fMRI environment (Savoy, Ravicz, & Gollub, 1999). These measures are all easily implemented in the PET environment as well. Similarly, measures of hormonal responses such as Cortisol can be collected in the scanner environment. The large differences in time scales of these various measures can cause interpretational issues when moving across levels. Nevertheless, the benefit of collecting such measures should be increasingly apparent.

Glucocorticoids and Behavioral States Reciprocal Determinism

Glucocorticoids (Cortisol in humans, corticos-terone in rats) are steroid hormones of the adrenal cortex that have potent effects on glucose metabolism and immune function, as well as on psychological processes (Gore & Roberts, 2003 Lovallo & Thomas, 2000 Schimmer & Parker, 1996). Glucocorticoids are classic stress hormones and have been commonly used as biochemical markers of stress reactions (McEwen, 2000). As illustrated in Figure 12.6, the secretion of glucocorticoids is regulated by the anterior pituitary hormone adrenocorticotropic hormone (ACTH), which in turn is controlled by the hypothalamic peptide corticotropin releasing hormone (CRH). CRH is released in a pulsatile fashion (see Veldhuis et al., 2001), regulated by pituitary, hypothalamic, and hip-pocampal circuits that bear glucocorticoid receptors and are sensitive to glucocorticoid levels. These circuits exert a feedback inhibitory influence on CRH release. The hypothalamic and pituitary negative feedback mechanisms...

Growth Hormone Receptors In The

The successful purification of GHRs made possible the development of specific antibodies to measure GHR proteins (4). These have been useful to demonstrate GHRs in peripheral target tissues where GHRs are of low abundance (e.g., within the epiphyseal growth plate). Immunocytochemistry has also been used to confirm that GHRs are indeed expressed in the brain, particularly in fetal and young animals (5), and show a widespread distribution including regions of the CNS not obviously expressing GHR in later life. Similar immunohistochemical studies demonstrated GHR expression in human fetal brain tissue (6). One potential complication is that GHR can also give rise to a GH binding protein (GHBP) either by proteolytic cleavage of the full-length receptor or as a translation product of an alternatively spliced mRNA in rodents (7,8). Because of this, antibody localization studies employing an epitope directed against the extracellular domain of the GHR will also recognize GHBP moieties able...

Why look for human obesity genes

The discovery of human obesity genes will undoubtedly lead to health benefits. Firstly some obesity syndromes are very severe, occur at a young age and are associated with other developmental and clinical manifestations. It is clear that knowledge of the underlying genetic defect in these syndromes will be of considerable clinical benefit in terms of recognising other treatable aspects of the particular syndrome and providing more informed genetic counseling. As illustrated by congenital leptin deficiency (see below) the precise identification of some of these syndromes may turn out to have therapeutic relevance.

Glucocorticoid remediable aldosteronism GRA

The last stages in the synthesis of the mineralo-corticoid aldosterone and the glucocorticoid cortisol take place in the adrenal cortex, and are catalyzed by two highly homologous enzymes which lie adjacent to each other on chromosome 8. CYP11B1 (11-beta hydroxylase) converts deoxy-cortisol to cortisol (the principal corticosteroid), a process involving 11-hydroxylation, and CYP11B2 (aldosterone synthase) converts deoxycorticoster-one to aldosterone (the principal mineralocorti-coid), a process involving 18-hydroxylation. The CYP11B1 promoter is responsive to plasma levels of adrenocorticotrophic hormone (ACTH) and thus CYP11B1 is constitutively active, regulated by negative feedback of cortisol on the hypotha-lamic pituitary axis. The CYP11B2 promoter responds to the activity of the renin angiotensin system, mediated via the action of angiotensin II on Type I angiotensin II receptors. In some families segregating hypertension, hypokalemia and hyperaldosteronism in an autosomal...

Apparent mineralocorticoid excess AME

Though cortisol is principally a glucocorticoid, the mineralocorticoid receptor exhibits the same affinity for cortisol in vitro as it does for aldoste-rone. Since the plasma concentration of cortisol is over 100 times higher than that of aldoste-rone, the discovery that cortisol could bind to the mineralocorticoid receptor raised the question of how the specificity of that receptor for aldosterone is preserved. This is the role of the short chain dehydrogenase-reductase enzyme 11-betahydroxy-steroid dehydrogenase type 2 (HSD11B2), which is principally expressed in the collecting ducts of the kidney and is responsible for converting cortisol to cortisone (which is inactive at the mineral-ocorticoid receptor Figure 25.3 ). The syndrome of hypertension and hypokalemic alkalosis produced by liquorice intoxication or the drug carbenoxolone (which is very similar biochemically to hyperaldosteronism, but without aldosterone excess) is due to the pharmacological inhibition of HSD11B2 and...

Vitamin B6 Has Several Roles in Metabolism

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the co-factor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin B6 is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, an-drogens, cortisol, and vitamin D.

Properties Of Enzymes Involved In Steroid Metabolism

Hydroxylation reactions play an important role in the metabolic pathways of many steroids, both those producing hormones as well as those generating bile acids. The cleavage of the cholesterol side chain necessitates the hydroxylation of both carbon-22 and carbon-20, while the production of testosterone necessitates hydroxylation of progesterone at carbon-17 followed by cleavage of the carbon-17-carbon-20 bond. In the biosynthesis of Cortisol, three hydroxylases, the 17a-, the 21-, and the 11 3-hydroxylases, are required. The conversion of deoxycorticosterone to aldosterone would seemingly involve three separate enzymes, which sequentially hydroxylate carbon-11, then carbon-18, followed by oxidation of the carbon-18 alcohol to an aldehyde. Surprisingly, it has been learned from molecular biological cloning that one enzyme carries out all three steps.

EGCG Modulation of Food Intake and Endocrine Systems

After 7 days of daily ip treatment with EGCG, circulating levels of testosterone are reduced by about 75 in male rats and 17(3-estradiol levels by 34 in female rats. The weights of A-sensitive organs, such as ventral prostate and seminal vesicles and estrogen-sensitive organs, such as the uterus and ovary were reduced by about 50 . Other catechins were not as effective as EGCG. We also found that the serum level of LH is reduced by 40-50 , suggesting that low LH production led to the reduced blood levels of sex hormones. In both male and female rats, we observed significant reduction in blood levels of leptin, IGF-I, and insulin (1, 26). Some of these peptide hormones may modulate the levels of sex hormone and indirectly alter tumor growth in the animals.

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