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Leptin and Energy Expenditure

In an attempt to maintain adequate energy stores, mammals increase energy expenditure during periods of abundance. In rodents, it is known that leptin increases energy expenditure through the induction of the mitochondrial uncoupling pro-tein-1 (UCP-1) and the newly identified mitochondrial uncoupling protein-2 (UCP-2) and mitochondrial uncoupling protein-3 (UCP-3) through the sympathetic nervous system 70 in both white and brown adipose tissue 71 . Increasing evidence from human studies suggests that leptin predominantly influences the human energy balance through appetite changes, but it appears not to be involved in regulating energy expenditure 72 . None of the expected factors, such as resting metabolic rate, total diurnal energy expenditure or dietary-induced thermogenesis, was related to blood leptin concentrations 73 .

Leptin and Diet Induced Obesity

After the discovery of leptin, the initial hypothesis that human obesity results from a deficiency in leptin has failed. Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected response. This fact suggests that obese humans are resistant to the effects of endogenous leptin. The resistance is also shown by the lack of effect of exogenous administration to induce weight loss in obese patients 64 . Leptin resistance may be defined as reduced sensitivity or complete insensitivity to leptin action, as occurs for insulin in type 2 diabetes 57 . Human and rodent studies indicate that the major cause of this resistance arises from an inability of leptin to cross the blood-brain barrier 81 . The leptin transporter is a saturable system beyond a certain plasma leptin level, increased production by the growing fat mass would be futile. Furthermore, severe hyperleptinaemia might down-regulate the...

Leptin Interacts with Ghrelin and Insulin

It is commonly assumed that the effects of leptin and ghrelin on metabolism, including food intake, are exactly opposite. Ghrelin is considered to be a hunger hormone, whereas leptin is a satiety signal 47 . Rising ghrelin levels in concert with falling leptin levels may serve as a critical signal to induce hunger during fasting 48 . It has been observed that leptin exerts a restraint on the orex-igenic effects of ghrelin in two ways, centrally by counteracting its appetite-promoting effects at the level of neuropeptide Y (NPY) signalling in the hypothalamus and peripherally by attenuating gastric ghrelin secretion 49 . Moreover, there is evidence suggesting that leptin and ghrelin may also work via the hindbrain 42 . Leptin and insulin interact with each other. Insulin plays a major role in the regulation of lep-tin production, stimulating the transcriptional activity of the leptin promoter, increasing leptin gene expression and elevating leptin circulating concentrations. These...

FiHydroxysteroid Dehydrogenase 3 Deficiency

Testosterone, the principal male sex steroid hormone, is synthesized in five steps from cholesterol, as shown below. In the last step, five isozymes catalyze the 17yS-hydroxysteroid dehydrogenase reactions that interconvert 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryogenesis and cause the disorders of human sexuality termed male pseudoher-maphroditism. Specifically, mutations in isozyme 3 of the 17yS-hydroxysteroid dehydrogenase in the fetal testis impair the for mation of testosterone and give rise to genetic males with female external genitalia and blind-ending vaginas. Such individuals are typically raised as females but virilize at puberty, due to an increase in serum testosterone, and develop male hair growth patterns. Fourteen different mutations of 17yS-hydroxysteroid dehydrogenase 3 have been identified in 17 affected families in the United States, the Middle East, Brazil,...

Salivary Cortisol Secretion in Response to Stress

To assess HPA axis functioning in response to stress, all daughters undergo a 15-minute stress session. They complete a 3-minute serial subtraction task followed by a 12-minute social competence interview, developed to induce emotional arousal by discussing stressful life situations. Four saliva samples are collected over the course of 50 minutes one sample immediately before task instructions, and three samples at 15, 30, and 45 minutes after the onset of the stressor. Following the laboratory stressor (i.e., during collection of the final two samples), participants watch a neutral videotape. As can be seen in Figure 17.4, the high-risk daughters exhibited both an elevated immediate response to the stressor and a slowed cortisol recovery. These data indicate that stress activates the HPA axis in individuals at heightened risk for depression to a greater extent than is the case for nonvulnerable individuals, and suggest a mechanism by which stress may play a role in the onset of...

Leptin and Cancer Anorexia Cachexia

The persistence of anorexia and the onset of cachexia in cancer patients, therefore, implies a failure of this adaptive feeding response 86 . Leptin, a member of the gp 130 family of cytokines, induces a strong T helper-1 lymphocyte response and is regarded as a proin-flammatory inducer 87 . Several data suggested a role of leptin in inflammatory diseases. Proinflammatory cytokines up-regulate leptin expression in white adipose tissue and increase plasma leptin levels in hamsters and mice 88 . However, in many common diseases associated with cachexia, such as chronic obstructive pulmonary disease and chronic inflammatory bowel disease, there is an inflammatory status caused by high proinflammatory cytokine levels, whereby leptin concentrations are decreased related to body fat mass. In patients with advanced non-small-cell lung cancer, serum leptin levels were lower than in controls and lower still in those who were cachectic who also showed an increase of...

Leptin and Immune Function

Levels of this adipocyte-derived hormone are proportional to fat mass, but may be lowered rapidly by fasting. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. There is enough reported evidence to suggest a role for leptin in linking nutritional status to cognate cellular immune function, and to provide a molecular mechanism to account for the immune dysfunction observed in starvation 44 . The decrease in leptin plasma concentrations during food deprivation leads to impaired immune function, whereas the restoration of leptin to normal levels by feeding after starvation is sufficient to ameliorate the immune response and is followed by a significant increase in Th1 activity, supporting further the role of lep-tin as a nutritional sensor for the immune functions 45 . Therefore, leptin is the signal that connects the energy stores with the immune system, and may play a role in the immunosuppression of starvation. Leptin seems to...

Leptin and Central Regulation of Appetite

The hypothalamus is the major site of leptin action in energy homeostasis 54 . Fasting causes a rapid decrease in endogenous leptin level. It is this acute decrease in leptin that signals to the hypothalamus that energy stores may be compromised, resulting in an increase in NPY and agouti-related protein (AgRP) gene expression, which stimulates food intake. At the same time, leptin inhibits the firing of neurons co-expressing the catabolic neuropeptides a-melanocyte-stimulating hormone (a-MSH) (derived from proopiomelanocortin, POMC) and CART 37, 55 . The AgRP-NPY and POMC-CART neurons synapse on each other both project rostrally to second-order neurons in the hypothalamic paraventricular nucleus and caudally to other second-order hypothalamic and extra-hypothalamic sites that are involved in the autonomic and behavioural processes that regulate energy balance 56 . Leptin decreases melanin-concentrating hormone (MCH), galanin and orexin gene expression and increases galanin-like...

Assessment of Serum Levels of Proinflammatory Cytokines and Leptin

The absorbance of the sample was analysed by a spectrophotometer at 450 nm. Serum leptin levels were determined with an ELISA assay using a monoclonal antibody specific for human leptin. The absorbance was measured by a spectrophotometer at 450 10 nm. More details about the techniques are reported in our previous studies 28,29 .

Leptin and Congenital Leptin Deficiency

Congenital leptin deficiency due to mutations in the leptin gene or receptor is a rare, but treatable, cause of severe early-onset obesity and various endocrine disturbances in both rodents and humans 74, 75 . According to the lypostatic theory, a state of 'perceived starvation' might exist in these subjects and results in a chronic stimulation of excessive food intake 39 . Leptin therapy has shown to have dramatically beneficial effects on weight, fat mass and appetite, hyperinsulinaemia and lipid levels, as well as on neuroendocrine phe-notypes and immune functions in these subjects 76, 77 . Leptin treatment blunts the changes in circulating thyroid hormone and corticosterone levels that are normally associated with food deprivation. It has been suggested that the inhibition of thyroid hormone secretion may have evolved to limit energy expenditure and prevent protein catabolism during starvation 78 . The effect of leptin on circulating thyroid hormone can be explained at least in...

Plasma Leptin Concentration

Plasma leptin concentrations correlate with adiposity, being high in obesity and decreasing after weight loss. Elevation of serum leptin in obesity appears to result from both increased fat mass and increased leptin release from larger adipocytes 42 . However, leptin levels are not constant in blood. They are considered to be pulsatile, with a frequency of about one pulse every 45 min 32 . In healthy subjects, circulating leptin concentrations exhibit a diurnal pattern, with a nadir in the mid-morning and a late-night nocturnal peak 5, 43 . The diurnal leptin pattern is dependent on insulin responses to meals and is therefore influenced by meal timing 44 and dietary macronutrient composition 45 . Gender-dependent differences have been found. The distribution of fat in the body differs between the male and female sexes. Females have more body fat and higher plasma leptin levels per gram of fat. Moreover, the brains of male and female rats are differentially sensitive to the cata-bolic...

Leptin and Reward Behaviour

Collective findings are consistent and compelling for the possible role of adiposity signals in modulating reward behaviour. Leptin may act directly at the midbrain ventral tegmental area (VTA) and also indirectly via signalling at the medial hypothalamus, with subsequent activation of pathways that project to the limbic circuitry. It is possible that the efficacy of leptin at low concentrations, such as levels that reflect the switch from fasting to fed status, is predominantly in the VTA, altering the reward threshold. With post-prandial elevations of leptin, the recruitment of inputs via the medial hypothalamus and via the limbic system may be inhibited in a synergic manner, resulting in decreased appetite or ingestive behaviour. It is possible that palatability and hedonic attributes of food may lead to enhanced activation of motivation circuitry, temporarily overriding the effectiveness of the adiposity signals in the hypothalamus 38 . Some studies provide evidence that a...

Leptin and Anorexia in Ageing

Ageing appears to be associated with leptin resistance. It has been found that the relatively hyper-leptinaemic state of ageing animals blunts the sensitivity of the hypothalamic energy regulatory system, thus decreasing appetite even during episodes of negative energy balance. It has been found that age-associated decreased levels of orexigenic signalling through AgRP and NPY neurons in the arcuate nucleus of the hypothalamus are accompanied by increased levels of anorexi-genic signalling through POMC CART neurons. This pattern of neuropeptide gene expression may contribute to the loss of appetite and anorexia associated with ageing 56 .

Role of Leptin and Neuropeptides

Loss of body weight is a strong stimulus to food intake in humans. Therefore, the presence of CAC in patients with cancer suggests a failure of the adaptive feeding response. A large amount of evidence has been provided in the last few years on the regulation of feeding and body weight. Leptin, a recently found hormone produced by the adipocyte ob gene, has been shown to be an essential component of the homeostatic regulation of body weight. Leptin acts to control food intake and energy expenditure via a neuropeptidergic effect or molecules within the hypothalamus. Complex interactions take place among the nervous, endocrine and immune systems inducing behavioural and metabolic responses 38-44 . mic effect of excessive negative feedback signalling from leptin. This could be via continuous stimulation of anorexigenic neuropeptides such as serotonin- and corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network consisting of opioid peptides and...

Leptin

Leptin, from the Greek leptos, meaning thin, is a product of the obese gene that was originally identified because its absence resulted in a syndrome of severe obesity in mice 30 . It is a hormone that provides information to the brain about the status of energy reserves of the organism, regulating feeding, substrate utilisation, energy balance, and the endocrine and immune systems 31 . Moreover, independent of its role in body weight regulation, it exerts effects on metabolism, cardiovascular and renal functions 32 . Leptin is a 16-kDa protein predominantly produced and secreted by adipocytes in white adipose tissue. Gastrointestinal tract, brain, placenta and skeletal muscle are additional sources 33 . Leptin acts throughout the leptin receptor 34 , which is a type 1 cytokine receptor. It exerts its effects by activating the janus-kinase signal transducer and activator of transcription-3 (STAT-3) pathways 1 . Among the six known leptin receptor spliced variants, the long form or...

Cortisol By

This procedure is an automated heterogeneous enzyme immunoassay that utilizes radial partition for its separation phase. Serum Cortisol is freed from its binding proteins by the addition of a sulfonic acid reagent. For urinary free Cortisol levels, urine is extracted first to removed metabolites or conjugates that would cross-react with the antibody. Alkaline phosphatase-labeled cortisol is then added to compete with patient cortisol for specific antibody binding sites on a borosilicate paper matrix. A washing step elutes unbound substances radially (in a circular motion). After the addition of substrate, the enzyme-labeled bound cortisol forms measurable product with an inverse relationship between the amount of reaction and the amount of patient cortisol present in the reaction. Urine, 24-hr free cortisol 20-90 g day Serum, 0800 hr total cortisol 5-23 g dL 1600 hr total cortisol 3-16 g dL Underfunctioning of the adrenal cortex is a chronic progressive disease, commonly due to...

Leptin and Satiety

Satiety is a condition defined by a feeling of fullness and disappearance of appetite after a meal. In humans, leptin is not considered a primary satiety factor because changes in food intake do not induce short-term changes in blood leptin concentration 64 . On the other hand, leptin may play a permissive effect on satiety, by sufficiently inhibiting the central nervous system orexigenic neurons and allowing satiety signals from gut hormones and baroreceptors to affect eating behaviour 65 . Acting in the forebrain (for example in the arcuate nucleus of the hypothalamus), leptin controls meal size by modulating the hindbrain (for example the nucleus of solitary tract) response to satiety signals such as cholecystokinin (CCK) 66 . This mechanism explains how long-term signals operate to affect short-term signals 67 . A recent study has demonstrated that acute increases in central leptin levels may potently augment post-prandial satiety and influence body fluid homeostasis in rats 68 ....

Plasma Protein Andtissue Binding

Many natural substances circulate around the body partly free in plasma water and partly bound to plasma proteins these include Cortisol, thyroxine, iron, copper and, in hepatic or renal failure, byproducts of physiological intermediary metabolism. Drugs, too, circulate in the protein-bound and free states, and the significance is that the free fraction is pharmacologically active whereas the protein-bound component is a reservoir of drug that is inactive because of this binding. Free and bound fractions are in equilibrium and free drug removed from the plasma by metabolism, dialysis or excretion is replaced by drug released from the bound fraction.

Scientific Foundations

For example, when the body becomes stressed, the pituitary gland at the base of the brain releases ACTH (adenocorticotropic hormone), which triggers the production of cortisol in the adrenal cortex. Cortisol promotes the production of glucose (blood sugar) from nutrients in the liver, thus providing fuel for cells when the body is under stress. When the stressful situation ends, adrenal hormone production returns to normal. The adrenal glands usually produce about 20 milligrams of Cortisol per day, mostly in the morning, but they can produce five times that much when needed. The control of corticosteroid production from the adrenal glands has interested scientists for quite some time. A disease resulting from a lack of circulating corticosteroids was known as early as the mid-nineteenth century. This disease characterized by weakness, tiredness, and weight loss is now called Addison's disease. Since early in the twentieth century, it was known that too much cortisol leads to Cushing's...

Preanalytical Errors And Specimen Problems

Some preanalytical problems may or may not be controlled directly by laboratory personnel, but information about such problems should be made available to health-care providers. These problems include patient-related factors such as ambulation, lying down or standing prior to collection, and biological differences, such as time of day, age, gender, and intake of certain foods or herb supplements. Ambulation prior to specimen collection can impact upon total proteins, lipids, and other protein-bound substances. Levels of cortisol and many other hormones vary throughout the day, so collection needs to be timed according to physician orders

Consequences of Altered Glucose Metabolism Oxidative Stress

50, 53, 54 we have demonstrated that patients with cancer at advanced stage showed a condition of oxidative stress characterised by high blood levels of ROS and reduced erythrocyte GSH peroxidase and SOD activity. Antioxidant activity was significantly reduced in patients with the most advanced stage (IV) and compromised performance status (EGOG PS 2-3). Moreover, oxidative stress was associated with high levels of proin-flammatory cytokines IL-6 and TNF-a, and CRP, and low levels of leptin 51 . The inverse correlation between leptin levels and the parameters of oxidative stress (ROS) strongly suggests that lep-tin is a signal of negative energy balance and low energy reserves and that oxidative stress is a consequence of the metabolic derangements, particularly of glucose metabolism.

Clinical Approach

Cortisol levels has normal or abnormal anterior pituitary function (Table 17-1). Treatment of Sheehan's syndrome consists of replacement of hormones, such as thyroxine, Cortisol, and mineralocorticoid, and estrogen and progestin therapy. Intrauterine adhesions are treated by hysteroscopic resection of the scar tissue.

Serotonin and Nitric Oxide

Nitric oxide (NO) has also been recently proposed as a neuromodulator of the central pathways of appetite control. Central blockade of NO production inhibits food intake 62 . This condition is reversed by administration of NO donors (l-arginine) 7 . NO seems also to be involved in many central feedback systems, such as those of leptin and 5-HT 63 .

High Constitutive Signalling of the Ghrelin Receptor

The degree that the Holst in vitro data (vide infra) translate to in vivo results and the circumstances under which this occurs may significantly depend on whether leptin and or SRIF inhibit the high constitutive signalling activity of the ghrelin receptor in vivo. If these two hormones are inhibitory this would be an additional mechanism for explaining how the ghrelin system is activated during starvation and GH secretion and food intake are increased. Neuroendocrine and neuroanatomical mechanistic studies evolving from the decreased action of ghrelin on the NPY AgRP hypothalamic arcuate neurons caused by leptin are considered of special relevance. When leptin was administered to lep-tin-deficient mice during critical periods of early development, Bouret et al. observed that the hypo-thalamic arcuate nucleus architecture was altered 26 . This again appears to be an example of hormonal hypothalamic imprinting on the developing brain that possibly results from the neonate surge of...

Tumour Necrosis Factor

TNF-a is a 17-kDa peptide that is largely produced by the monocyte macrophage cell line. Other cells, including T-cells, NK cells, mast cells, and adipocytes, also produce this cytokine. Production of TNF-a is synergistically regulated by other cytokines,such as IL-1 and IFN-y 39 , and TNF-a in turn stimulates leptin and IL-6 production 1 . Studies have shown that injecting rats with recombinant human TNF-a led to significant depletion of body protein. It was also demonstrated that injection of TNF-a directly into the cerebral ventricles of rats suppressed food and water intake, while peripheral administration of an equal or higher dose had no such effect 39 . While TNF-a failed to produce a sustained weight loss, the net metabolic alterations exerted by the cytokine may

Role of the Central Melanocortin System in Cachexia

Some studies have led to the assumption that melanocortin neurons mediate the anorexic effects of elevated leptin, while others have shown that the melanocortin system exerts its effects independent of leptin 81 . POMC neurons mediate the inhibition of food intake and energy storage through the production of a-melanocyte-stimulating hormone (MSH) from a POMC precursor 81 . Central administration of MC4-R agonist can lead to inhibition of food intake, increasing energy expenditure, lower serum insulin, and reduced body weight 81 , whereas inhibition of the melanocortin system with an antagonist, or deletion of MC4-R, leads to hyper-phagia and obesity 82,83 .

Causes Of Hyponatremia

The free water excretion is impaired (urine not maximally concentrated, 150-200 mOsm kg). If the urine is maximally dilute, it is handling free water normally but its capacity for excretion has been overwhelmed, as in central polydipsia. More commonly, free water excretion is impaired and the urine is not maximally dilute as it should be. Two important diagnoses must be considered at this point hypothyroidism and adrenal insufficiency. Thyroid hormone and Cortisol both are permissive for free water excretion, so their deficiency causes water retention. Isolated Cortisol deficiency can mimic SIADH. In contrast, patients with Addison disease also lack aldosterone, so they have impaired ability to retain sodium. Patients with adrenal insufficiency are usually hypovolemic and often present in shock.

Regulation of Appetite in the Elderly

Adaptive Relaxation Stomach

The hormone leptin is released from adipose tissue 18 and exerts its effects by decreasing food intake and increasing the metabolic rate. Circulating leptin levels increase in older men and decrease in older women 19 . The increase in lep-tin levels in men is related to the decrease in testosterone that occurs with aging 1 , which, in turn, is associated with muscle loss 20 and an increase in body fat 21 . Testosterone replacement in older men leads to a decline in leptin levels 1 . The increase in leptin with aging in men is considered a major factor in the increased anorexia of aging that occurs in males compared to females.

Magnetic Resonance Imaging MRI and spectroscopy

Computed Tomography Fatty Liver

Figure 13.3 Assessment of Abdominal Fat Storage by Computed Tomography (CT) Representative cross-sectional abdominal CT scans of a lean (A) and an obese (B) research volunteer, demonstrating the fat muscle CT contrast shown with demarcations of visceral (large arrowheads), deep subcutaneous (open arrows) and superficial subcutaneous (closed arrows) adipose tissue (AT) depots. The fascia (small arrowhead) within subcutaneous abdominal AT was used to distinguish superficial from deep depot. In the two CT scans shown, the area of superficial subcutaneous AT was similar (144 vs 141 cm2), whereas areas of deep subcutaneous (126 vs 273 cm2) and visceral (84 vs 153 cm2) AT were quite different. Insulin-stimulated glucose metabolism was 6.1 and 4.0 mg min-1 kg FFM-1 in lean and obese volunteers, respectively (FFM fat-free mass). Reproduced from Kelley D E et al. (2000) Am J Physiol Endocrinol Metab 278 (5) E941-E948. Courtesy of the American Physiological Society. Figure 13.3 Assessment of...

Studies of Neurotransmitter Function

Other transmitter-related findings in bipolar depression include increased sensitivity to acetylcholine (Sitaram et al. 1982) and reduced Y-aminobutyric acid (GABA) in body fluids (Brambilla et al. 2003 Petty et al. 1993). Cerebrospinal fluid (CSF) GABA levels in euthymic subjects with bipolar disorder were the same as those in control subjects (Berret-tini et al. 1982, 1986) therefore, low GABA levels may be a characteristic of depressive episodes in general. There is also a complex array of endocrine findings, most involving the hypothalamic-pituitary-adreno-cortical axis (HPA). Reported HPA abnormalities include increased cortisol excretion with reduced sensitivity to negative feedback regulation, resulting in an increased incidence of dexamethasone nonsup-pression in both bipolar and nonbipolar depressions (Stokes et al. 1984). Despite original suggestions that HPA dysfunction was related to a specific type of treatment-responsive depressive episode, there are no reliable or...

Role of Ghrelin in Cachexia

Many aspects of appetite regulation that involve peripheral signalling to hypothalamic pathways remain poorly understood. Growth hormone (GH) secretion from the anterior pituitary is regulated by GH-releasing hormone (GHRH), which stimulates the release of GH as well as its inhibitor somatostatin 76 . GH secretagogues are synthetic compounds able to stimulate secretion of the hormone 77 but which act through a receptor different from that for GHRH receptor. Instead, ghrelin was discovered to be the natural ligand for that receptor. Ghrelin is mainly secreted by gastric endocrine cells in the fundus into the systemic circulation 78 . Fasting increases, while feeding decreases circulating ghrelin concentrations 78 . These changes are negatively correlated with the serum concentrations of leptin and insulin.

Disorders with Hypokalemia and a Normal or High ECF Volume

Treatment For Hyperkalemia

B) Those with low mineralocorticoid action 5. An epithelial ENaC in the luminal membrane which is permanently in an open conformation due to a mutation (Liddle's syndrome). 6. Blocking the destruction of cortisol in principal cells by creating a relatively low activity of 11 p-HSDH (e.g. licorice). 7. Insertion of an artificial Na+ channel in the luminal membrane of the CCD (e.g. amphotericin B). B) Those with low mineralocorticoid action 5. An epithelial ENaC in the luminal membrane which is permanently in an open conformation due to a mutation (Liddle's syndrome). 6. Blocking the destruction of cortisol in principal cells by creating a relatively low activity of 11 p-HSDH (e.g. licorice). 7. Insertion of an artificial Na+ channel in the luminal membrane of the CCD (e.g. amphotericin B). - Pathophysiology GRA is a rare form of adrenal hyperplasia in which aldosterone secretion is regulated exclusively by ACTH 72 . There is also marked overproduction of C-18 oxidation products of...

Physiological Effects Of Glucocortioids

Of the naturally occurring steroids only cortisol, corticosterone, cortisone, and 11-dehydrocorticosterone have appreciable glucocorticoid activity. Cortisol, which is found in the highest concentration, accounts for most of this activity. About 75 of plasma cortisol is bound to cortisol binding globulin (CBG, an alpha globulin), 15 is bound to plasma albumin, and 10 is unbound (free), representing the physiologically active portion. CBG also has a high binding affinity for progesterone, deoxycorticosterone, and some synthetic analogs. Large doses of cortisol have been shown to antagonize the effect of active vitamin D metabolites on the absorption of Ca2+ from the gut, inhibit mitosis of fibroblasts, and cause degradation of collagen. All of these effects can lead to osteoporosis, which is a reduction in bone mass per unit volume. Glucocorticoids can also delay wound healing because of the reduction of fibroblast proliferation. Connective tissue is reduced in quality and strength. In...

Licorice Glycyrrhizin

One trial (20), which evaluated a glycyrrhizin-based compound against other herbs, included 193 hepatitis C patients, followed prospectively for 2-16 yr for evidence of progression to cirrhosis or the development of hepatocellular carcinoma. Although glycyrrhizin appeared to slow the histological progression of the disease, both groups appeared to progress to carcinoma more frequently than in similar patients treated with IFN. Side effects attributed to glycyrrhizin included hypokalemia in 11 and hypertension (HT) in 3.6 . In a single randomized control study of iv glycyrrhizin vs placebo, among 58 IFN nonresponders or patients unlikely to respond (cirrhotic patients with genotype 1), the herb resulted in lower ALT, with no effect on HCV RNA levels (21). The adverse effects of glycyrrhizin in humans are well-characterized. Glycyrrhizin inhibits 11- -hydroxysteroid hydrogenase in the kidney, inhibiting the conversion of cortisol to cortisone. This results in a...

StomatinMEC2 band 7 homologue

The third member of the gene family consists of an 80-kDa precursor cloned originally as 17 -hydroxysteroid dehydrogenase type IV (17 -HSD4). This precursor comprises a C-terminal domain similar to SCP-2 34 , which is fused to a peptide with acyl-CoA 2-enoyl hydratase 3-hydroxyacyl-CoA dehydrogenase activity (also known as peroxisomal bifunctional enzyme, PBE) 35 . Processing occurs after import of the 80-kDa precursor into peroxisomes at the junction between the acyl-CoA 2-enoyl hydratase and 3-hydroxyacyl-CoA dehydrogenase domains 36 . The SCP-2-like domain is required for import of the 80-kDa precursor into peroxi-somes and confers a similar intrinsic lipid transfer activity to the fusion protein as was demonstrated for SCP-x 37 .

Neurohormonal Abnormalities

Increased Afterload Heart Graphics

The hormone cortisol is also considered to be part of the general stress response and exerts a catabolic effect. Increased cortisol was demonstrated in untreated patients with severe CHF (Fig. 2) 49 , which was probably due to an elevated release of adrenocorticotropic hormone 50 . This catabolic anabolic imbalance was confirmed by a study in which the anabolic steroid dehy-droepiandrosterone was lowest in cachectic CHF patients and cortisol levels were particularly increased in cachectic CHF patients 26 . The protein leptin is involved in the regulation of food intake and energy balance 51 , and it serves as an important signal from fat to brain. Raised levels of leptin can decrease food intake and increase resting energy expenditure 52 . The role of leptin in the development of cardiac cachexia has not yet been elucidated, but it was reported that plasma leptin levels are increased in CHF 53 and higher leptin levels are associated with increased sympathetic activity 52 . However,...

Galanin and Galanin Like Peptide

In neurons also expressing leptin receptor 51 . Both galanin and galanin receptor have also been demonstrated in adipose tissue in rats 53 . The intracerebroventricular administration of galanin induces food intake 54 . This effect has been suggested to be mediated by modulation of leptin expression and levels 51, 54 . Some studies affirm that galanin increases, in particular, fat ingestion 55 . Galanin administration inhibits leptin levels and its expression in adipose tissue increases during fasting 53 . However, the chronic administration of galanin does not induce hyperphagic behaviour or weight gain 56 , in agreement with the observation that galanin knockout mice or galanin over-expressing mice maintain normal weight 51 . In all, this peptide seems to be much more involved in the short-term regulation of feeding rather than in long-term metabolic balance 51,54 . Similarly to POMC and unlike galanin, the central expression of GALP is negatively regulated by fasting and is reduced...

Congenital Adrenal Hyperplasia

Hydroxyprogesterone

Congenital adrenal hyperplasia (CAH) also known as the adrenogenital syndrome can be considered as a family of inborn error of steroidogensis (see Fig. 1). All CAH variants are inherited as autosomal recessive traits. Each member of this family is characterized by a specific enzyme deficiency that impacts cortisol production by the adrenal cortex, and if severe enough can lead to sexual ambiguity in both males and females. The enzymes usually affected are 21-hydroxylase (types I and II), beta hydroxylase (type III), 3 beta-hydroxylase (type IV), 17 hydroxylase (type V) and cholesterol 20-alpha hydroxylase (type VI). The most common syndromes are types I and II, which are caused by a 21-hydroxylase enzyme deficiency. The identification of the specific enzyme deficiency relies heavily on laboratory findings since all variants affect the glucocorticoid (cortisol) pathway in some manner. Although formation of cortisone and cortisol are blocked in type I and II CAH, precursors are still...

Evidence for Autonomic Nervous System Dysfunction

Increased sympathetic activity has been demonstrated in patients with IBS. Heitkemper et al. studied urinary catecholamine (NE and epinephrine) and cortisol levels in women diagnosed with IBS against women who reported similar symptoms but did not seek health care services and asymptomatic control women (122). Women with IBS had significantly higher urinary levels of all of these neuroendocrine indicators of arousal suggesting heightened sympathetic nervous system activation. Whether greater symptom distress in the IBS women resulted in increased sympathetic activation and health care seeking or the higher sympathetic activation increased pain perception leading to health care seeking is unclear. These investigators later demonstrated significantly lower parasympathetic tone and higher ANS balance in constipation-predominant compared to diarrhea-predominant subgroups of IBS but only when symptom severity scores were high. No difference was seen between IBS and control women, and...

Cinnamon And Mydriasis

One of the side effects of adrenocorticotropic hormone (ACTH) and corticoid therapy in humans is the development or reactivation of gastroduodenal ulcers. Daily subcutaneous administration of Cortisol or Ax-cortisol to rats for 4 days results in the regular development of gastric ulcers (38). This procedure has been adapted to testing antiulcer activity (39). There are certain differences between steroid ulcers and natural ulcers in localization, rate of development, and severity (40).

Adipokines Is Adipose Tissue an Endocrine Organ

Adipose Tisue Asan Endocrine Organe

The adipocyte as an endocrine organ. Recent work suggests that adipose tissue behaves as a true endocrine organ, releasing many active compounds involved in maintaining the homeostatic response and energy balance. These compounds include cytokines, such as TNF and IL-6 leptin (involved in food intake and thermogenesis) acute-phase reac-tants, such as CRP resistin (involved in insulin resistance) ASP (involved in lipid synthesis), Acrp30 (probably involved in adipocyte differentiation) and PAI-1 (a haemostatic factor) Fig. 2. The adipocyte as an endocrine organ. Recent work suggests that adipose tissue behaves as a true endocrine organ, releasing many active compounds involved in maintaining the homeostatic response and energy balance. These compounds include cytokines, such as TNF and IL-6 leptin (involved in food intake and thermogenesis) acute-phase reac-tants, such as CRP resistin (involved in insulin resistance) ASP (involved in lipid synthesis), Acrp30 (probably involved...

And Frontal Brain Asymmetries

Ferrin Metabolism

In this study, relationships between approach and avoidance temperaments, patterns of anterior brain asymmetry, situational strategies to regulate negative emotion (suppression and reappraisal), and the outcomes of these strategies on emotion processes were examined. Emotional responses to a situational stressor were measured via self-report, facial affect coding, and salivary cortisol. Individuals characterized by approach temperament used reappraisal more advantageously than they did suppression. Reappraisal instructions were effective in reducing the degree of emotional responding in the self-report, behavioral, and physiological domains. Individuals characterized by avoidance temperament, in contrast, were more adept at using suppression to achieve the same results. A comparison of estimated marginal means revealed that the suppression technique facilitated approximately the same magnitude of emotion regulation for avoidance-biased individuals as the...

Endocrine Glands Involved In Reproduction

The hypothalamus is derived from neuroendocrine tissue in the mesencephalon, or middle section of the brain. It provides the tertiary level of control and stimulation of hormone secretion. The hypothalamus makes releasing hormones such as thyroid-releasing hormone (TRH) and Gn-RH, both peptide in nature. The primary function of these hormones is to stimulate pituitary secretion of secondary hormones such as LH and FSH. However, these hormones also respond to other hormones in a positive and negative feedback system such that a highly coordinated monthly cycle occurs in the mature female. There is a similar coordinated cycle in the mature male that spans a 24-hour cycle. Other hypothalamic hormones that play a role in sexual development and reproduction include TRH and cortisol-releasing hormone (CRH), which have the ability to stimulate secondary endocrine glands.4

Proinflammatory Cytokines

IL-6 is the most frequently detected cytokine in patients with acute infection, injury, cancer and after surgical procedures 13 . The biological actions of this protein include regulation of acute-phase protein synthesis 29, 30 and differentiation of lymphocytes 31 . It also induces fever via prostaglandin production 13 . Administration of IL-6 to humans increases energy expenditure, fatty acid and ketone production, fat oxidation, glucose production, lactate production and glucose oxidation 32 . Such effects account for many of the manifestations of inflammatory stress, implicating IL-6 as the direct cause of them, perhaps the mediator of some of the effects of TNF-a, which secondarily stimulates IL-6 production. IL-6 in turn stimulates production of cate-cholamines, glucagon and cortisol, which may mediate some or all of the effects of IL-6. Interestingly, IL-6 levels also increase during exercise, another circumstance besides injury in which nutrient mobilisation is essential, and...

Lipodystrophic Syndrome

Recently, Oral et al. 36 reported that treatment with recombinant leptin was safe and effective in the treatment of lipodystrophy. Fasting blood glucose and glycosylated haemoglobin values decreased markedly after 4 months of therapy in the eight patients with diabetes, and serum triglyceride levels declined in all nine with lipodystrophies. Leptin therapy appeared to reduce hepatic steatosis, decrease intramyocellular lipid contents, and improve insulin sensitivity 37,38 .

Orienting and Defensive Reflexes

Hypac Hormonal Axis

The hypothalamic-pituitary-adrenocortical (HYPAC) axis is a hormonal pathway for stress. The RLAs show increased corticotropin-releasing factor from the hypothalamus, which results in increased adrenocorticotropic hormone from the pituitary gland. The end result of this pathway would be increased release of cortisol from the adrenal cortex. The RHAs are less responsive in the HYPAC stress reactive pathway.

Protein Energy Malnutrition

Recently, leptin has been considered one of the main markers of nutritional status. Leptin is a cytokine-type peptide hormone that is produced mainly by adipocytes it decreases appetite and increases energy expenditure 63 . The effect of liver disease on leptin status is a controversial issue, although some studies have shown that serum leptin increases in cirrhosis of alcoholic aetiology 64, 65 . Currently, a high serum leptin concentration in cirrhotic patients is thought to result from the increased protein-bound fraction, which is directly related to energy expenditure 66 . Since ghrelin, which is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor, competes with leptin, it was also investigated in cirrhotic patients 67 . Tacke et al. reported that ghrelin increased in liver cirrhosis independent of its aetiology however, the precise mechanisms remain unclear 68 . Ghrelin might increase to counteract metabolic decompensation in liver cirrhosis by its...

Ectopic ACTH Syndrome

A wide range of tumors has been described to produce biologically active ACTH. Many studies have shown that the molecular mechanism of this syndrome is due mainly to a precursor of the ACTH molecule which is proopiomelanocortin (POMC) and is a 31 kD glycoprotein. These precursor molecules, which are produced normally by the normal cells, are produced by some tumors in greater concentrations. Some tumors convert these precursors to biologically active ACTH, thus causing this paraneoplastic syndrome 4 , The ectopic ACTH syndrome differs from the classical Cushing's disease by several markers (1) serum and urine Cortisol concentrations are usually markedly increased (2) plasma ACTH and POMC levels are usually markedly increased and the ratio of POMC to ACTH concentration is high (3) Hypokalemia is common and (4) Dexamethasone does not suppress ACTH and Cortisol levels.

Examining Pathways Between Pubertal Effects and Adjustment in Girls

A series of regression models were run to examine the potential mediated pathways from either hormonal levels or pubertal timing to depressive affect or aggression, controlling for age. Despite the hypothesis that estradiol would lead to emotional arousal which would lead to depression, there was no support for this pathway in the analyses. However, as seen in Figure 16.6, the effect of pubertal timing on depressive affect was mediated by emotional arousal. The fact that emotional arousal did not explain the estradiol effect on depressive affect as expected warranted further exploration. Because links between adrenal response (e.g., cortisol response) and psychosocial stress have been extensively noted, DHEAS levels (another indicator of adrenal response) were examined in association with early maturation. The interaction between hormonal arousal (the upper third of the distribution of DHEAS considered high hormonal arousal) and timing (early versus other) was predictive of depressive...

Proinflammatory Cytokines and Anorexia

A third potentially important cause of CACS may be the abnormal functioning of neuropep-tides, leptin, ghrelin, and or their reciprocal inter actions. Body weight loss is a strong stimulus of food intake in humans. Therefore, the presence of CACS in patients with cancer suggests a failure of the adaptive feeding response. A large amount of evidence has accumulated in the last few years on the regulation of feeding and body weight. Leptin, a recently discovered hormone produced by the adipocyte ob gene, is an essential component of the homeostatic regulation of body weight. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions take place among the nervous, endocrine, and immune systems inducing behavioural and metabolic responses. Proinflammatory cytokines, proposed as mediators of CACS, may have a central role in the long-term inhibition of feeding by mimicking the hypo-thalamic effect of...

Modulation of Pain by the Hypothalamic PituitaryAdrenal Axis

Mast Cell Crh Stress

The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hypophyseal portal blood supply. It contains vital centers for functions including appetite, thirst, thermal regulation, and the sleep cycle, and acts as an integrator of many neuroendocrine inputs to control the release of pituitary hormone-releasing factors. Amongst other important influences, it plays a role in the circadian rhythm, menstrual cycle, and responses to stress, exercise, and mood. The pituitary gland is located in the sella turcica at the base of the brain and is around 1 cm in diameter and between 0.5 and 1 g in weight. CRH produced in the hypothalamus induces the release of adrenocorticotropin (ACTH) from specialized cells in the anterior pituitary. This in turn stimulates the release of cortisol from cells in the zona fasciculata and reticularis of the adrenal glands. Figure 4 (See color insert) The...

Physiology of K Homeostasis

Insulin Shift Hyperkalemia

Even though the concentration of glucocorticoids is much higher than aldosterone in blood and both have an equal affinity for the mineralocorticoid receptor, glucocorticoids do not usually stimulate K+ secretion in the CCD. The reason for this lack of effect of glucocorticoids is that principal cells have a pair of enzymes called 11 P-hydroxysteroid dehydrogenase (11 P-HSDH) that converts cortisol to an inactive metabolite (cortisone) that does not bind the mineralocorticoid receptor (Figure 6) 29 . This pair of enzymes acts in concert. First, a low-affinity, high-capacity enzyme destroys most of the cortisol. Second, a high-affinity, low-capacity enzyme removes the remaining cortisol so that there is now an insufficient amount of this hormone Figure 6. Influence of 11 P-hydroxysteroid dehydrogenase on aldosterone-like actions in the CCD. Cortisol has a very high affinity to the aldosterone receptor. As Cortisol enters principal cells of the CCD, the pair of enzymes 11 P-HSDH (shown...

Causes of Cachexia in Elderly Individuals

Compounding the effects of sarcopenia in many elderly individuals are disease states or acute illnesses that can lead to accelerated muscle mass loss and a state of cachexia. Acute illness appears to result in the loss of weight and muscle mass very rapidly whereas cachexia caused by chronic disease is a much slower process (unpublished observations). Among the chronic illnesses causing cachexia are chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cancer. The causes of cachexia in CHF appear to be elevations in TNF-a, IL-6, norepinephrine, epi-nephrine, and cortisol. Furthermore, anabolic stimuli, such as IGF-1 and DHEA, are reduced in CHF patients 66 . A potential causative factor in these humoral changes is tissue hypoxia 66 . In non-obese CHF patients, inadequate energy and protein intake are observed 67 . A common finding of COPD is an increase in resting energy

Alphaglucosidase inhibitor blocks hydrolysis of an

Than the primary tumor of the same cell line metyrapone - metabolic hormone that inhibits biosynthesis of cortisol and corticosterone and is used to test for normal functioning of the pituitary gland also known as metapyrone micelle - ultramicroscopic particle microalbuminuria - small amounts of albumin found in the urine, also called dipstick-negative increase in the excretion of albumin in urine microcytic - of smaller than normal size (red blood cells)

Physiological Regulation

Brown Adipose Tissue And Thermogenesis

P-Adrenergic receptors (pARS) transmit the thermogenetic signal to peripheral target tissue (brown fat, and possibly muscle and other tissues) and play an important role in diet-induced ther-mogenesis and therefore also in prevention of diet-induced obesity. Various components of the energy balance system in the brain have been identified and include the leptin receptor, melanocyte stimulating hormone (MSH), the melanocortin-4 receptor (MC4 receptor), neuropeptide Y (NPY), and agouti-related protein (AgRP) (Fig. 2) 6 . Alterations in DIT may be of great importance in controlling body weight and in promoting obesity, as indicated by the fact that most animal models of obesity (ob ob, db db and MC-4 receptor gene knock-out mice) have defects in adaptive thermogenesis.

Impaired Insulin Action Insulin Resistance

Candidate Genes Indeed, in some cases, the specific cause for the impaired insulin action is known. The insulin receptor (IR), a ligand-stimulated tyrosine kinase, mediates the first step in insulin action. Consequently, the IR gene has been considered as the primary candidate gene contributing to insulin resistance in T2DM 39 . Another strong candidate gene for association with T2DM is the insulin receptor substrate (IRS), which is phosphorylated by the activated receptor. IRS phosphorylation leads to activation of multiple downstream signaling pathways and finally culminates in the translocation of glucose transporters to the cell membrane and in the stimulation of glycogen synthesis. It has to be said that this complex signaling pathway is still far from being completely understood 40 . Four IRS isoforms are currently known. The prevalence of mutations in IRS-1 was found to be higher in T2DM patients than in control subjects. Interestingly, disruption of IRS-2 in mice impaired both...

Contributions To Neuronal Atrophy And Cell Death

It is not clear whether healthy aging in humans is accompanied by neuron loss, nor is it clear whether high levels of cortisol in humans could lead to cell death. In the few studies to quantify hippocampal neuron numbers in postmortem human brains, the number of hippocampal neurons decreased with age in area CA1, the dentate gyrus, and the subiculum 131, 132 . Using MRI techniques to estimate volumetric changes in brain structures, volumetric loss in healthy subjects is particularly pronounced in various cortical regions, including frontal and parietal cortices, but there appears to be little volumetric loss in subcortical areas such as hippocampus, thalamus, and the amygdala 134 . Young and middle-aged humans with elevated cortisol due to Cushing's syndrome exhibit loss of hippocampal volume 134 however, this effect is reversed when treatment is given to normalize corticosterone levels 135 . Although volumetric loss in human cases could be accounted for by cell death, the simple...

Physiological Control of Ghrelin Secretion

Notably, although playing a functional complementary role in the regulation of appetite at the hypothalamic level, leptin has been shown to be devoid of any modulatory effect on ghrelin secretion 28 . In both anorexia and obesity, ghrelin secretion is normalised by recovery of ideal body weight 18,34,35 . These changes are opposite to those of leptin, suggesting that both ghrelin and leptin are hormones signalling the metabolic balance and managing the neuroendocrine and metabolic response to starvation 3,35,36 .

Stress And Glucocorticoid Effects On Learning And Memory

Studies in humans also support a link between high circulating GC levels and poor learning and memory, although these impairments are not specific to hippo-campal function. However, two studies in nonhuman primates have indicated that GC receptors are expressed in the frontal and prefrontal cortices at levels similar to or greater than the hippocampus 10, 68 , predicting that GC effects on memory may not be greatest in hippocampus-dependent tasks in the primate. Injection of synthetic cortisol in young adults during the peak (highest level) or trough (lowest level) of the diurnal rhythm of endogenous secretion produced an impairment or facilitation of memory, depending on the time of injection 68 . That is, at the highest levels (the combination of both exogenous and endogenous GCs), acutely elevated GCs impaired performance, while at the lowest levels, performance improved. Repeated injections of synthetic cortisol over ten days in healthy, young adult humans have been shown to...

Genomewide Analysis To Identify Hypertensionrelated Genes

Encoding the ACE locus, a much-studied candidate gene for hypertension. The final locus that has not been previously implicated in BP variation is on chromosome 18. An interesting candidate gene in the chromosome 18 interval is the melanocortin receptor 2, which is the physiological receptor for corticotropin. Given the known effects of glucocorticoids on BP, it is of interest that receptors involved in the regulation of cortisol secretion lie in both the chromosome 17 and chromosome 18 intervals.

Diseases Of The Adrenal Cortex

When the cortex region of the adrenal gland is overfunctioning, it is often due to a secreting adenoma, a benign hormone-secreting tumor. Primary hypercorti-solism is the name of this disorder because the disease resides in the primary organ of this endocrine structure, the adrenal cortex. It is associated with increased levels of cortisol throughout the day, loss of diurnal variation, and decreased levels of ACTH. ACTH is low due to the negative feedback response of the pituitary gland, which is functioning normally in primary hypercortisolism. Hypercortisolism in the adult is characterized by hyperglycemia and changes in fat and water distribution. Other characteristics include bruising and poor wound healing, weight gain, weakening of bones, and depression. The weight gain tends to be located in the middle of the body with accompanying muscle wasting, known as truncal obesity. Fat accumulation on the upper shoulders and collar bone causes a hump on the upper back and jutting...

Acquired Generalised Lipodystrophy Lipoatrophic Diabetes or Lawrence Syndrome

Lipo Dostrophy Images

Syndrome and dermatomyositis, have been reported in association with AGLD, suggesting an immunomediated fat loss as a possible pathogenetic basis 3 . Panniculitis, characterised by a granulomatous infiltration of adipose tissue, may be an early manifestation of the disease 5 . Acute viral infections often precede AGLD onset. A higher frequency than casually expected of astrocy-tomas of the third ventricle have been reported. Low levels of leptin and adiponectin have also been described in these patients 6 .

Clinical Correlation

Other hormones also affect carbohydrate metabolism. Epinephrine, a hormone that is released by the adrenal medulla at times of stress, inhibits insulin secretion and stimulates glycogenolysis and lipolysis. Glucocorticoids, such as cortisol, are released from the adrenal cortex to reduce blood glucose concentration by inhibiting gluconeogenesis the absorption of dietary glucose. Thyroxine, a thyroid hormone, increases glycogenolysis and gluconeogenesis and inhibits absorption of dietary glucose through the intestine.

Role of Bone Tissue in Osteoarthritis Progression or Initiation

Osteoblasts, the result of upregulation of a1 chains. There was no change in the a2 chains. Together with the reduced number of crosslinks in OA bone tissue 144 , this could explain the reduction in bone mineralization. In vivo, the increase in bone collagen may have induced the MSCs to differentiate into osteoblasts. Indeed, OA patients exhibit enhanced maturation of osteoblasts from bone marrow stromal cells, while adipocytes and chondrocytes mature more slowly 168 . Of note, leptin stimulates the differentiation of mesenchymal cells into osteoblasts while impeding adipocyte maturation 227 . Leptin also stimulates production of osteoblast and collagen biomarkers 85 .

Investigating the pathogenesis of problematic hypoglycaemia

Pathogenesis Nsclc

For comparative studies, subjects should be age and gender matched, as there are important differences in counterregulatory responses between sexes and age groups (Matyka et al. 1997 Davis et al. 2000). Mixing genders and ages will at the very least increase the variance of the measures made and may obscure differences resulting from other factors. If groups are of mixed gender in a cross sectional study, the gender distribution must be matched. Vigorous exercise and caffeine should be avoided prior to the study as they can also affect counterregulatory responses (Debrah et al. 1996 Sandoval et al. 2006). Subjects should be studied in the same position (lying or standing) as there is a greater perception of hypoglycaemic symptoms in the standing position than in the lying position (Hirsch et al. 1991). It is usual to study subjects in the fasting or post-absorptive state. This allows a steady-state baseline. In the fed state, symptoms of hypoglycaemia are decreased, but...

Opioid Peptides Cannabinoids and Cocaine and Amphetamine Regulated Transcript

Central leptin administration is followed by a decrease in hypothalamic endocannabinoid levels 41-43 . Moreover, the blockade of CB1 receptor inhibits starvation-induced hyperphagia in rodents 43 . Cocaine- and amphetamine-regulated transcript is co-expressed in ARC in POMC neurons 3,44 , and is directly modulated by leptin 44 . It is also expressed in PVN, NTS, lateral and dorso-medial hypothalamus and nucleus accumbens 45 . At the peripheral level, CART is expressed in the myenteric gut plexus, vagus nerve, pancreatic somatostatin cells, and antral gastrin cells 45 . Until now, no specific receptors for CART have been identified 45 , thus a full description of the activities of this peptide is still lacking. The intracerebroventricular injection of CART is followed by reduction in food intake 45, 46 , even in co-administration with NPY 46 , coupled with a decrease in plasma insulin and leptin and an increase in lipid oxidation 47 . However, other experimental models showed that...

Ghb With Synthetic Glycogen For Cancerous Cells

In aldosterone synthetic pathway, 387f in cortisol synthetic pathway, 380f 11-Deoxycortisol, in cortisol synthetic pathway, 379, 380f, 381 Deoxyhemoglobin, 317-318, 320 Deoxyribonucleic acid. See DNA (deoxyri- for catecholamine metabolites, 398 for cortisol, 383 for drugs of abuse, 530 for glycated hemoglobin, 163 for thyroid function, 404-405 Enzyme immunometric assay, for human breast cancer, 488, 490 Flasks, 87-88, 88f Flatulence, 358 Fluorescence in fluorometry, 112-113, 113f of porphyrins, 195-197 Fluorescence polarization immunoassay (FPIA), 136 for acetaminophen, 517 for antibiotics, 509 for catecholamine metabolites, 398 for cortisol, 383 for thyroxine, 406 Fluorescent in situ hybridization (FISH), for immunoassay (FPIA) Fraction of inspired oxygen (Fio2), 309-310 Fraction of oxyhemoglobin, 317-318 Fractional excretion of sodium (FE ), 214 Framingham cardiac risk study, 26 Free cortisol, measurement of, 422t Free thyroxine (T4), 404, 408, 421t Free triiodothyronine (T3), 422t...

Functional Anatomy of White Adipose Tissue

The alteration - detected on chromosome 6 -consisted of a C to T point mutation at codon 105, turning it into a stop codon and interrupting the synthesis of a 167 amino acid secretion protein, which was named leptin from the Greek leptos (thin) 8 . The mouse gene appears to be expressed solely in WAT and is 84 homologous to the human gene. Within a few months, three groups demonstrated independently that leptin administration to obese mice corrected in a few weeks all the defects related to its absence, and that treated mice were then no longer distinguishable from lean controls 10-12 . The leptin receptor was discovered in 1995 13 . Demonstration of at least five alternatively spliced forms 14 , and reports that the functional form (i.e. the one activating intracellular signalling) appears to be prevalently expressed at the hypothalamic level and is mutated in mice phenotypically very similar to ob ob mice (except for a proneness to develop diabetes, hence called db db) 14,15 ,came...

Effects of Current Therapy of Chronic Viral Hepatitis on Drug Metabolism

In a recent study, Pageaux et al. (23) studied the effects of IFN-a on in vivo caffeine metabolism (as a measure of CYP1A2 activity) and in vivo cortisol metabolism (as a measure of CYP3A activity) in patients with CHC. They found no significant changes in either of these activities, and concluded that drugs that are metabolized by these isoenzymes can be used together with IFN-a, without a significant risk of adverse drug interactions.

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

Whole Body Skeletal Muscle

The first part was shown to be true in the case of a three days (Bachmann et al. 2001) high fat diet and intravenous intralipid heparin infusion induced peripheral insulin resistance (Bachmann et al. 2001 Boden et al. 2001). Researchers could observe a parallel increase of IMCL content, relatively more pronounced in the tibialis anterior muscle of young healthy humans (Bachmann et al. 2001 Boden et al. 2001). Similar results, accompanied by molecular adaptations favouring fat storage in muscle, were found in another study after one week of high fat diet (Schrauwen-Hinderling et al. 2005). Inducing insulin resistance by i.v. amino acid infusion during euglycaemic-hyperinsulinaemia (Krebs et al. 2001) was met by a subtle increase of IMCL content in soleus muscle. IMCL content decreased with increasing insulin sensitivity due to 8-10 months of leptin replacement in patients generalised lipodystrophy (Simha et al. 2003) and 6 months of caloric restriction with or without exercise in an...

Psychobiological Functioning Of Girls At Risk For Depression

The research that we have reviewed thus far indicates that, with few exceptions, depressed adults are characterized by negative biases in attention and memory functioning by dysregulated HPA axis functioning, as reflected by elevated levels of cortisol secretion and by abnormalities in both the structure and function of the hippocampus, ACC, and amygdala. There is also a smaller (and less consistent) literature indicating that depressed children may share a subset of these same characteristics. Given that these indices of emotion dys- We are collecting data from both mothers and daughters that assess psychobiological aspects of depression, emotion regulation, and stress reactivity. Mothers and daughters participate in emotion information-processing tasks with a negative-mood-inducing component converse with each other about a stressful topic, during (and following) which salivary cortisol is collected undergo a stressful interview, during (and following) which salivary cortisol is...

Pineal Gland and Cancer

From an endocrinological view, these apparently contradictory finding could be explained if the cancer-induced changes in the circadian pattern of melatonin availability were manifested over a period of time 24 h, i.e. just as different patterns of cortisol incretion are characteristic of different adrenal-gland diseases.

CD36null Mice the Fasting Phenotype

Cd36 Null Mice

These observations have led us to propose the following model (shown in Fig. 1.5) to explain the CD36-null fasting phenotype. The increased fasting serum FA is likely a result of both increased mobilization from adipose tissue and decreased peripheral FA utilization. The elevation in serum FA increases flux and uptake of FA by the liver. This would increase triglyceride synthesis and incorporation into lipoproteins, as evidenced by the increase in fasting VLDL-triglycer-ide. FA oxidation is significantly decreased in CD36-null oxidative muscle but may be normal in glycolytic muscle due to the increased serum FA concentration and the lower oxidative capacity of this tissue. The presumed increase in hormone-sensitive lipase activity in adipose tissue may result from the fasting hy-poinsulinemia observed in these mice. Circulating levels of cortisol as well as sympathetic activity to adipose depots are also likely to be increased, further stimulating lipolysis. The decrease in insulin...

Differences in Body

Differences in body fat arise at puberty when young women begin to store fat in their stomach, buttocks, and legs. This, in addition to skeletal differences, gives women's bodies their curvy shape. Men usually carry their fat in the abdomen. Overall, women have about 10 more body fat then men, which is necessary to maintain fertility. As we discussed in Chapter 2, body fat is required for female fertility because a hormone called leptin, secreted by fat cells, tells the brain if there are enough fat stores to support a pregnancy. When a female does not have enough body fat, the hormones that regulate menstruation are blocked and menstruation ceases. Lack of menstruation can be permanent and results in sterility and bone damage. Excessive exercise or starvation that leads to the cessation of menstruation, called amenorrhea, causes permanent damage when the estrogen that normally increases prior to ovulation is not produced.

Potential Explanations for the Decreasing Age of Pubertal Onset

Other hypotheses regarding the earlier onset of puberty focus on more intrinsic factors. For example, perinatal factors, such as birth weight, have been found to play a role in subsequent pubertal development. In one study, girls who were smaller at birth but had a rapid catch-up period of growth between birth and age 6 were earlier maturers (Persson et al., 1999). Mechanisms for this association are not clear, but it is likely that the prenatal environment may influence subsequent timing of onset of development, given that sex hormones are active prenatally in organizing the brain for subsequent pubertal development and reproductive functioning (Fechner, 2002). A more widely discussed hypothesis is that higher body fat is associated with earlier maturation. In general, overweight girls tend to mature earlier than girls of normal weight, and thin girls tend to mature later. Numerous studies have indicated that in the past thirty years, there is an increasing prevalence of obesity in...

Serum and Urine Steroid Levels

Determination of levels of different hormones in serum is important for diagnosing various endocrinological disorders. MEKC can effectively separate and quantify a variety of corticosteroids such as corticosterone, cortisone, cortisol, aldosterone, 21-deoxycortisol, 1-dehydroaldosterone, and 17-isoaldosterone (23). CE can also identify and separate estrogens such as urinary estrone and estriol, but not 17 -estradiol, because its concentration is too low to be detected by this method (24). A competitive solution-phase immunoassay has been developed for separation and quantitation of serum cortisol by CE combined with laser-induced fluorescence (25,26). An assay for urinary free cortisol, unaffected by other urinary metabolites, has also been shown to detect cortisol concentrations as low as 10 g L (27). Chapter 11 contains a detailed discussion of the use of CE in the detection of steroids whose levels, when measured, are clinically useful.

Children at Risk for Depression

The results of the studies described above suggest that the pattern of HPA functioning and reactivity in depressed children and adolescents is similar to that found in depressed adults. Moreover, there is some evidence that levels of cortisol activity among depressed children may predict the course of the disorder. Little research, however, has examined whether HPA dysregulation functions as a risk factor for the onset of a depressive episode in youth. Ashman and colleagues (2002) found abnormal HPA reactivity in response to a laboratory stressor in children whose mothers were depressed but who themselves were not depressed. More recently, Halligan, Herbert, Goodyer, and Murray (2004) reported that having depressed mothers was associated with higher and more variable morning cortisol levels in their children. In a prospective study, Essex, Klein, Cho, and Kalin (2002) found that preschool-age children of depressed mothers exhibited elevated cortisol levels, and that these were...

Emotion Regulation Stress Reactivity And Risk For Depression

Only recently have researchers begun to integrate these areas of research. Young and Nolen-Hoeksema (2001), for example, have demonstrated that the use of maladaptive emotion regulation strategies, such as rumination, is associated with heightened cortisol levels in healthy adults. In this chapter, we present an integrative assessment of emotion regulation and of stress reactivity and recovery in a group of young girls at risk for depression. We use a range of methodologies, including self-report measures, information-processing performance, HPA axis functioning and reactivity, and neural responses to emotional stimuli following exposure to stressful experiences. In the following sections, we briefly describe the assessment of emotion regulation and stress reactivity and recovery in depression from the perspectives of information processing, neuroendocrine functioning, and patterns of neural activation, and we provide an overview of the relevant literature summarizing studies on...

The Normal Adult Brain

Diminution of energy-rich phosphates was more severe in hippocampus than in cerebral cortex. In agreement with these findings is the effect of long-term cortisol treatment which damaged nerve cells preferentially in the hippocampus. Hippocampal neurons have been demonstrated to inhibit the HPA-axis-mediated release of cortisol from the adrenal gland. Neuronal damage in the hippocampus then leads to a long-lasting hypercortisolism. It, thus, becomes obvious that insulin and cortisol act as functional antagonists in the brain (Sapolsky 1994). Both, the age-associated increase in the concentration of circulating cortisol (for more details, see below) and the maintained elevation of cortisol after stress may participate in the diminution of insulin receptor function (Lupien et al 1994). The elevation of cortisol also in the CNS is mirrored by its drastic increase in cerebrospinal fluid during aging as compared to adulthood. Another contributing factor to the reduced function of the...

Pathophysiology of Cachexia Mechanisms of Cachexia

The differences found between body weight and cellular mass are due either to an excess of extracellular water or to fat deposits. Fat is subject to variations not synchronous with those of the cellular mass, related to genetic factors (initial number and size of fat cells) and to hormonal causes, i.e. leptin, lipoprotein lipase (LPL), estradi- ol, progesterone, glucagon, insulin, corticosteroids, growth hormone. In non-complicated starvation, fat reserves are depleted first, followed by protein reserves 32 . In AIDS, depletion of cellular mass can start in the presence of preserved fat deposits 33,34 .

Cytokine Regulation of the Acute Phase Response

Several cytokines affect food intake directly or through other mediators, such as corticotropin-releasing hormone, serotonin or leptin. Leptin, a cytokine secreted from adipocytes, which has prominent effects on feeding behaviour and energy balance, is believed to be a major peripheral regulator of long-term body composition. It is also thought to be responsible for self-correcting changes in energy intake and expenditure that can be demonstrated after voluntary overfeeding and underfeeding 10 . However, animal studies demonstrated that endotoxin leads to a dose-dependent increase in plasma leptin and white fat leptin mRNA, which implies that leptin might be a mediator of anorexia in cachexia. There is a normal relationship between plasma leptin concentration and body fat content in healthy persons as

Steroid hormones are classified into five major categories progestins mineralocorticoids glucocorticoids androgens and

Deficiency of 21-hydroxylase inhibits the synthesis of glucocorticoids (e.g., cortisol) and mineralocorticoids (e.g., aldosterone), leading to overproduction of testosterone in the adrenal glands and underproduction of cortisol. The latter effectively increases adrenocorticotropic hormone (ACTH), which stimulates the adrenals to grow and synthesize steroids, exacerbating the testosterone overproduction. This leads to masculinization of females.

See also Biochemistry of Obesity

In mice, defects in the ob gene leads to mice with body weights as much as three times normal. The ob gene codes for a protein called leptin, which is normally synthesized in adipocytes and acts as a hormone, binding to a specific site in the brain. Obese mice lacking leptin eat as if perpetually starved. Conversely, injecting leptin into these mice causes them to lose weight dramatically. Obese humans, on the other hand, appear to contain high levels of leptin.

Treatment of intercurrent illness

The normal adrenal cortex responds to severe stress by secreting more than 300 mg day of Cortisol. Intercurrent illness is stress and treatment is urgent, particularly of infections the dose of corticosteroid should be doubled during the illness and gradually reduced as the patient improves. Effective chemotherapy of bacterial infections is specially important.

Central nervous system findings

The CNS hypothesis of CFS suggests that the symptoms of the illness are caused by a dysregulated neuroendocrine system (Demitrack 1993 Demitrack 1996 Goldstein 1993 Jefferies 1994). Dysregulation is thought to occur through a range of stressful events such as viruses, emotional stress, sleep disruption or overwork, which serve to disrupt the integrity of the hypothalamic-pituitary-adrenal (HPA) axis leading to a glucocorticoid deficiency such as decreased levels of cortisol in the body. The HPA plays a key role in co-ordinating people's physiological response to stress and their cycle of sleeping and waking. The acute stress response is regulated by a complex array of biochemical processes, starting with the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from centres in the brain such as the hypothalamus. These hormones stimulate the release of yet another hormone, adrenocorticotropic hormone (ACTH), from the pituitary gland, which in turn leads to...

Potential Reasons for Ethnic Differences in Age of Pubertal Onset

A finding across three large-scale studies conducted in the 1980s and 1990s, the PROS study (Her-man-Giddens et al., 1997), NHANES III (Wu et al., 2002), and the National Heart, Lung, and Blood Institute Growth and Health Study (Morrison et al., 1994), is that African American girls begin breast and pubic hair development about a year earlier than White girls and begin menses about half a year earlier. The reasons for the earlier age of secondary sexual characteristic onset for African American girls are not clear. Possible factors to consider include differences in diet and weight, environmental hazards or environmental estrogens, or differences in contextual stress and cultural attitudes between ethnic groups (Graber, 2003). Physiological differences that have been hypothesized to play a role in timing of pubertal onset include lower insulin sensitivity (Arslanian, Suprasongsin, & Janosky, 1997) and higher serum leptin levels (Wong et al., 1998) in African American children compared...

Endocrine And Weight Loss - References

Friedman JM (2002) The function of leptin in nutrition, weight, and physiology. Nutr Rev 60 S11-S14 S68-S84,S85-S87 38. Mersebach H, Svendsen OL, Holst JJ et al (2003) Comparisons of leptin, incretins and body composition in obese and lean patients with hypopituitarism and healthy individuals. J Clin Endocrinol Metab 58 65-71

Proinflammatory Cytokines and the Acute Phase Response

Among the specific causes of CACS, there is evidence of a chronic, low-grade, tumour-induced activation of the host immune system that shares numerous characteristics with the acute-phase response found after major traumatic events and septic shock. The latter is characterised by an increased production of cytokines 27, 28 high levels of catecholamine, cortisol, and glucagon 27, 29-31 increased peripheral amino-acid mobilisation and hepatic amino acid uptake 27, 32 increased hepatic gluconeogenesis and acute-phase protein production 27, 33, 34 and enhanced mobilisation of free fatty acids and increased metabolism 35 . The acute-phase response is a systemic reaction to tissue injury, typically observed during inflammation, infection or trauma. It consists of the release of hepatocyte-derived plasma proteins, known as acute-phase reactants, which include C-reactive protein, fib-rinogen, complement factors B and C3, and of a reduced synthesis of albumin and transferrin. An acute-phase...

Prostate Cancer Stem Cells A Target for New Therapies

What then causes this change There are no known mutagens in prostate, although the gland will undergo proliferative changes in response to steroids and perhaps sexual activity. For example, low androgen and high estrogen levels can result in involution and prostatic remodelling. The prostate is also profoundly sensitive to infection, as shown by the frequency of prostatitis in the human population (MacLen-nan et al. 2006). The commonest result of this is an inflammatory response, with resultant cytolysis and requirement for repair (Karin 2006). Under these conditions the 'activated' stem cell is likely to accrue an advantage, and were an element of genetic instability to be present, then further changes in response to the new environment could occur. It has been suggested that the earliest such changes are observed as prostatic inflammatory atrophy (De Marzo et al. 1998 Nelson et al. 2004). The changes could be reversible, such as chromatin remodelling and methy-lation...

Cancer and the North American Diet

Adipocytes, the cells that store fat, increase or decrease in number, depending on the amount of fat being consumed and used. The fat in high-fat diets cannot be metabolized at the rate that it is being ingested, and yet the digestive system is programmed to absorb as much as it can. Consequently, the unused portion is stored in adipocytes, which are capable of proliferating to meet the demand. In other words, development of obesity involves storage of fat and an increase in the number of fat-storing cells. Adipocytes were first identified around the turn of the 20th century, and for more than 90 years these cells were thought of as simple fat-storage depots. This perception changed dramatically in 1995, when several research groups in the United States and Europe discovered that adipocytes synthesize and secrete several growth factors, one of which is called leptin. Leptin has since been shown to be a potent growth factor, capable of stimulating the proliferation of many kinds of...

Impairment of the Immune System

Leptin is a marker consistent with energy reserves and may be the signal that connects energy stores with the immune system. Moreover, several studies showed that leptin plays a role in immunosuppression the decrease in leptin plasma concentrations during food deprivation leads to impaired immune function, whereas the restoration of leptin to normal levels by feeding after starvation is sufficient to ameliorate the immune response and is followed by a significant increase in Th1 activity, further supporting the role of leptin as a nutritional sensor for the immune functions 59,60 .

The Intriguing Role of TNF Is the Cytokine an Adipostat

TNF-a, which is expressed and secreted by adipose tissue, influences thermogenesis and, indirectly, via IL-1 or leptin 38 , food intake. The cytokine also has a direct (possibly paracrine) function in adipose tissue, limiting its mass by stimulating lipolysis and decreasing LPL activity. Up to now, there have been no reports showing that leptin could have a similar function in lipid metabolism in adipose tissue. Conversely, TNF-a can also travel to the brain and influence hypothalamic function. One problem confronting such a hypothesis is the presence of the blood-brain barrier. However, a number of peripheral peptides, including angiotensin II, can rapidly affect the hypothal- amus through nerve cells in the region of the cir-cumventricular organs, which lie outside the blood-brain barrier 39 . Alternatively, signals could be brought to the hypothalamus through nerve cells in the region of vagal afferent axons. Indeed, the intracraneal administration of cytokines results in a more...

Study End Points Efficacy

The results are reported in Table 2 and Figs 2 and 3. Proinflammatory cytokines IL-6 and TNF-a decreased significantly, while leptin increased significantly. ROS and GPx showed a trend toward a decrease and increase, respectively, but the changes were not significant. Correlations between changes ofLBM and clinical (PS), nutritional functional (appetite, grip strength), laboratory (IL-6, TNF-a, leptin, ROS and GPx) and QL variables. A significant negative relationship was found only between LBM and IL-6 changes (Table 4). Therefore, multivariate regression analysis was not performed. Correlations between changes of fatigue and clinical (PS), nutritional functional (appetite, grip strength) and laboratory (IL-6, TNF-a, leptin, ROS and GPx) variables. No significant relationship was found (Table 5).

Systemic Inflammation

There is evidence that a chronic, low-grade, tumour-induced activation of the host immune system that shares numerous characteristics with the 'acute-phase response' found after major traumatic events and septic shock is involved in CAC. Septic shock is a situation characterised by an increased production of cytokines 29,30 , high levels of catecholamines, cortisol and glucagon 29, 31-33 , increased peripheral amino acid mobilisation and hepatic amino acid uptake 29,34 , increased hepatic gluconeogenesis and acute-phase protein production 29,35,36 , enhanced mobilisation of free fatty acids 37 and increased metabolism 38 . The acute-phase response is a systemic reaction to tissue injury, typically observed during inflammation, infection or trauma, characterised by the release of a series of hepatocyte-derived plasma proteins known as acute-phase reactants, including C-reac-tive protein, fibrinogen, complement factors B and C3, and by reduced synthesis of albumin and trans-ferrin. An...

Calculating glucose thresholds for hormone release

Glucose thresholds for release of counterregulatory hormones or onset of other responses to hypoglycaemia are defined as the plasma glucose concentration at which the response is fisrt significant. They can thus only be reliably identified in slow reductions in plasma glucose, preferably stepped, as described above. The critical issue is to decide before starting what determines a significant change. This can either be to a specific value or by a predefined degree of increase. The gold standard is to perform euglycaemic studies of the same duration in the same patients in the same conditions and compare the hypoglycaemic responses with the eugly-caemic absence of response in each subject. For smaller pilot studies, where this is impractical, some investigators have used a statistical definition such as a change in excess of two standard deviations over the mean basal readings - for this, one strictly requires at least five baseline measures for each subject in order to define the...

Cytokine Peptide Interactions

Other endogenous cytokine-peptide interactions relevant to wasting, cachexia and the cachexia-anorexia syndrome include reciprocal cytokine-leptin (a member of the long-chain helical cytokine family)-neuropeptide Y-corti-cotropin-releasing hormone-glucocorticoid interactions, and perhaps also among cytokines and other CNS neuropeptide regulators involved in the control of energy balance including cocaine- and amphetamine-regulated transcript, melanin-concentrating hormone, agouti-related protein, a-melanocyte-stimulating hormone, and hypocre-tins orexins 8,10,12, 22,27 . Various of these can affect metabolic processes directly (e.g. gluconeo-genesis, glycogenolysis). The hypothalamus plays a critical role with multiple neuronal groups involved, including the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, and the lateral hypothalamus. The arcuate nucleus has leptin-responsive neurons with different functions, e.g. the pro-opiomelanocortin-producing neurons that...

The Role of Proinflammatory Cytokines in Cancer Cachexia Personal Studies

29 advanced-stage cancer patients with tumours at different sites, we found that serum levels of proin-flammatory cytokines, particularly IL-6, were significantly higher in cancer patients than in healthy individuals and that serum levels of proinflamma-tory cytokines inversely correlated with those of leptin 45 . In addition, there was a direct correlation between Eastern Cooperative Oncology Group performance status (ECOG PS) and serum levels of proinflammatory cytokines, i.e. IL-6 and TNF-a serum levels of patients with ECOG PS 0-1 were significantly lower than those of patients with ECOG PS 2-3. More interestingly, serum levels of proinflammatory cytokines correlated with patient survival. Very high levels of proinflammatory cytokines, particularly IL-6 (and low levels of lep-tin) correlated with a short survival time. Analysis of clinical response, survival, and serum levels of proinflammatory cytokines leptin showed that patients with very high levels of proinflammatory...

The Treatment of Diabetes Mellitus

To date, the precise mechanisms underlying the actions of TZDs are largely unknown 76 . PPARy is expressed at a much higher level in adipose tissue than in muscle and liver. However, TZDs enhance insulin sensitivity also in muscle and liver. This suggests that the primary effect of TZDs occurs in adipose tissue and is transmitted to muscle and liver via mediators, such as TNFa, leptin, adiponec-tin, and FFAs 50 . Both TNFa and leptin expression are reduced upon PPARy activation. In turn, PPARy activation induces lipoprotein lipase, thereby increasing triglyceride uptake by adipose tissue and reducing circulating FFAs, which then reduces insulin resistance in the liver and the muscle. In addition, rosiglitazone treatment significantly increased plasma adiponectin levels in T2DM subjects 77 . Interestingly, TZDs seem to reduce insulin resistance even in the absence of adipose tissue 78 . Enhanced expression of GLUT4 may be another mechanism contributing to the improved insulin action...

Treatment Strategies to Prevent Resistance to Estrogen Deprivation

A number of pathways stimulate the activity of the aromatase enzyme including prostaglan-dins IL6 and TNFa. Potentially this could cause resistance to aromatase inhibitors by increasing the substrate. Thus, there remains interest in attempting to reduce aromatase activity by inhibitors of prostaglandin synthesis via COX-2. Potentially TNFa and IL6 production by macrophages and adipocytes could be reversed by calorie restriction (as could several other pathways including NFKB and leptin). In this regard, it is of interest that a recent study examining gene expression profiles in subcutaneous abdominal fat in obese premenopausal women showed upregu-lation of multiple anti-inflammatory genes and downregulation of pro-inflammatory genes after a 1-month 800-calorie diet (Clement et al. 2004). We have recently reported that loss of 5 or more of body weight (and maintaining the loss) reduces premenopausal breast cancer by 40 and postmenopausal disease by 25 (Harvie et al. 2005). The...

Liver intrahepatic lipids

Pharmacological and lifestyle intervention studies successfully found the association between improved insulin sensitivity or splanchnic glucose uptake and decreased hepatocellular fat content in T2DM after glitazone treatment (Katoh et al. 2001 Carey et al. 2002 Mayerson et al. 2002 Bajaj et al. 2003), in lipodystrophic patients due to the leptin treatment

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