Lose Weight By Controlling The Fat Storage Hormone

Trouble Spot Nutrition

Created by Janet Hradil, Trouble Spot Nutrition is a 3 Phase Hormonal Solution That Melts Away Trouble Spot Fat In Less Than 15 Minutes A Day. Leptin, cortisol, and testosterone all have an influence on our weight issues, but not many of us know it. Janet Hradil has created Trouble Spot Nutrition with the intent of teaching people how their hormones affect their weight loss efforts, and how nutrition can easily correct hormone issues and help fight fat faster than ever before. In each of your fat cells, there is an enzyme, 11 beta-hydroxysteroid dehydrogenase-1 (Hsd), that takes inactive cortisone (a hormone) and turns it into cortisol, a fat storing compound. If you have high amounts of Hsd, you will have high amounts of fat storage. While Hsd is genetically determined, you can use nutrition to reduce levels and stop the unwanted fat storage, even on your trouble spots. Read more...

Trouble Spot Nutrition Overview


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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...

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 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...

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 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 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...

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 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 .

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 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,...

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...

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 .

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...


A fundamental advance in our understanding of control of energy balance came with the discovery of the adipocyte-derived hormone leptin. Leptin is a 164-kDa protein that is transcribed in adipocytes of a variety of species, including humans, and after cleavage of a signal peptide, it is secreted into the bloodstream where it circulates at concentrations proportional to body fat stores 34 . Leptin production is regulated by the peripheral signal pathway from the adipose tissue to the hypothalamus, which is involved in the regulation of feeding and energy balance 35 . Thus, leptin is the major peripheral regulator of long-term body composition and is responsible for self-correcting changes in energy intake and expenditure 36 . Several in vitro and in vivo studies showed high serum levels of leptin during acute inflammatory diseases. So, this hormone has been hypothesised to be responsible for anorexia and weight loss occurring in chronic inflammatory disease 37, 38 . By contrast,...

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 ....

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...

Positive Energy Balance Overweight and Obesity

When the energy balance is positive, the adipose organ prevalently undergoes an increment in its white component. White adipocytes become hypertrophic and subsequently hyperplastic (likely due to a close causal relationship). In fact, it has been suggested that adipocytes are unable to expand beyond a given maximum volume, or 'critical size', which is genetically determined and specific for each depot 77 . Adipocytes that have reached the critical size trigger an increase in cell number 78-80 . In a recent review, Hausman et al. 81 , after considering the evidence for this theory, conclude that not only paracrine factors, but also circulating factors as well as neural influences may play a large role in regulating adipose tissue development and growth. They suggest that in the development of obesity, enlarged fat cells produce and release proliferative paracrine factors as internal controllers of preadipocyte proliferation, and that their proliferative response is modulated by neural...

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.

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.

Thyroxine Binding Globulin

By virtue of sequence homology, TBG belongs to the superfamily of serine proteinase inhibitors (serpins) 34 , which consists of a variety of heterogeneous proteins including i-antitrypsin (also known as proteinase inhibitor, PI), i-antichy-motrypsin, antithrombin III and cortisol-binding globulin (CBG) 35 . TBG and CBG are the only serpins that transport small lipophylic molecules having lost the serpin-characteristic function of

Hypoglycaemic stimuli for research Insulin tolerance test

Most experimental hypoglycaemia is induced by insulin. An intravenous insulin challenge, called the insulin tolerance or insulin stress test, was the first test used to determine the effect of hypoglycaemia (Dell'acqua 1951 Hanzlicek & Knobloch 1951). This method was used in early studies that identified the role of the adrenal gland in protective responses to hypoglycaemia (Vogt 1951 De Pergola & Campiello 1953) and has also been used in the past to induce hypoglycaemic seizures as a treatment for severe depression (Mueller et al. 1969) and as a stimulus for gastric acid secretion in the standard Hollander test assessing the completeness of vagotomy (Colin-Jones & Himsworth 1970). It is still used to determine pituitary reserve for growth hormone and cortisol release. Prior to performing an insulin tolerance test, it is important to rule out complete deficiency of counterrgulatory hormones and establish cardiovascular status. A 9 am cortisol, baseline thyroid function and...

CD36null Mice the Fasting Phenotype

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...

Measurement of counterregulatory hormones

The hormonal counterregulatory response to hypoglycaemia is a carefully orchestrated release of hormones that has a natural hierarchy in the non-diabetic individual that protects the individual from severe hypoglycaemia (Mitrakou et al. 1991). The first step is a reduction in insulin production, followed by the release of glucagon, adrenaline, cortisol and growth hormone (Cryer et al. 1989). Samples for glucagon are collected in lithium heparin tubes containing 50 l of trasylol, while cortisol, C-peptide and free insulin are collected in serum tubes. Following immediate centrifugation at 3,000 rpm for 10 minutes, the plasma is decanted of and stored at -80 C before being analysed by radioimmuno assay.

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...

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

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...

Other Acquired Localised Lipoatrophies

Other atrophies of small, circumscribed areas of subcutaneous fat layers can appear after a local trauma or prolonged pressure, or at the site of drug (mainly of protein structure) injection. Extractive hormones, e.g. bovine insulin, growth hormone, ACTH, calcitonin, and vasopressin, have been reported to be responsible for this form of fat atrophy at injection sites. Local formation of immunocomplexes, or protein precipitate or activation of complement fractions could induce a local lipolytic response mediated by inflammatory agents, and may explain the zonal loss of subcutaneous fat. Tumour necrosis factor (TNF)-a release induced by insulin may mediate adipocyte atrophy 19 . An asymptomatic, discoid or funnel-shaped depression appears. Microscopic examination of biopsy samples of tissue from atrophic area shows the disappearance of fat cells. A dedifferentiation of fat cells to fibroblast-like cells can be postulated, rather than adipocyte necrosis. In fact, the subcutaneous fat may...

Proinflammatory Cytokines

TNF-a has been found to promote lipolysis. However, the mechanisms by which this is achieved are unclear. TNF-a administration also induces increase of cortisol, glucagon and insulin levels and these effects seem to be mediated by IL-1 the concomitant administration of recombinant IGF-1 reduces the percentage of protein loss by 15 with an associated improvement of glucose metabolism. TNF-a has been implicated as a factor associated with the development of insulin resistance. Studies in women have found a positive association between plasma insulin levels and TNF-a mRNA from subcutaneous adipose tissue 30 , which is supported by a study showing increased adipose TNF-a secretion in obese patients with insulin resistance 27 . Extensive research has highlighted several potential mechanisms by which TNF-a induces insulin resistance. These include accelerated lipolysis and a concomitant increase in circulating FFA concentrations, down-regulation of GLUT4...

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.

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 .

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

Cytokines and Insulin Resistance

The expression of the proinflammatory cytokine IL-6, like that of TNF-a and IL-8, is increased in human fat cells from insulin-resistant individuals, and IL-6 is also associated with the insulin resistance of obesity and type II diabetes 73 . Interestingly, TNF-a markedly increases IL-6 mRNA and protein secretion. Chronic IL-6 treatment selectively impaired hepatic insulin signalling in vivo, further supporting a role for IL-6 in hepatic insulin resistance. IL-6, like TNF-a, exerts long-term inhibitory effects on the gene transcription of IRS-1, glucose transporter-4 (GLUT-4) and PPARy. Moreover, IL-6 reduced GLUT-4 mRNA and insulin-stimulated glucose transport in vivo 74 . IL-6 also decreased refeed-ing-dependent glucokinase mRNA induction and reduced insulin sensitivity. This decrease was characterised by a reduction in tyrosine phospho-rylation of IRS-1 and a decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiological insulin...

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.

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...

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...

Aging and the Incidence of Cancer

The increased incidence of cancer in those age 50 and older is also coincidental with the onset of sexual senescence in both men and women. It is quite possible that the hormonal changes that occur during this period contribute to our increased susceptibility to cancer. Age-related hormonal changes are primarily concerned with a shift in the ratio of estrogen to testosterone (ET ratio) in both men and women. Young women have a high estrogen testosterone ratio (a lot of estrogen, very little testosterone), whereas young men have a low estrogen testosterone ratio (a lot of testosterone, very little estrogen). Estrogen levels drop dramatically in women after menopause, and men show a similar decline in the level of testosterone at a corresponding age. As a consequence, men and women approach a similar ET ratio between the ages of 50 and 80, which is thought to influence the rate at which genetic instability occurs. In addition, many scientists believe the shift in the ET ratio is largely...

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...

Tracers for the study of triglyceriderich lipoprotein kinetics Chylomicrons

The fate of dietary fatty acids can be traced by adding a radiolabeled triglyceride to a mixed meal and tracking the appearance of the labeled fatty acid in the plasma space and its subsequent uptake in regional fat depots (Roust & Jensen 1993 Romanski et al. 2000 Jensen et al. 2003). Triglycerides or fatty acids labeled with stable isotopes can be administered as part of a meal in order to generate labeled chylomicrons (Evans et al. 2002 Barrows et al. 2005). The technique can be extremely useful in assessing patterns of dietary fat storage. It has the advantage that the secreted chylomicrons contain physiological mixed triglycerides. A limitation is that tracer input (i.e. the rate of absorption of labeled chylomicrons) is unknown.

Neuropeptide Y and Agouti Related Protein

NPY AgRP neurons represent the most important target of central and peripheral orexigenic and anorectic signals. In particular, they are inhibited by leptin and insulin and activated by the orexigenic peptide ghrelin 12-14 . Interestingly, an intestinal peptide, named PYY, the chemical structure of which closely resembles that of NPY 2,10,15 , has been reported to exert its anorectic effect acting as an antagonist of the NPY Y2 receptor. In fact, its administration is devoid of any effect in Y2 knockout mice 15 .

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 .

Signals from the Adipocytes

Leptin, Adiponectin and Resistin Leptin is a peptide expressed and secreted by white adipose tissue, proportionally to fat body mass 2, 7 . Both leptin and its receptor have also been isolated in human gastric mucosa 32 , suggesting a possible paracrine regulation of the other gastric peptides 10,32 . Leptin plays a central role in the regulation of energy intake and expenditure. Leptin increases some hours before meals in rodents and after several days of overeating in humans 72 , while it decreases during fasting 2 . The main activity of leptin is exerted at the central level, in particular in ARC and PVN 7 , via the activation of specific receptors named OB-Rb 73 . Specifically, leptin inhibits NPY and AgRP neurons, achieving a decrease in food intake 2,7,32 . Leptin (ob ob)- or leptin receptor (db db)-knockout mice are obese, hyperphagic and hyper-insulinaemic 73, 74 . As in mice, genic mutations leading to leptin deficiency have also been described in humans as a rare cause of...

Protein Energy Malnutrition

The main cause of protein-energy malnutrition in Crohn's disease patients is anorexia, probably resulting from postprandial abdominal pain, diarrhoea, dietary restriction, and the side effects of medications 5,6 . In addition, animal studies have shown that anorexia can result from increased levels of tumour necrosis factor (TNF)-a, interleukin (IL)-1, and other cytokines 7, 8 . These weight-loss-inducing cytokines increase the expression of leptin mRNA in adipose tissue as well as plasma levels of leptin, despite the decrease in food intake that normally suppresses leptin expression 1011 . Thus, leptin may also be involved in anorexia accompanying Crohn's disease. In contrast, Lanfranchi and Geerling showed that energy intake was not decreased, but tended to increase in patients with Crohn's disease in the stage of remission or low activity 13, 14 . These results suggest that the amount of dietary intake in patients with Crohn's disease depends on the activity of the disease.

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...

Timing of Nutritional Support

Most studies have investigated the effects of nutritional supplementation in clinically stable patients. Anamnestic data, however, indicate that in some patients weight loss follows a stepwise pattern, associated with acute (infectious) exacerbations. During an acute exacerbation, energy balance is often negative due to a further increase in REE, but particularly due to a temporarily dramatic decrease in dietary intake 65 . Furthermore, these patients may have an increased risk for protein breakdown, which may limit the effectiveness of nutritional supplementation 66 . Factors contributing to weight loss and muscle wasting during an acute exacerbation include an increase in symptoms, more pronounced systemic inflammation, alterations in leptin metabolism, and the use of high doses of glucocorticoids 64, 65 . One study showed a positive effect of nutritional support during hospitalisation for an acute exacerbation, but clearly more research is needed to evaluate the relative...

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

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...

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 .

Interventions To Reduce Cytokines

Testosterone levels decline with aging in both men 87 and women 88 . Testosterone replacement in men increases muscle mass 89-91 and strength 92, 93 , and decreases fat mass 90, 94, 95 . Adipocytes are a potent source of cytokines, including TNF-a and leptin. The effect of testosterone on functional status may be mediated by reducing cytokine excess through an effect on adipocytes 96-98 .

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 .

Biochemical Phases of Cachexia

Then lipids alone are not sufficient to maintain glucose levels, as their use is limited by the accumulation of ketones (ketoacidosis) and by the decrease of insulin. At this point, the organism, which has depleted glycogen stores and is self-limited in using lipids, goes on to use muscular and visceral proteins to produce glucose. About 75 grams of proteins day are used for gluconeogenesis during normal starvation, with urinary loss of about 12 grams nitrogen day. If the fast is prolonged, the organism adapts itself to utilise more ketone bodies and to reduce nitrogen loss to between 8 and 3 g day. Differently from normal starvation, in stressed starvation it is not hypoglycaemia that starts catabolic events, but the increase of hormonal factors, including cortisol, glucagon, epi-nephrine, leptin, cytokines (tumour necrosis factor TNF , interleukin IL -1, IL-2, IL-6, IL-10, interferons IFNs , and prostaglandins PGs ). These hormones may not increase in the blood rather, in...

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.

Evidence for Hypothalamic PituitaryAdrenal Dysfunction

Human studies have demonstrated the effects of CRH and its antagonism, both in healthy subjects and in FGD. Fukudo et al. demonstrated that intravenous CRH induced greater abdominal symptoms, higher ACTH levels, and exaggerated gut motility in IBS patients compared to controls (128). This suggests a heightened sensitivity of the HPA axis in IBS patients, which may be at the hypothalamic-pituitary level as no significant difference was found between levels of cortisol response between the two groups. Peripheral administration of a-helical CRH has been shown to improve GI motility, visceral perception, and negative mood in response to gut stimulation in IBS patients, suggesting that CRH-signalling pathways play an important role in the pathophysiology of IBS. The precise site of action of intravenously administered CRH antagonists on GI function is unknown. Human studies have reiterated the findings of animal studies regarding the involvement of mast cells in the immunoregula-tory...

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

Whole body fat distribution subcutaneous and visceral fat

Even though the total fat mass determines the plasma pool of FFA and thereby the FFA flux from adipose to non-adipose tissue (Lewis et al. 2002), there are differences in the relationship of subcutaneous and visceral fat depots to features of peripheral and hepatic insulin sensitivity (Misra et al. 1997). Visceral fat cells are more sensitive than subcutaneous fat cells to the lipolytic effect of catecholemines and less sensitive to the antilipolytic and fatty acid re-esterification effects of insulin (Kahn & Flier 2000). Furthermore, the venous effluent of visceral fat depots leads directly into the portal vein, resulting in greater FFA flux to the liver. This makes the visceral fat depots more efficient than subcutaneous fat in influencing the carbohydrate metabolism in the human body (Kissebah 1996).

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...

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

Body Fat Distribution Mri

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...

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...

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...

From Fats To AcetylcoA Oxidation

During fasting, fat cells supply fuels for other parts of the body. Because fats are insoluble and fatty acids have only a limited solubility, fat cells convert fatty acids into soluble, circulating fuels called ketone bodies (Fig. 13.8) (the word ketone means any chemical containing a carbon atom with single bonds to two other carbons and a double bond to an oxygen). The fundamental ketone body is acetoacetate, which the liver synthesizes from acetyl-CoA. Acetoacetate is then reduced to 3-hydroxybutyrate. These two molecules are important circulating fuels in mammals. Heart muscle, for instance, prefers ketone bodies to glucose as a fuel source.

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...

The Team Approach

While reviewing the workload for the day at 7 00 a.m., the CLS working in the special chemistry section of the laboratory noticed that a cortisol specimen on Mrs. Jones was missing. Her physician had requested that the laboratory draw specimens for cortisol analysis at 8 00 a.m. and 8 00 p.m. to confirm a possible diagnosis of Cushing's syndrome. After a search for the missing specimen, it is discovered that the 8 00 p.m. cortisol was never drawn. The phle-botomist suggests that the laboratory draw the second specimen at 8 00 a.m. today and submit the two 8 00 a.m. cortisols in place of the 8 00 a.m. and 8 00 p.m. cortisol. The CLS thinks of four possible courses of action 2. Analyze the cortisol that was collected at 8 00 a.m. and cancel the second collection since the physician only needs to see what the patient's cortisol level is in the morning. 3. Collect a second sample at 11 00 a.m. today along with other tests that were ordered and run it with the 8 00 a.m. sample, as that...

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...

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...

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,...

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.

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


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...

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...

And Frontal Brain Asymmetries

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

Lipoatrophy Associated with Multiple Symmetric Lipomatosis Launois Bensaude Syndrome or Madelung Collar

Multiple Lipomatosis Pictures

There is evidence for a mitochondrial dysfunction in muscle fibres. Levels of respiratory-chain enzyme show a significant decrease of cytochrome-c oxidase, succinic dehydrogenase, and citrate synthase activity 52 . Reduced mito-chondrial enzyme activity could provide the pathogenetic basis of the multisystemic clinical manifestations of MSL. Cultured MSL adipocytes synthesise UCP-1, the selective marker of brown adipocyte, but unlike in normally functioning brown fat cells, UCP-1 gene expression was not significantly induced by noradrenaline. Thus, MSL may be the consequence of a defective noradren-ergic modulation of proliferation and differentiation of brown fat cells 53 .

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.

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.

Sex Differences In Stress Responses

Sexual dimorphism in the stress response is well known. Whereas in rodents the hypothalamic-pituitary-adrenal (HPA) response, as measured by adrenocorticotropic hormone (ACTH) and cortisol levels, is greater in females than in males (Kitay, 1961 Jones, Brush, & Neame, 1972 Young, 1996), the pic

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...

Making Fatty Acids And Glycerides

All cells need fatty acids for membrane lipids. Fat cells make large amounts of fat (triacyl-glycerols) in times of plenty. The basic machinery is a multienzyme complex (in bacteria) or a multidomain protein (in eukaryotes) that uses the substrate acetyl-CoA. In both cases the growing fatty acid chain is not released it swivels from enzyme to enzyme or domain to domain in the array, adding two carbons for each complete cycle until the limiting length of 16 carbons is reached The product, palmitic acid, is then released. Although the reactions look similar (Fig. 13.12), the process is not a reversal of j oxidation (page 290). It uses entirely different enzymes, takes place in the cytosol rather than in the mitochondria, and is separately regulated. Like much of biosynthesis it is reductive, and the reducing power comes not from NADH but from the closely related dinucleotide NADPH.

Mechanism Of Action

Glucocorticoids diffuse into the cell but access to the receptor may be prevented, for example in kidney, by the enzyme 11-beta hydroxysteroid dehydrogenase, which converts active Cortisol into inactive cortisone. When activated, the receptors translocate to the nucleus where they can upregu-late gene transcription by dimerising on specific DNA response elements and recruiting co-activator proteins, but can also oppose other transcription factor function, for example NFkB and AP-1, by protein-protein interaction. The anti-inflammatory actions of glucocorticoids are mediated mainly by this latter mechanism, suggesting that one day drugs may be found which have the beneficial

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.

Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

Lawrence Syndrome Lipodystrophy

Cholesterol plasma levels are part of the syndrome. Total cholesterol levels are not constantly increased, but occasionally can be remarkably high 25 (Table 3). Muscle mass, evaluated by DEXA, is preserved on even increased compared with age-, sex- and BMI-matched subjects. The increase in resting energy expenditure is related to the higher fat-free mass body mass ratio. Two subtypes of CGLD have been identified and are distinguished according to the mode of inheritance 26-29 . Type 1 CGLD is related to an autosomal recessive genetic defect in AGPAT2 isoform. This enzyme, involved in the biosynthesis of triglycerides and phospholipids, is expressed at high levels in adipose tissue. Thus, a defect in AGAPT function may reduce triglyceride synthesis in fat cells. Type 2 CGLD is related to an autosomal recessive involvement of seipin, a protein of unknown function 30 . Mutation of the seipin gene has been reported to cluster in a large consanguineous pedi-

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...

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).

Physiology of K Homeostasis

Aldosterone And Cortisol Principal Cell

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...

I11111110 14 18 22 2 6

FIGURE 5.46 Daily rhythm of cortisol secretion. The graph shows the daily variation in serum cortisol concentration of human subjects. Each data point corresponds to the mean ( SE) of 31 young men. The duration of the prevailing light-dark cycle is shown by the horizontal light and dark bars. Serum cortisol concentration starts rising in the middle of the night and reaches a peak at wake time. (Source Selmaoui, B. & Touitou, Y. (2003). Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects a study of three different 24-h cycles over six weeks. Life Sciences 73 3339-3349.)

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

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.

Role of Local Vascularization in Joint Tissue Integrity

The traditional view that subchondral bone is richly vascularized, whereas hyaline cartilage is not, may no longer be true because histo-chemical studies have shown that the deep layer of hyaline cartilage is vascularized. The articular vasculature, therefore, derives its nutritional supply partly from the vascular bed of subchondral bone, as well as from the synovial fluid. Therefore, any loss of vascular tone in the subchondral bone could affect the cartilage. Early microvascular damages that affect the venous circulation in the bony tissue, therefore, may be considered a plausible cause of altered chondrocyte function 98 . Whether these vascular changes are secondary to bony changes or their primary cause remains unexplored. However, OA and cardiovascular disease risk factors have been shown to be correlated 115,146,220 , and abnormal vascularization of OA tissues may be a means to initiate cartilage tissue damage 166 . The hypothesis that OA may be viewed as an atheromatous...

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