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 Summary


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Author: Janet Hradil
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This ebook comes with the great features it has and offers you a totally simple steps explaining everything in detail with a very understandable language for all those who are interested.

All the modules inside this ebook are very detailed and explanatory, there is nothing as comprehensive as this guide.

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 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...

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...

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 .


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 ....

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...

Mammalian Photoentrainment

Through a dedicated pathway (the retinohypothalamic tract), which originates in the retina (3,4). Eye loss in every mammal, including humans, confirms that photoentrainment originates within the eye (5). However, studies during the 1990s in mice with hereditary retinal disorders produced some very puzzling results. Despite that fact that most of the rods and cones had been lost in these mice, and no visual light perception was detected, photoentrainment to the light-dark cycle still occurred. It seemed extraordinary that the sensitivity of the circadian system to light did not parallel the loss of either rod or cone photoreceptors, or the loss of visual function (6). This work paved the way for the development of a transgenic mouse model (rd rd cl) that was engineered to lack all functional rods and cones. Despite the ablation of the classical photo-receptors, both circadian entrainment and the regulation of pineal melatonin remained intact in these animals (7,8). There had to be...

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...

The Human Adipose Organ

All the major molecules produced by murine fat cells (e.g. leptin, adiponectin, TNF-a, angiotensinogen, PAI 1, resistin, adipsin) are also produced by human adipocytes. Also in our species, regulation of the amount of fat tissue depends on the energy balance. If there is a positive balance, adult individuals exhibit an increase in adipocyte size, which, upon attainment of a critical size, will induce the development of new fat cells (see also 'Vessels and Nerves').

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.

Anatomy And Functions Of Lymphoid Tissues

The bone marrow is the site of generation of most mature circulating blood cells, including red cells, granulocytes, and monocytes, and the site of early events in B cell maturation. The generation of all blood cells, called hematopoiesis (Fig. 2-9), occurs initially, during fetal development, in blood islands of the yolk sac and the para-aortic mesenchyme, then shifts to the liver between the third and fourth months of gestation, and gradually shifts again to the bone marrow. At birth, hematopoiesis takes place mainly in the bones throughout the skeleton, but it becomes restricted increasingly to the marrow of the flat bones so that by puberty, hematopoiesis occurs mostly in the sternum, vertebrae, iliac bones, and ribs. The red marrow that is found in these bones consists of a sponge-like reticular framework located between long trabeculae. The spaces in this framework contain a network of blood-filled sinusoids lined by endothelial cells attached to a discontinuous basement...

The Important Role Of Stress

That drug abuse patients are more vulnerable to stress than the general population is a clinical truism. Numerous preclinical studies have documented that physical stressors (e.g., foot shock or restraint stress) and psychological stressors can cause animals to reinstate drug use (e.g., Shaham, Erb, & Stewart, 2000). Furthermore, stressors can trigger drug craving in addicted humans (Sinha, Catapano, & O'Malley, 1999). One potential explanation for these observations is that abused drugs, including opiates and stimulants, raise levels of cortisol, a hormone that plays a primary role in stress responses cortisol, in turn, raises the level of activity in the mesolimbic reward system (Kreek & Koob, 1998). By these mechanisms, stress may contribute to the abuser's desire to take drugs in the first place, as well as to his or her subsequent compulsion to keep taking them.

Physiological Regulation

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.

Adam W Carrico Michael H Antoni Lawrence Young and Jack M Gorman

Because HIV-positive persons endure a chronic disease that requires adaptation across a variety of domains, individual differences in the ways they adapt to these challenges may affect not only quality of life but also disease processes. Research in psychoneuro-immunology (PNI) has examined the potential bio-behavioral mechanisms whereby psychosocial factors such as stressors, stress responses, coping, and negative affective states influence disease progression (Antoni, 2003a). Psychosocial factors are thought to relate to immune-system function in humans via stress- or distress-induced changes in hormonal regulatory systems (Kiecolt-Glaser et al., 2002). Several adrenal hormones, including cortisol and catecholamines (norepinephrine and epinephrine), are altered as a function of an individual's appraisals of and coping responses to stressors (McEwen, 1998). What is particularly relevant to HIV AIDS research is the observation that a variety of neuroendocrine abnormalities occur in...

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...

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

Stress Management And Psychiatric Interventions

Stress management techniques such as relaxation training, cognitive restructuring, and coping skills training may reduce negative mood states in HIV-positive persons by lowering physical tension and increasing self-efficacy (Antoni, 2003a). These affective changes are thought to be accompanied by an improved ability to regulate peripheral catecholamines and cortisol via decreases in ANS activation and improved regulation of the HPA axis, respectively. Neuroendocrine regulation may be associated with a partial normalization of immune system functions, providing more efficient surveillance of pathogens such as latent viruses that may increase HIV replication and enhance vulnerability to opportunistic infections or neoplasias. This normalization of stress-associated immune system decrements may ultimately forestall increases in viral load and the manifestation of clinical symptoms over extended periods. A relatively small number of controlled trials have examined the effects of...

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...

Carbonyl and quinone reductases

SDRs are enzymes of great functional diversity found throughout nature. In humans, cytosolic carbonyl reductase (CBR1) is a major member of the SDR superfamily that metabolizes a wide variety of xenobiotics, including the anticoagulant warfarin, anthracycline derivatives like daunorubicin, and aldehyde and ketone products of lipid peroxidation.74 A recent mouse knockout study demonstrated a critical role for CBR1 in the doxorubicin cardiotoxicity that is attributed to the reduced metabolite, doxorubicinol.75 CBR3 is a second member of the cytosolic human carbonyl reductases, but its substrate specificity is not well documented. The major human microsomal carbonyl reductase, 11 -hydroxysteroid dehydrogenase, also belongs to the SDR family. Each enzyme demonstrates a cofactor preference for NADPH, transferring the pro-S hydrogen to the substrate, i.e., the opposite of ADH. The AKRs perform oxidoreduction on a wide variety of natural and foreign substrates. A systematic nomenclature for...

The CRF hypothesis and stress

CRF is synthesized in the hypothalamus and elicits the release of adrenocorticotropic hormone (ACTH) from the pituitary. CRF was isolated from sheep hypothalamus and its structure as a 41-amino-acid peptide determined.96 The hypothalamic paraventricular nucleus (PVN) is the major region in the brain of CRF-containing cell bodies and through axonal projections to the capillaries of the median eminence can secrete CRF directly into the portal system where it acts at the pituitary to regulate ACTH secretion into the circulation. The principal role of ACTH is to stimulate the release of cortisol from the adrenal gland, thus completing the HPA axis, a primary component of the neuroendocrine response to stress. Similarly, projections from the PVN to the lower brainstem and spinal cord have been demonstrated to regulate autonomic function and help to further mediate the behavioral responses to stress. High densities of CRF-containing neurons are localized in particular to prefrontal,...

Investigating the pathogenesis of problematic hypoglycaemia

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...

Hormone Interference Estrogens and Progestins

High-dose progestins are used as last-line endocrine therapy 223 . They inhibit the adrenal steroid biosynthesis. The decrease of estrogen levels is comparable to that caused by the administration of aromatase inhibitors. In post-menopausal women, the progestin megestrol acetate (MGA) decreases serum plasma level of DEAH, androstenedione and cortisol to less than 10 223,224 .

Dehydrogenases and reductases

ADH is a member of the family of medium-chain alcohol dehydrogenases.32 The major function of most short-chain alcohol dehydrogenases32 in mammals is steroid metabolism. Nevertheless, many of them play important roles in drug toxification and detoxification. The 3a-hydroxysteroid dehydrogenase (3a-HSD) of rat and man oxidizes vicinal dihydrodiols of polycyclic aromatic hydrocarbons to catechols and these to quinones.33 Hence, 3a-HSD is also called dihydrodiol dehydrogenase. This reaction sequesters the pre-bay dihydrodiols of polycyclic aromatic hydrocarbons away from their critical toxification pathway to the ultimate carcinogenic dihydrodiol bay-region epoxides to produce instead the much less toxic catechols33 (Figure 3). In addition, it inactivates the highly mutagenic and carcinogenic bay region diol epoxides.34 Both of these reactions are protective, but the formation of catechols, which are further oxidized to quinones, is on the other hand also a potential toxification, since...

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...

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.

Endosomes And Lysosomes

The primary function of mitochondria is generation of energy in the form of ATP for molecular and cellular activities. Sources for mitochondrial energy generation are fatty acids and glycogens, or glucose polymers. Fatty acids are a more efficient form than glycogen for energy generation. The oxidation of fatty acids can generate energy 6 times as much as that of an equal amount of glycogen. Fatty acids are mainly stored in fat cells,

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...

Endocrine Disorders Associated with Myofascial Pain

Muscle weakness, wasting, spasm, and pain are frequently associated with Cushing's disease secondary to an adrenocorticotropic hormone (ACTH)-secreting tumor of the pituitary, with associated adrenal hyperplasia and Cushing's syndrome (secondary to a primary adrenal tumor or ectopic production of ACTH). Other signs and symptoms include female facial hirsutism, round, red facies, purple abdominal striae, thin skin with easy bruising, thinning scalp hair, and osteoporosis. Hypertension and mild diabetes mellitus along with affective changes and spinal fractures (secondary to osteoporosis) may also be seen. Laboratory testing shows elevation of a 24-hour urinary free cortisol level and a high morning plasma cortisol. Treatment includes surgical removal of the tumor and chemotherapy.

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...

Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

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-

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

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 .

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 per-oxidase 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...

Predictors of Response to Cyclic Antidepressants

Specific laboratory measures and the interaction between specific life events and personality-cognitive characteristics (Mazure et al. 2000) have been reported to have predictive power with respect to subsequent antidepres-sant response. These laboratory measures include serum cortisol response to administration of oral dexamethasone (Spar and La Rue 1983) pretreatment measures of orthostatic hypotension (Diehl et al. 1993 Jarvik et al. 1983) response to a test dose of methylphenidate (Spar and La Rue 1985) pretreatment red blood cell counts (Mentre et al. 1998) pretreatment folate blood levels (Alpert et al. 2003) specific polymorphisms of the norepinephrine transporter gene (Yoshida et al. 2004) subacute reduction in prefrontal cortical activity per quantitative electroencephalography (Cook and Leuchter 2001) and dopaminergic supersensitivity as measured by the apomorphine challenge test (Healy and McKeon 2000). However, none of these laboratory measures has yet gained widespread...

CASE 3 Cushings Syndrome In A Child Case Description

Laboratory studies confirmed the presence of ACTH-dependent hypercortisolism. A 24-h urine free cortisol (UFC) was 205 g d (normal < 30 g d) and morning serum cortisol 29 g dL decreased only to 22 g dL following overnight 1-mg dexamethasone suppression test. A pituitary MRI was unremarkable and a basal plasma ACTH was 54 pg mL (normal 9-52 pg mL).

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 .

CASE 2 Hypertension And Hypokalemia Case Description

Given the strong family history of hypertension, young age of onset, and appearance of hypokalemia, his physician pursued testing for secondary causes of his hypertension. Twenty-four-hour urine collections for catecholamine and cortisol excretion were normal. Random plasma aldosterone (PA) and plasma renin activity (PRA) levels revealed values of 37.1 ng dL (normal 3.0-35.0 ng dL, normal salt diet) and < 0.1 ng mL h (normal upright value 0.4-8.8 ng mL h, normal salt diet), respectively. Given these data, a diagnosis of primary hyperaldosteronism was made. He was started on spironolactone 50 mg daily, but additionally required labetalol and losartan for blood pressure conrol. Later, his dose of spironolactone was increased to 200 mg daily. A CT scan with 5-mm slices of the adrenal glands showed no evidence of an adenoma, and was reported as normal. Given the patient's extensive family history of early-onset hypertension, it was thought he may suffer from glucocorticoid-remediable...

CASE 3 Acute Hyperkalemia Case Description

The possibility of adrenal insufficiency was raised and the patient was given 2 mg of dexamethasone intravenously (iv) and underwent a rapid cosyntropin stimulation test (250 mcg iv as a bolus). The cortisol values were 5.6 mcg dL, 16.5 mcg dL, and 21.3 mcg dL at 0, 30, and 60 min, respectively. The dexamethasone was stopped. It was subsequently recommended that plasma renin activity (PRA), and aldosterone levels should be checked 2 h after assuming an upright posture. The upright PRA was 0.5 ng mL h (normal 0.4-8.8 ng mL h, normal salt diet) with a simultaneous aldosterone level of 2.4 ng dL (normal 3-35 ng dL, normal salt diet), and potassium level of 6.7 mmol L.

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...

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 .

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...

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...

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...

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 .

Biological Mechanisms Of

Sensitization occurs as a result of repetitive activation by trauma reminders, which elevate sensitivity of limbic networks (Post, Weiss, & Smith, 1995), and that as time progresses these responses become increasingly conditioned to trauma-related stimuli (LeDoux, Iwata, Cicchetti, & Reis, 1988). In support of these proposals, there is evidence that people who eventually develop PTSD display elevated resting heart rates in the initial week after trauma (Bryant, Harvey, Guthrie, & Moulds, 2000b Shalev et al., 1998 see also Blanchard, Hickling, Gaslovski, & Veazey, 2002). There is also evidence that lower cortisol levels shortly after trauma predict subsequent PTSD (McFarlane, Atchison, & Yehuda, 1997 Delahanty, Raimonde, & Spoonster, 2000). Cortisol may act as an anti-stress hormone that restores equilibrium, and lower cortisol levels may reflect an incapacity to lower arousal following trauma (Yehuda, 1997). The importance of increased arousal in the acute phase is...

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...

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.

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...

What Is Blood Pressure

Carries angiotensin I to your lungs, it's converted to angiotensin II, a very potent constrictor of blood vessels. Angiotensin II also stimulates the adrenal cortex to produce yet another hormone, called aldosterone. This steroid hormone, closely related to cortisol, plays a major role in stimulating the kidney to excrete potassium and to retain sodium. In fact, in its absence, the body may retain potassium to a dangerous degree. (See Chapter 12.) But we now know that aldosterone also exerts a number of harmful effects, especially on the heart. This curious set of circumstances complicates treatment.

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...

Neurohormonal Abnormalities

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,...

Definition of Terms and Anatomy

The subcutaneous fat (panniculus adiposus) is located below the reticular dermis and extends to the superficial fascia. The tissue is divided into lobules composed of aggregates of adi-pocytes (fat cells, lipocytes) separated by a meshwork of fibrous septae (trabeculae). The fibrous septae extend down from the reticular dermis and house small- to medium-sized arteries, arterioles, venules, lymphatics, and nerves. An arteriole supplies the center of each lobule with drainage to peripheral venules in the fibrous septae. Lymphatics are not present within the lobules. Each adipocyte is supplied by capillaries. Therefore, venous processes are

Etiology of Metabolic Syndrome The Search for the Single Causal Mechanism

The other major focus in the search for the single causal mechanism underlying MetS has been the cause consequences of visceral obesity. These relate to both hormonal and metabolic consequences of obesity. The impact of several adipocytokines has been examined for their roles as etiological factors in MetS. These include leptin, adiponectin, and resistin as well as inflammatory hormones (TNF-a) and additionally nonesterified free fatty acids.36 The pattern of endothelial dysfunction and sympathoadrenal activation has been linked to these mediators as well as the inflammatory phenotype characteristic of patients with MetS.

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...

Experimental Disease Models

Making them a suitable species for early preclinical research. Their relatively small size and body weight also make optimal use of precious peptides and small molecules that are being evaluated for their antiobesity effects. While there are many similarities in how animals control food intake, energy expenditure, adipose tissue physiology, and gastrointestinal function, there are many differences that limit the predictive validity of these models. For instance, rats have no gallbladder and are unable to store bile and therefore this changes the digestive process compared to humans. Also, there are many notable differences in hormonal regulation that need to be considered. For example, in rodents, leptin produced impressive reductions in food intake, increased metabolism, and reduced adiposity (see Section 6.18.7). In most human obese patients, leptin had very little effect on any of these parameters. With this in mind, these types of studies become important to facilitate...

Regulation of Appetite in the Elderly

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.

New Research Areas Leptin The discovery of the peptide hormone leptin was a major advance in obesity research.17 Leptin is a 148-amino-acid protein that is primarily secreted from adipose tissue in proportion to fat mass. Structurally, it belongs to the type 1 cytokine superfamily and is characterized by a long-chain four-helical bundle structure similar to growth hormone (GH), prolactin, and interleukin-3. The leptin receptor (Ob-R) was originally cloned from mouse choroid plexus and is alternatively spliced, giving rise to six different forms of the receptor, known as Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re, and Ob-Rf. Ob-R is a member of the class 1 cytokine receptor superfamily. Ob-Rb is expressed at high levels in the hypothalamus and is believed to mediate the central effects of peripherally secreted leptin. Natural mutation of the leptin gene is found in genetically obese (ob ob) mice, while the gene for the receptor is mutated in fatty (fa fa) rats and in diabetic (db db) mice. Chronic...

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 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.

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 .

Modulation of Pain by the Hypothalamic PituitaryAdrenal Axis

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...

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...

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 .

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...

CASE 2 Amenorrhea And Pituitary Neoplasm Case Description

A central abnormality was suspected because of interrupted pubertal development. LH, FSH, TSH, prolactin, cortisol, and thyroxine were all within normal limits for a woman in early puberty. Estradiol was low, but within normal limits for development. A coned-down lateral X-ray of the sella turcica showed a 2 cm area of calcification in the hypothalamus. A follow-up contrast-enhanced MRI study showed a 2 cm solid and cystic mass below the floor of the third ventricle without involvement of the pituitary gland. The optic tracts were laterally displaced around this tumor. Visual field testing was normal. Dynamic pituitary testing with GnRH (100 mcg intravenous bolus), thyrotropin-stimulat-ing hormone (500 mcg intravenous bolus), growth-hormone releasing hormone (1 mcg kg), and corticotropin-releasing hormone (1 mcg kg) resulted in normal FSH, LH, thyrotropin, prolactin, growth hormone, ACTH, and cortisol responses.

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...

Magnetic Resonance Imaging MRI and spectroscopy

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...

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

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...

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

Very lowdensity lipoprotein chylomicrons and triglyceride transport

In the periphery, LpL acts on these particles to release the TG to adipose tissue for fat storage or to muscle tissue where they can be used for energy. The resulting TG-depleted and cholesteryl ester-enriched VLDL remnant particles can be recycled to the liver by the interaction of a specific hepatic LDL receptor (LDLr) with apoB and apolipoprotein-E (apoE). Alternatively, further remodeling of VLDL remnants produces cholesteryl ester-enriched particles first IDL and then LDL. In contrast to VLDL and chylomicrons, the smaller and denser LDL and HDL particles help move cholesterol to and from the periphery, respectively.

Adipokines Is Adipose Tissue an Endocrine Organ

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...

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...

Nutritional Considerations

Dietary and lifestyle changes can reduce estrogenic effects and increase progesterogenic effects (15). Nutritional and botanical strategies are aimed at balancing the endocrine system by reducing estrogen and increasing progesterone. This strategy can help restore hormonal balance and reduce seizures. Estrogen elimination can be maximized by maintaining liver function and preventing liver toxicity. It is necessary to create healthy intestinal flora and function by increasing motility and function to encourage the growth of the good bacteria that decrease estrogen and avoid the growth of the bad bacteria that increase estrogen. Finally, lifestyle factors such as stress, exercise, and exposure to environmental toxins, drugs, alcohol, and poor diet compromise liver efficiency and affect the metabolism of hormones (15).

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...

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...

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.

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.

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...

Atherogenesis And Atherosclerosis

As most fat cells and pericytes) assists in leukocyte adhesion and trafficking (19). VAP-1 is upregulated during inflammation (20). It exhibits enzymatic properties that lead to production of oxidative substrates, promulgating EC destruction and leukocyte recruitment (21). Transmigration across the endothelium also involves junctional molecules, such as platelet-endothelial (PE)CAM-1, DNAM-1 and ZO-1 (22,23). As the inflammation ensues, EC vasomotor regulatory functions and antithrombotic properties are further lost. Specifically, activated EC over-express tissue factor, ET-1, and AT-II. This is associated with further downregulation of vasodilators, NO, and PGI2. Engagement of cell surface receptors transduces intra-cellular signals for nuclear gene expression via activation of transcription factors such as NF-kB. Leukocyte activation enhances secretion of proinflam-matory cytokines and chemokines. Chemokine release, such as MIF, M-CSF, MCP-1, IL-8, GRO, and MIP-1, leads to increased...

Mechanisms of Renal Dysfunction

Recent studies have focused on exploring the mechanisms by which obesity increases sympathetic outflow. One of these is hyperleptinemia. Leptin can regulate energy balance by decreasing appetite and stimulating thermogenesis via sympathetic stimulation. Acute infusion of leptin increases sympathetic activity and the hypertensive effect of leptin was completely abolished by combined a- and -adrenoceptor blockade.22 Hyperinsulinemia also plays a role in the activation of the sympathetic nervous system associated with obesity. In rats, insulin causes an enhancement of sympathetic activity in different tissues such as the kidney.23 High circulating levels of free fatty acids in obese subjects may participate in the activation of the sympathetic nervous system. Collectively, these data suggest that leptin, hyperisulinemia, and increased plasma free fatty acids could contribute to the activation of sympathetic system in obese subjects.

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.

Diet and Physical activity

Study, Oeffinger et al. observed cardiovascular disease risk factors such as obesity, dyslipidemia, hypertension, and insulin resistance in 62 of a cohort of young adult survivors treated for ALL in association with sedentary activity levels 37 . The higher prevalence of obesity in survivors treated with cranial radiation has been attributed to lower physical activity and resting metabolic rate, and hormonal insufficiency 32 . In particular, hypothalamic insult may predispose to obesity through leptin insensitivity 39 and adult growth hormone deficiency, which is associated with higher rates of dyslipidemia, insulin resistance, and cardiovascular mortality 40, 41 .

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).

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

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