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 here...

Trouble Spot Nutrition Overview


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My Trouble Spot Nutrition Review

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The very first point I want to make certain that Trouble Spot Nutrition definitely offers the greatest results.

As a whole, this ebook contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

The Glucocorticoids Hydrocortisone Cortisol And Others

As stated previously, the glucocorticoids affect the metabolism of fat, glucose, and protein in the body. The principal glucocorticoid is hydrocortisone (cortisol). a. Physiological, Actions of the Glucocorticoids. The glucocorticoids regulate blood brain glucose levels. They also inhibit the inflammatory process. The glucocorticoids also decrease the immunological responses of the body by decreasing antibody formation. About 90 percent of the glucocorticoids produced is hydrocortisone (cortisol). One of the most significant metabolic actions of glucocorticoids is gluconeogenesis. Gluconeogenesis involves the formation of glycogen or glucose from noncarbohydrates such as fat or protein. This, of course, can act to raise the concentration of glucose in the blood. Glucocorticoids can also raise the concentration of glucose in the blood by decreasing the use of glucose by skeletal muscle. Glucocorticoids play an important role in the body's reaction to stress, although the specific...


The discovery that was perhaps the greatest catalyst in propelling understanding of adipokines was that of leptin. The discovery of this adipocyte hormone was revealed by the identification of a single gene and its protein product that was able to explain the phenotype of the ob ob mouse, a recessive, genetic model of obesity (3). Ob ob mice are extremely hyperphagic, obese, insulin-resistant, and infertile. By using genetic analysis, it was discovered that these mice produced a mutant RNA for the leptin protein. The product of the ob gene was termed leptin, which is both exclusively synthesized and (insulin sensitizers) Leptin, Adiponectin secreted by adipocytes and circulates in the blood. Possibly owing to an estrogen effect, serum levels are higher in females than males, even after correcting for body fat (4). Administration of leptin to ob ob mice demonstrated proof of the concept, as it significantly reduced food intake while ameliorating obesity, insulin resistance,...

The Dualcenters Hypothesis

Historically, the conceptual framework that dominated thinking about the role played by the hypothalamus in the control of food intake was the dual-centers hypothesis proposed by Stellar in 1954 (1). In the same year that the discovery of leptin refocused attention on the role of the hypothalamus in energy balance, Psychological Review honored this article as one of the 10 most influential articles it had published in a century of publications. Stellar eloquently argued that the hypothalamus is the central neural structure involved in motivation generally and in the control of food intake more specifically. This control is divided into two conceptual categories controlled by two separate hypothalamic structures. The first category was satiety and was thought to be controlled by the ventromedial hypothalamus (VMH). The most important data that contributed to this hypothesis were that bilateral lesions of the VMH resulted in rats that ate more than controls and became obese. These...

CNS Regulation of Food Intake

Cartoon drawing of a coronal section of the brain. It represents the key nuclei in the hypothalamus that influence food intake and body weight regulation. There are peripheral signals, leptin, insulin, and ghrelin, which interact with the hypothalamus these are depicted with arrows pointing to the arcuate nucleus. Additionally, there are signals that originate in the brainstem, CCK and GLP-1 these are depicted with an arrow and are denoted as arising from the brain stem. Last, there are nutrients and neurostransmitters that interact with many of the hypothalamic nuclei, and there are arrows that represent their interactions. The hypothalamic nuclei are represented as shapes, and these shapes are labeled as arcuate (ARC), ventromedial nucleus (VMH), paraventricular nucleus (PVN), and lateral hypothalamus (LH). The concept conveyed here is that there are orexigenic (anabolic) neuropeptides that stimulate food intake, and there are anorexigenic (catabolic) neuropeptides,...

Integration Of Adiposity Signals

The information about total body fat derived from insulin and leptin must be integrated with satiety signals as well as with other signals related to learning, social situations, stress, and other factors, for the control system to be maximally efficient. Although the nature of these interactions is not well understood, several generalizations or conclusions can be made. For one, the negative feedback circuits related to body fat and meal ingestion can easily be overridden by situational events. As an example, even though satiety signals might indicate that no more food should be eaten during an ongoing meal, the sight, smell, and perceived palatability of an offered dessert can stimulate further intake. Likewise, even though an individual is severely underweight and food is available, the influence of stressors can preclude significant ingestion. Because of these kinds of interactions, trying to relate food intake within an individual meal to recent energy expenditure or to fat...

Adrenocorticotropic hormone see

Adrenocorticotropic hormone (corticotropin, ACTH) is the main controlling factor for the adrenal production of cortisol and androgens. It is produced in the anterior pituitary by cleavage of a large and complex polypeptide (241 amino acids), called propiomelanocortin (POMC), which also includes melanocyte-stimulating hormone (MSH), beta-endorphin, met-enkephalin, beta-lipotropin, and a number of other peptides of presently unknown function. The secretion of ACTH is controlled primarily by the hypothalamus-derived corticotropin releasing hormone (CRH) and secondarily by catecholamines and vasopressin. ACTH release is also stimulated by stress and by hypoglycaemia. CRH production and ACTH release is inhibited by both natural and synthetic corticosteroids, which suppress mRNA for POMC synthesis. ACTH is released in pulses, especially in the mornings, thus explaining the diurnal rhythm of cortisol secretion. The normal level of ACTH is 1.3 16.7 pmol L.

Central Signals Related To Energy Homeostasis

Neural circuits in the brain that control energy homeostasis can be subdivided into those that receive sensory information (afferent circuits), those that integrate the information, and those that control motor, autonomic, and endocrine responses (efferent circuits). Peptides such as insulin, leptin, and CCK i.e., adiposity and satiety signals are afferent signals that influence food intake. Additional, more direct, metabolic signals arise within the brain itself and also influence food intake, and these are discussed below. These nutrient-sensing cells in the brain have begun to be more fully characterized. As previously mentioned, there are glucose-sensing neurons cells, and these appear to contain receptors and enzymes that are consistent with another type of cell that senses changes in glucose, the pancreatic P-cells. Like P-cells, certain populations of neurons and glia detect changes in glucose levels and generate signals that influence metabolism and behavior (113,114). In...

Anabolic Effector Systems

Neuropeptide Y (NPY) is one of the most potent stimulators of food intake (115-117), and is proposed to be an anabolic effector that induces positive energy balance. NPY is a highly expressed peptide in the mammalian CNS (118,119), and is well conserved across species. Hypothalamic NPY neurons are found primarily in the arcuate (ARC) and dorsomedial nuclei, and in neurons such as the PVN (120-125). Endogenous release of NPY is regulated by energy balance. Specifically, in the ARC, food deprivation, food restriction, or exercise-induced negative energy balance each results in upregulation of NPY mRNA in the ARC and increased NPY protein. Repeated administration of NPY results in sustained hyperphagia and rapid body weight gain (126,127). The response of the NPY system to negative energy balance is mediated, at least in part, by the falls in both insulin and leptin that accompany negative energy balance. Central insulin or central peripheral leptin infusion attentuates the effect of...

Cocaine AmphetamineRelated Transcript

Cocaine-amphetamine-related transcript (CART) (189) was first identified as a gene whose expression is regulated by cocaine and amphetamine. CART is expressed in many of the POMC-expressing neurons in the ARC. CART expression is reduced during negative energy balance and is stimulated by leptin (190). Exogenous administration of CART peptide fragments into the ventricular system potently reduces food intake (190192) and ventricular administration of antibodies to CART produce significant increases in intake, implicating a role for endogenous CART in the inhibition of food intake (190). However, at these same doses, CART also produces a number of other behavioral actions that make its exact role in the control of food intake unclear (193). CART is a very prevalent peptide and its distinct role in the regulation of food intake and body weight is further confused by data indicating that when delivered specifically into the arcuate nucleus, CART actually produces an increase in food...

Proglucagon Derived Peptides

Preproglucagon is a peptide made both in the periphery and in the CNS. Preproglucagon encodes two peptides with described central activity glucagon-like-peptide 1 (GLP-1) and glucagon-like-peptide 2 (GLP-2). Both peptides are made in the L-cells of the distal intestine and have well-described functions in the periphery, with GLP-1 critical for enhancing nutrient-induced insulin secretion (202) and GLP-2 playing an important role in maintenance of the gut mucosa (203). Preproglucagon is also made in a distinct population of neurons in the nucleus of the solitary tract, with prominent projections to the PVN and DMH (204,205) as well as to the spinal cord. Preproglucagon neurons appear to be targets of leptin, as peripheral leptin administration induces fos expression, a marker of neuronal activation, in them (206,207). Both GLP-1 and GLP-2 have distinct receptors, with the GLP-1 receptor found predominantly in the PVN and the GLP-2 receptor in the DMH. When administered into the...

Alphahydroxylase Deficiency

Cortisol, dehydrocorticosterone acetate if salt wasting is present. Lack of 21-hydroxylase causes a decrease in Cortisol with a consequent increase in ACTH, which in turn produces hyperplasia of the adrenals resulting in an increase in androgen production that gives rise to signs of female pseudohermaphroditism (as in this case) or enlarged genitalia in the male. May occur with or without salt wasting. p.326

Depression with Psychotic Symptoms

Demographic and clinical characteristics (phenomenology, course and prognosis), family history, treatment response and neurobiological markers have been used as variables to validate the diagnostic autonomy of delusional from non-delusional depression 3,10,49-51 . Findings derived from the community survey of the ECA study indicated that delusional depression is different on a number of variables from other subtypes of MD, and the differences are not accounted for by demographic factors, symptom profile and severity 48 . The majority of studies have failed to substantiate a clear and significant difference in many other variables 51,52 . Some authors reported higher association of delusional depression with a number of neuro-biological markers (lower levels of serum dopamines-hydroxylase (DBH) and cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) higher cortisol non-suppression to DST and higher hospitalization rates) 53 . Whereas it may still be argued that the...

Proglucagon Gene Products

Recent evidence supports an anorexigenic role for OXM in both animals and humans. In animals, central administration of OXM has been shown to acutely inhibit food intake (73,74), and chronic intracerebroventricular (ICV) and IP administration reduces both food intake and weight gain (74,75). The latter is thought to be the effect of reduced food intake as well as increased energy expenditure (75). In humans, Cohen and coworkers (76) demonstrated a significant reduction in hunger scores and calorie intake (in a free-choice buffet meal by 19.3 ) following parentral administration of OXM. More recently, Wynne et al. (77) have confirmed that the appetite inhibitory effect of OXM is long-lasting, resulting in significant weight reduction. In this study, subcutaneous injections of OXM three times per day for 30 d, in a double-blind placebo-controlled trial in 26 overweight human volunteers, was shown to significantly reduce weight (5.5 lb in the active group compared with 1 lb in those on...

Orexigenic Gut Peptides Ghrelin

Variations, being high at night and declining in the early hours of the morning along with leptin levels. The postprandial decline of ghrelin is proportional to calorie intake and nutrient sensing but not stomach volume load. In keeping with this, glucose, but not water saline, infusion into the stomach caused suppression of ghrelin (105). However, no changes in ghrelin level were observed without normal gastric emptying, which suggests a requirement for a postgastric factor. The effect of glucose on ghrelin is independent of insulin actions. Further studies in humans showed that carbohydrate, and to a lesser extent fat, reduces, whereas protein appears to stimulate, ghrelin levels in normal (106) and type 1 diabetic patients (107). However, the micronutrient content and calorie load can not wholly explain the postprandial suppression of ghrelin other factors might be involved. Whereas leptin, GHRH, testosterone, thyroid hormone, and para-sympathetic activity upregulate ghrelin,...

Gut Adipose Interaction

Gut hormones have been shown to interact with long-term signals from adipose tissue. GLP-1 is known to improving insulin sensitivity and, thereby, glycemic control. In rodents, peripheral administration of PYY3-36 for 4 wk resulted in improved glycemic control reduce body weight and visceral fat (33). Recently, Wynne et al. (77) showed a significant reduction in leptin and an increment in adiponectin, markers of adiposity, associated with reduced body weight in 14 patients who had subcutaneous OXM injections for 4 wk.

Endocannabinoids and Energy Homeostasis

The body's endogenous endocannabinoid system includes two endogenous agonists for cannabinoid-(CB)-1 receptors, anadamide and 2-arachidonoyl-glycerol (2-AG). Both of these endocannabinoids (ECs) are fatty acid signals derived from cell membranes. They exert a coordinated action at multiple tissues to promote increased food intake, lipogenesis, and storage of fat. Endocannabinoids interact with multiple hypothalamic circuits and transmitter systems to stimulate food intake in general, and they also act in reward areas of the brain to selectively enhance intake of palatable foods. Activation of CB1 receptors increases enzyme activity that causes de novo fatty acids to be formed in the liver and circulating lipids to be taken up by fat cells. All these actions are reversed in animals lacking CB1 receptors, and there is growing evidence that activity of the endocannabinoid system is toni-cally increased in animal and human obesity. Acute or chronic administration of selective synthetic...

Protein Energy Malnutrition

Th lymphocytes also differentiate along two functionally polarized lines, Th1 and Th2, under a diverse range of influences, including the cytokine milieu, the nature of the protein ligand, cortisol, norepenephrine, and microbial burden.158 Th0 cells are stimulated to differentiate into Th1 cells under

Flaws of Current Diagnosis of Depression

That this statement is not a pure chimera, is demonstrated by the concept of stressor-precipitated, cortisol-induced, serotonin-related, anxiety aggression-driven depression (SeCA depression), a diagnostic concept representing a ''verticalized'' symptom structure 2 . Disorders in anxiety and aggression regulation are considered to be the primary symptoms, and related to certain disturbances in the serotonin system. They are both the precursor symptoms and the key symptoms that might trigger disturbances in mood regulation, which then would lead to the development of a depressive syndrome.

Human Chorionic Gonadotropin HCG

Cortisol is the most abundant glucocorticoid hormone secreted by the adrenal cortex. Glucocorticoid hormones play an important role in maintaining blood glucose levels, metabolizing food, and functioning as antiinflammatory agents. Cortisol stimulates the liver to produce glucose, inhibits the effect of insulin, and decreases the rate at which cells use glucose. Measuring blood Cortisol levels is the best way to evaluate adrenal activity. Under normal circumstances Cortisol secretion is higher in the morning and lower in late afternoon and early evening. Variations from Normal. Consistently elevated Cortisol levels are found in patients with Cushing's syndrome and those individuals under the stress of trauma or surgery. Other conditions associated with an increased Cortisol level include hyperthyroidism, adrenal adenoma, and an overproduction of adrenocorticotropic hormone (ACTH). Decreased levels are seen in Addison's disease, hypopituitarism, hypothyroidism, hepatitis, and...

Interfering Circumstances

Pregnancy, recent isotope scans, and physical and emotional stress can cause increased Cortisol levels. Caffeine and smoking cause elevated Cortisol levels. Estrogen, oral contraceptives, and aldactone may also elevate Cortisol levels. Decreased levels are associated with drugs such as prednisone, androgens, and phenytoin.

Hormones and cell signalling General principles

There are three general classes of hormones (1) peptide hormones, e.g. thyroid-stimulating hormone and adrenocorticotropic hormone (2) steroid hormones, e.g. oestrogens, testosterone and cortisol and (3) derivatives of the amino acid tyrosine, e.g. thyroxine and adrenaline (epinephrine). Peptide and amine hormones are stored in secretory vesicles until needed. Steroid hormones are not stored they are synthesized from intracellular stores of cholesteryl esters after a stimulus.

Classification of Diabetes Mellitus

The most common associations with insulin resistance are obesity and lack of physical fitness. A wide range of other conditions is associated with insulin resistance (see Table 1.2) and many also increase the risk of developing diabetes. In prospective studies, obesity is the strongest modifiable risk factor that predicts future risk of diabetes in nondiabetic populations.37 Body fat distribution is important also visceral (abdominal) obesity, as measured by the waist hip ratio, is a stronger predictor than body mass index.38 It is thought that the increased fat mass in obese individuals augments insulin resistance by a number of different mechanisms, including increased release of free fatty acids and a number of adipocytokines including tumor necrosis factor-a, leptin, resistin, and interleukin-6. Some workers have also proposed, in the lipotoxicity theory that obesity not only affects insulin sensitivity, but also pancreatic function, with excess fatty acids...

P Hydroxydehydrogenase1

Cushing's disease or administration of exogenous glucocorticoids such as prednisone are often associated with increased weight gain, central adiposity, increased food intake, insulin resistance, and in certain individuals, increased likelihood of developing diabetes. However, in general, obese individuals do not have increased circulating levels of cortisol. Interestingly, over the past few years, research has demonstrated that certain enzymes can actually convert inactive cortisol metabolites into active cortisol. One of the first hints that AT was in fact an endocrine organ was its identification as a major site for steroid hormone metabolism (129). 11 PHydroxydehydrogenase (11 HSD)-1 is an enzyme that converts circulating inactive metabolites of glucortiocoids into the active hormone, cortisol. This enzyme has been detected in liver, lung, brain, vasculature, and adipose tissue (130). 11 HSD-1 increases local adipose tissue cortisol levels by converting local inactive cortisol...

Macronutrient Balance

Arguably, one of the greatest metabolic challenges individuals face in the context of modern lifestyles is to create opportunities that favor fat oxidation. Fasting or undernourishment creates this opportunity, but happens rarely in modern life. Indeed, with a schedule of three meals daily, a majority of the 24 h is spent in postprandial metabolism. The other physiological circumstance for promoting fat oxidation is low- to moderate-intensity physical activity, especially sustained duration of physical activity. For many in modern society, careful scheduling and a commitment to undertake daily exercise are required as work and daily living no longer require manual labor. Thus, the structure of modern life impedes the physiology of fat oxidation and disposes instead to fat storage.

Placental Transport And Metabolism Of Retinol During Mammalian Development

Among them, the more specific RDH, catalyzing the oxidation of 9-cis but not all-trans retinol, is expressed in human and mouse placenta (Gamble et al., 1999). Other enzymes with an RDH activity are described in placenta 17b-hydroxysteroid and 11 b-hydroxysteroid dehydrogenases (Brown et al., 2003 Lin et al., 2006 Persson et al., 1991). Moreover, the human type 1 isoforms of 3b-hydroxysteroid dehydrogenase isomerase are expressed in the placenta (Thomas et al., 2004), with a potentiality to oxidize the retinol in retinal. An RDH is also found in the yolk sac of rat embryos (Bavik et al., 1997).

Physiological Effects of Insulin

There is a second point that can be taken from this review of daily partitioning of ingested fat between oxidation and storage because of the quite small fractional turnover of the pool of stored fat, there is implicitly a strong metabolic primacy for tightly regulating fractional release of stored FFA. Insulin is crucial in regulating this process, normally having potent effects to govern rates of lipolysis. In normal-weight individuals, it is estimated that a circulating insulin concentration of 15 U mL, or only twice normal fasting levels of insulin, is sufficient to achieve 50 suppression of fasting rates of lipolysis. This is of higher sensitivity than the effect of insulin to control hepatic production of glucose and far more sensitive than the levels of insulin that are needed to achieve robust stimulation of glucose uptake into skeletal muscle. Therefore, one summation of normal insulin action is that this promotes glucose oxidation rather than that of fat, along with...

Postnatal Influences on Offspring

As would be expected, maternal diet is a primary determinant of milk composition. Cafeteria diets composed of highly palatable junk foods increase the long-chain and decrease the medium-chain fatty acid content of maternal milk and have an additive effect to the presence of maternal obesity in lowering the protein and raising the long-chain fatty acid content of milk (104). Diets high in polyunsaturated fatty acids have the effect of lowering pup body weight and adiposity and leptin levels (58). Feeding dams a high-fat diet also accelerates the onset of independent feeding in neonates by 1 to 2 days (116) in association with increased weight gain (117) and the development of hypertension and abnormal glucose homeostasis as adults (118). Furthermore, feeding successive generations of dams a high-fat diet leads to progressive increases the level of obesity of their offspring (119). This feed-forward effect may have important relevance to the increasing incidence of obesity in the...

Perinatal Environment And Brain Development

The brain is undoubtedly the master controller of energy homeostasis, but it requires neural, hormonal, and metabolic signals from the body and external environment to perform this task. Mammals have evolved a unique set of metabolic sensing neurons to receive these multiple inputs from the periphery. These neurons are arrayed in multiple interconnected sites throughout the brain (151-154). These neurons were originally recognized as glucose-sensing because, unlike most neurons that use glucose only to fuel their metabolic needs, these neurons utilize glucose as a signaling molecule to alter their firing rate when ambient glucose levels change (155,156). It is now clear that many of these same glucose-sensing neurons also utilize metabolites such as lactate (157-159), ketone bodies (160), and fatty acids (161) as signaling molecules. They also have receptors for and respond to hormones such as leptin and insulin (162-166). Because of their ability to use metabolic substrates, as well...

Anatomy of the Face and Neck

Humans develop fat deposits in specific, characteristic sites. As people gain weight existing fat cells become larger (fat cells do not multiply) in these areas. Weight gain is common with aging, and in people who are even mildly obese the characteristic fat deposits become more pronounced. In more obese individuals, the middle neck area below the chin is one such characteristic fat deposit others include the lower abdomen and upper outer thighs. Because weight gain is a feature of aging in most people, increased prominence of fat in the jowls and neck is a common manifestation of aging. Excessive fat in the neck can result in a double chin.

Aging of the Face and Neck

Deep level atrophy is unknown it is probably determined by genetic tendencies. Certain disease states (e.g., AIDS) can greatly accelerate facial atrophy. The solution to atrophy is volume augmentation with natural materials (most useful is a patient's own fat tissue) or with synthetic implants (usually made of a plastic or silicon material). Fat augmentation has the advantage of being totally natural and works best when the fat cells are placed within the facial muscles. Fat augmentation is permanent and can restore volume deficits that result from atrophy of both muscle and bone. Alternatively, anatomical implants made of artificial materials can be placed in the chin or cheek areas. Implants are usually placed immediately above bone.

Lipidsoluble Hormones

Lipid-soluble hormones diffuse through the cell membrane, where they bind to their respective receptors inside the cell. The receptors have a DNA-binding domain (usually Zn-fingers) and interact with specific response elements in enhancer (or possibly silencer) regions associated with certain genes. For example, the Cortisol receptor binds to its response element in the enhancer region of the phosphoenolpyruvate carboxykinase (PEPCK) gene. By increasing the amount of PEPCK in the hepatocyte, Cortisol can increase the capacity for gluconeogenesis, one of its mechanisms for responding to chronic stress often associated with injury. The enhancer mechanism was reviewed in Chapter 5.

Regulation Of Fuel Metabolism

The pathways that are operational in fuel metabolism depend on the nutritional status of the organism. Shifts between storage and mobilization of a particular fuel, as well as shifts among the types of fuel being used, are very pronounced in going from die well-fed state to an overnight fast, and finally to a prolonged state of starvation. The shifting metabolic patterns are regulated mainly by the insulin glucagon ratio. Insulin is an anabolic hormone that promotes fuel storage. Its action is opposed by a number of hormones, including glucagon, epinephrine, Cortisol, and growth hormone. The major function of glucagon is to respond rapidly to decreased blood glucose levels by promoting the synthesis and release of glucose into the circulation. Anaboiic and catabolic pathways are controlled at three important levels

Diacylglycerol Transferase

Triglyceride synthesis has been implicated to occur through the acyl CoA diacylglycerol transferases (DGATs), enzymes that catalyze the final reaction in the glycerol phosphate pathway. DGAT enzymes are highly expressed in tissues associated with triglyceride synthesis. In humans, an abundant expression of DGAT enzymes has been observed in adipose tissue and liver (142,143). Dgat1- - mice are leaner than wildtype mice and have smaller adipocytes (120,144). When fed a high-fat diet, Dgat1- -mice are resistant to obesity and are protected from diet-induced hepatic steatosis (120). These effects are likely caused in part by increased energy expenditure. Moreover, Dgat- - mice demonstrate an increase in spontaneous physical activity (145), increased expression of UCP-1 (144,146), and increased leptin sensitivity (144). An intact leptin pathway appears to be required for the effects of DGAT deficiency on energy metabolism. Although DGAT1 deficiency reverses obesity and insulin resistance...

Endocrine Causes of Obesity

Many patients are concerned that they have a metabolic or glandular cause for their obesity. This may be a reflection of the frustration that some of these individuals feel over the difficulties that they have had in battling a weight problem over many years. They may be looking for a medical explanation of why they have not succeeded in their goal of losing weight. Endocrine causes of serious obesity are not common. The three most commonly cited are hypothyroidism, Cushing's syndrome, and hypothalamic obesity. To evaluate the patient for hypothyroidism, questions can be asked about cold intolerance, constipation, irregular menses, fatigue, or depression. The presence of easy bruisability, proximal muscle weakness (difficulty getting out of a chair, trouble getting things out of a high cupboard), a change in appearance, or osteoporosis may be signs of hypercortisolism. The patient can be examined for signs of hypothyroidism including bradycardia, cool dry skin, a firm palpable...

Pharmacological Treatments Theoretical Basis

Three types of investigations have provided information on possible neuro-biological abnormalities in depressed young people. The first is the study of cortisol secretion, measured by investigationssuchasthe DST. Several studies have shown that, in comparison with non-depressed patients, depressed young people are less likely to show suppression of cortisol secretion when the exogenous corticosteroid dexamethasone is administered 11 . The specificity of the DST for depressive disorder is, however, less for young people than it is for adults 89 . The second investigation is the study of sleep. Polysomnographic (PSG) studies of depressed adults have found that they tend to show abnormalities of sleep, including shortened rapid eye movement (REM) latency (time from the start of sleep to the first period of REM sleep) and reduced slow wave sleep 90 . Many PSG studies with depressed adolescents have shown sleep abnormalities, mainly of REM sleep 91-96 . These generally positive results...

Exercise Lifestyle Modification

There is some evidence that lifestyle modification (diet and exercise) may be an effective adjunct to the treatment of PCOS. The use of hypocaloric diets improves the metabolic derangements in those patients, and low-calorie, low-fat diets have been shown to improve clinical parameters and lower insulin and testosterone levels in PCOS patients (169,170). Weight reduction has also been shown to increase noradrenalin sensitivity in PCOS patients, as PCOS patients have a marked reduction in the lipolytic effects of noradrenalin owing to a decreased number of noradrenalin receptors on fat cells (171), resulting in dyslipidemia. Metformin, in addition to a hypocaloric diet, improves hirsutism, menstrual function, visceral adipose tissue, and glucose-stimulated insulin secretion (172,173). Thus, it appears that diet and medication in combination may be helpful in patients with PCOS.

Abnormal Glucose Metabolism and Type 2 Diabetes

Fat distribution is also very important in diabetes risk (22-25). Central or upper body fat deposition is independently associated with insulin resistance (23), diabetes (24,25), and cardiovascular disease (26). Intra-abdominal or visceral obesity is strongly associated with insulin resistance, as well as with dyslipidemia, hypertension, and glucose intolerance (27-30). In Japanese American men intra-abdominal fat deposition was closely correlated with type 2 diabetes, whereas subcutaneous fat deposits in the abdomen, thorax, or thigh were not statistically significant predictors (31).

Chronic relapsing infection models reactivated toxoplasmosis

Attempts have been made to develop animal models based on reactivation of a chronic infection. It was first observed in 1966 that when infecting splenectomized mice, or mice treated with cortisone or 6-mercaptopurine (6-MP), with the T. gondii Beverley strain, the course of the disease was greatly altered in the experimental animals, distinguished by signs of severe neurological involvement and meningoencephalitis (Stahl et al., 1966). Reactivation of an otherwise chronic infection had succeeded in hamsters infected with the RH strain by the administration of cortisone, cyclophosphamide, or whole body irradiation (Frenkel et al., 1975). On the other hand, in mice only little reactivation using cortisol acetate, azathioprine or cyclosporine was observed (Sumyuen et al., 1996), but reactivation was obtained with dexam-ethasone (DMX) (Nicoll et al., 1997). However, brain cysts were only demonstrated in a minority of the animals.

Neuroendocrine modulation of immune responses

The interplay between the neuroendocrine and immune systems is bi-directional, as exemplified by the control of Cortisol release from the adrenal glands during stress. Cortisol has well-known anti-inflammatory properties and it also suppresses the immune system. The signal for the release of cortisol originates in the brain. Electrical signals generated in the brain, and also IL-1 and IL-6 synthesized in brain cells, stimulate the hypothalamus to produce corticotrophin-releasing hormone (CRH), which induces the anterior lobe of the pituitary gland to release adrenocorticotrophic hormone (ACTH). CRH can also induce lymphocytes to produce their own ACTH. The ACTH is released into the bloodstream and, on reaching the target organ (adrenal glands), stimulates the adrenal cells to secrete cortisol. At excessive concentrations, ACTH inhibits the release of CRH and ACTH by negative feedback to the hypothalamus and anterior pituitary gland.

Proposed Physiological Mechanisms

Elegant homeostatic regulatory mechanisms exert tight control over blood glucose concentrations during the postprandial period to ensure a smooth transition from the fed to the postabsorptive state. In the normal fed state, nutrients stimulate release of incretins, including glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), into the circulation from endocrine cells located in the gut. The incretins augment the effects of rising blood glucose in stimulating insulin release from the P-cells. Insulin promotes an anabolic response characterized by glucose uptake in liver and muscle, and fat uptake in adipose tissue. In the postabsorptive state, counter-regulatory hormones (i.e., glucagon, epinephrine, cortisol, growth hormone) antagonize insulin action, stimulating release of stored metabolic fuels to maintain euglycemia. Metabolic fuels are directed away from storage via increased hepatic glycogenolysis, lipolysis, and gluconeogenesis.

Schizophrenialike Schizoaffective Disorder

Specific morphological, physiological, neuropsychological or biochemical studies have rarely been undertaken in schizoaffective disorder. That lack is probably due to diagnostic inconsistencies and disagreements over the years and to the general assumption to characterize such issues first in the well-defined pure mood disorders and schizophrenia. Nevertheless, a number of biological studies of schizophrenia have included patients with schizoaffec-tive disorder, where internal data analyses failed to distinguish them from the larger group of schizophrenic patients under study. The exceptions are some endocrine studies, like one where the 24-h plasma cortisol response to dexamethasone in 19 patients with coexisting depressive and psychotic features, and 12 non-depressed patients with only psychotic features were examined 202 . The rate and degree of abnormal dexamethasone suppression was greatest in patients who met RDC criteria for primary depressive disorder. Patients who met...

Neuroendocrine Changes

Le Roux et al. (12) have demonstrated a pleiotropic endocrine response to bariatric surgery, which might account for the appetite reduction that leads to long-term changes in body weight. Compared with lean and obese controls, postsurgical RYGB patients had increased postprandial plasma (PYY) and glucagon-like-peptide (GLP)-1, which favor enhanced satiety. Furthermore, those patients had early and exaggerated insulin responses, potentially mediating improved glycemic control. None of these effects was observed in patients losing equivalent weight through gastric banding. Leptin, ghrelin, and PP were similar in both surgical groups (12).

Transgenic And Knockout Animals In Studies Of Food Intake Body Composition And Obesity

In addition to the studies of GH described earlier in this chapter, transgenic and targeted gene-disruption technologies are used to elucidate the mechanisms controlling food intake, body composition, and the pathogenesis of obesity. Within the past few years, the applications of these genetic techniques in whole animals have identified a number of new molecules and physiologic pathways involved in the regulation of body wt, and have led to important new insights into the pathophysiology of eating disorders and obesity. These include the hormone leptin, the short and long forms of the leptin receptor, uncoupling proteins, agouti and agouti-related proteins, melanocortin-recep-tor isoforms, melanin-concentrating hormone, orexin, mahogany, and the proteins responsible for tub and fat, two monogenic mouse models of obesity. These efforts, in addition to characterization of several spontaneous obese mutants, provided a number of novel genetic models in which a single gene or pathway has...

Hyperphagia and Obesity in 5HT2CReceptor Knockout Mouse

Serotonin modulates numerous autonomic functions. It acts through the activation of a large family of G-protein-coupled-receptor subtypes that are widely expressed throughout the brain. The complexity of this signaling system and the paucity of selective drugs have made it especially difficult to define specific roles for 5-HT-receptor subtypes. Mutant mice lacking functional 5-HT2C receptors have been generated to elucidate the physiological function of this widely expressed receptor (156,157). Unexpectedly, 5-HT2C receptor-deficient mice display substantial overweight as a result of increased appetite. This obesity is characterized by leptin and insulin resistance, impaired glucose tolerance, and increased responsiveness to high-fat feeding. Thus, these mutant mice have established a role for the 5-HT2C receptor in the serotonergic control of feeding and energy expenditure. These findings also demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding,...

Studies of Peripheral Mechanisms of Metabolic Regulation

Body wt and food intake were unchanged, while sensitivity to leptin was increased No change in body wt or appetite Increased food consumption and reduced freewheel running and circulating leptin No change in body wt or appetite response to leptin administration Late-onset obesity, increased appetite Obesity and features of type II diabetes

Beta Adrenergic Receptor

These transgenic animals are less susceptible to diet-induced obesity. They have smaller adipose tissue depots than their nontransgenic litter mates, reflecting decreased lipid accumulation in their adipocytes. In addition to increasing the lipolytic rate, overexpression of the beta 1 adrenergic receptor induced appearance of the abundant brown fat cells in sc white adipose tissue. These results demonstrate that the beta 1-adrenergic receptor is involved in both stimulation of lipoly-sis and proliferation of brown fat cells in the context of the whole organism.

Why are Humansbut not Micewith IR Mutations Growth Retarded

As we stated earlier, humans with mutations of the IR gene are profoundly growth-retarded, while mice are hardly affected. A potential explanation of this finding is that humans and mice do not follow the same developmental timing. For example, if we compare the development of eyelids in mice and humans, it is evident that mice are born at a gestational stage corresponding to about 26 wk in human fetuses (58). Likewise, if we examine body composition in newborn mice, we will find that lipid content is significantly lower in mice compared to humans (2 vs 16 , respectively) (59). There are no data on the time course of growth retardation in humans with leprechaunism, but there are some data suggesting that, in patients with pancreatic agenesis, intra-uterine growth retardation is not apparent at gestational ages of 18-20 wk (60,61). On the other hand, there is an abundant literature on excessive fetal growth caused by maternal hypergly-cemia associated with secondary fetal...

Pregnancy And Valve Pathology Physiological Adaptation

During pregnancy the cardiovascular system of the mother adapts in order to fulfill the needs of the growing fetus. A scala of neurohumoral responses occur to achieve this adaptation2. High estrogen levels and an increased sympathetic nervous tone stimulate the renin-angiotensin-aldosterone system, cause water and salt retention, and thus increase plasma volume and increase heart rate and ventricular stroke volume already starting at the fifth wek of pregnancy with a maximum around 24 to 28 weeks of pregnancy. The pregnant state also stimulates erythropoesis, but to a lesser degree than plasma volume, developing a physiologic anemia. The low resistance of the total (including the placental) circulation decreases systemic vascular resistance. Overall, these changes result in a larger total blood volume, a physiologic left ventricular hypertrophy5 and a 30-50 rise in cardiac output2. During late pregnancy, the enlarged uterus may obliterate flow in the caval vein leading to a gradual...

CNS Regulation by Adiposity Signals and Effector Pathways

There are at least two peripherally derived hormones that provide key afferent information to the CNS for body weight regulation. Leptin, a peptide hormone secreted from adipocytes in proportion to fat mass, has received tremendous attention during the last decade. Considerable evidence has been derived that implicates leptin as one of the body's adiposity signals (11-14). Leptin levels in the blood correlate directly with body fat, and peripheral or central administration of leptin reduces food intake and increases energy expenditure. Importantly, leptin levels are better correlated with subcutaneous fat than with visceral fat in humans, such that the reliability of leptin as an adiposity signal varies with the distribution of body fat. There is a sexual dimorphism with respect to the way in which body fat is distributed. Males tend to have more body fat located in the visceral adipose depot, whereas females tend to have more fat in the subcutaneous depot. Because females tend to...

Drugs on the Near and Distant Horizons

There are two cannabinoid receptors, CB-1 (470 amino acids in length) and CB-2 (360 amino acids in length). The CB-1 receptor has almost all the amino acids that comprise the CB-2 receptor, and additional amino acids at both ends. CB-1 receptors are distributed throughout the brain in the areas related to feeding, on fat cells, in the gastrointestinal tract, and on immune cells. Marijuana and tetrahydrocannabinol stimulate the CB-1 receptor and increase high-fat and high-sweet-food intake fasting increases the levels of endocannabinoids, such as anandamide and 2-arachidonyl-glycerol. The rewarding properties of cannabinoid agonists are mediated through the mesolimbic dopaminergic system. Rimonabant is a specific antagonist of the CB-1 receptor, and inhibits sweet food intake in marmosets as well as high-fat food intake in rats, but not in rats fed standard chow. In addition to being specific in inhibiting highly palatable food intake, pair-feeding experiments in diet-induced obese...

Direct Plasma Injection using Restricted Access Media

Chart Medical Injections

Ipratropium, procaine, sotalol, terbutaline 41 , benzodiazepines 22, 25 , salbutamol, clenbuterol 26 , cortisol, arachidonic acid, and prednisolone 42 . Coupling an ADS packing material column to a chiral column has been reported for the direct determination of stereoselective drugs such as ketoprofen 21 , trihexyphenidyl 23 , atenolol 24 , pirlindole 28 , citalopram 29 , and glucuronides of entacapone 43 .

The Endocannabinoid System

Model of signals controlling energy homeostasis. During meals, signals such as cholecys-tokinin (CCK), glucagon-like peptide (GLP)-1, apolipoprotein A-IV (apo A-IV), peptide-YY (PYY), and others that arise from the digestive viscera (stomach, intestine, pancreas, and liver) trigger nerve impulses in sensory nerves traveling to the hindbrain, where they influence meal size. Other signals related to meals such as amylin and ghrelin, and signals related to body fat content such as leptin and insulin, collectively called adiposity signals, circulate in the blood to the brain. Adiposity signals are transported through the blood-brain barrier in the region of the hypothalamic arcuate nucleus (ARC) and interact with catabolic neurons that synthesize proopiomelanocortin (POMC) and secrete a-MSH, or with anabolic neurons that secrete NPY and AgRP. These neurons in turn project to other hypothalamic areas including the paraventricular nuclei (PVN) and the lateral hypothalamic area...

Clinical Indications For Glucocorticoids

(1) Chronic adrenal insufficiency (Addison's Disease). Addison's disease may develop as a result of adrenal surgery or due to destructive lesions of the adrenal cortex. The replacement therapy associated with this condition requires approximately 20 to 30 milligrams of hydrocortisone (cortisol) or its equivalent daily, with increased amounts of medication during periods of stress. (NOTE Doses as high as 100 milligrams of hydrocortisone per day may be necessary during periods of stress.) Furthermore, mineralocorticoid therapy will also be necessary with monthly injections of deoxycorticosterone (Doca , Percorten ). (3) Congenital adrenal hyperplasia syndrome (CAH). In CAH, the production of hydrocortisone (cortisol) and, at times, aldosterone is interfered with or prevented due to an inherited enzyme deficiency. The treatment of CAH requires the administration of hydrocortisone. The dosage of this agent must be adjusted over a long course of therapy to permit linear growth in children.

Control of Gluconeogenesis by Response Elements

Cortisol Cortisol Cortisol Figure 1-5-6. Cortisol and Glucagon Stimulate Gluconeogenesis Through Enhancer Mechanisms Cortisol secreted in response to stress, is permissive for glucagon in hypoglycemia and acts through an intracellular receptor, which, like other steroid receptors, is a zinc-finger DNA binding protein. Cortisol induces PEPCK gene expression by the following sequence Cortisol diffuses into the hepatocyte, where it These effects of CREB and the cortisol-receptor complex are not entirely independent of each other. Each contributes, along with several other transcription factors, to assembling a complex of activator proteins that ultimately determine the level of PEPCK gene expression.

Congenital Adrenal Hyperplasia

CAH results from Cortisol deficiency, which causes increased corticotropin secretion and subsequent hyperplasia. Risk Factors Etiology. CAH is a series of autosomal recessive disorders 21-hydroxylase deficiency is the most common cause of CAH, followed by 1 l 3-hydroxylase deficiency and 3(3-hydroxysteroid dehydrogenase.

Physiological actions of glucagon

Although insulin is the main glucose-lowering hormone, a number of humoral factors may increase blood glucose concentrations, including glucagon, catecholamines, cortisol, and growth hormone. Glucagon is a peptide hormone released by a-cells of the pancreas in response to drops in blood glucose concentration. In vivo experiments in dogs have shown that glucagon secretion increases twofold in response to a fall in glucose from 100 mg dl (5.6 mmol l) to 80 mg dl (4.5 mmol l).5 The principal target organ of glucagon action is the liver, in which it increases glycogenolysis and gluconeogenesis and inhibits glycogenesis and glycolysis.* Glucagon acts via hepatic cell surface G-protein-coupled receptors by a number of intracellular mechanisms whose net result is that hepatic glucose production increases and blood glucose rises. Increasing evidence suggests that, in type 2 diabetes, hyperglucagonemia and or an imbalance between the glucagon insulin ratio is present.6

Superior Arcuate Line Vocal Fold

The amount of subcutaneous fat available for harvest should be evaluated prior to VFL. For patients who have an extremely small amount of subcutaneous fat, liposuction is not a reasonable harvest technique, and in fact, even open fat harvest can be problematic. In this specific patient group, subcutaneous open fat harvest will most likely be more involved and may have an increased complication rate than in patients with generous subcutaneous fat deposits. Furthermore, in the extremely lean patient, surgical harvest of subcutaneous fat may not yield adequate amounts of fat for successful VFL.

Lacrimal Functional Unit

Nerves from the parasympathetic spheno-palatine (pterygopalatine) ganglion are associated with the secretory glands of the lacrimal functional unit. Parasympathetic cholinergic nerves are primarily responsible for signalling reflex tear secretion, and acetylcholine (M3) receptors are present on secretory epithelia of lacrimal glands and on mucin-producing goblet cells in the conjunctiva 5 . Other parasympa-thetic neurotransmitters have also been detected near the lacrimal epithelium and meibomian glands 13 . Evidence for nerves of sympathetic origin has been found for the main and accessory lacrimal glands, the meibomian glands, and conjunctival goblet cells. Maintenance of the lacrimal gland secretory environment is also regulated by serum-derived factors, including androgen, oestrogen, progesterone, cortisol, insulin, thyroxin, and growth factors 43 .

The Pineal Gland and the Biological Clock

Every day our serum Cortisol level peaks at approximately our wake-up time, growth hormone reaches its maximum blood level at the beginning of our sleep phase, prolactin does so soon after, while thyrotropin hormone peaks in the last part of our sleep phase. In the same way, mostly every hypothalamic, hypophyseal and hypophysis-dependent hormones show a fixed temporal pattern with peaks and troughs everyday at the same time and with a stable phase-relationship between them as well as with other types of physiological and behavioral rhythmic variables. For example, blood pressure and core body temperature, subjective alertness and potassium excretion, also vary predictably day by day, with values raising during the day and falling during sleep. Figure 2.71 illustrates the

Insulin Sensitizing Agents

Metformin was approved for the treatment of type 2 diabetes by the FDA in 1994, but was used clinically for almost 20 yr before that in other parts of the world. The effects of the drug are therefore well known. Metformin is a biguanide that works primarily by suppressing hepatic gluconeogenesis, and in muscle and fat cells it enhanced glucose uptake and utilization, therefore improving insulin sensitivity in the periphery. This effectively lowers glucose and insulin levels. Its most serious, but rare, side effect is lactic acidosis, which has been reported in individuals with renal deficiency, liver disease, and heart and respiratory failure. The most common side effect is gastrointestinal disturbance, but this rarely is a cause to discontinue the drug. Metformin could also decrease folic acid and vitamin B12 absorption.

Corticotropin Releasing Hormone and Urocortin

Urocortin is a second peptide in the CRH family. Urocortin administration reduces food intake but unlike what occurs following CRH, reductions in food intake are not associated with other aversive effects (198). Urocortin is produced in the caudal brainstem and has prominent projections to the PVN (199). Given the central importance of the CRH system to activity of the HPA axis, the important role of peripheral glucocorticoids in controlling metabolic processes, and the inverse relationship between peripheral leptin and glucocorticoid levels, unraveling the complicated relationship of the CRH urocortin systems in control of energy balance remains a critical but elusive goal. (For a more thorough review of the CRH system and energy balance see refs. 200,201)

Magnetic Resonance Spectroscopy Quantification of Ectopic

Unlike CT or MRI, proton magnetic resonance spectroscopy (H1 MRS) is able to partition the lipid signal into separate intra- and extramyocellular lipid (IMCL and EMCL) components within the skeletal muscle. As it has been suggested that IMCL is an important fat depot that is associated with deleterious effects on insulin sensitivity, it may be important to accurately quantify this depot. Briefly, the principles of MRS are very similar to those of MRI, and in many cases MRS can be acquired using the same machine, and is used in conjunction with MRI in order to carefully landmark and place the region of interest or voxel in a location that is free from visible macroscopic fat depots. This voxel is generally 2 to 3 cm2, and it is important that the voxel contain as little visible interstitial tissue or fat as possible, as the presence of large fat deposits such as subcutaneous fat or large quantities of EMCL will obscure the relatively smaller IMCL signal. Similar to MRI, H1 MRS uses...

Genetic or Spontaneous Diabetes Mellitus Models

Receptor defect for the same hormone was suspected. These studies eventually led to the discovery of the satiety hormone leptin, which has been found to be one of several recently discovered mediators of body mass composition (30). The ob ob mice lack the gene to produce leptin and thus are never satiated. There is a rare human form of diabetes mellitus that involves a lack of leptin that is owing to a lack of the ob gene (31). The db db mouse, however, lacks the receptor for leptin in the hypothalamus (32). These experiments have led to the new field of the hormonal regulation of body mass composition.

Neuroregulation of Appetite

This chapter reviews current literature on hormonal and neural signals critical for the regulation of individual meals and body fat. Body weight is regulated via an ongoing process called energy homeostasis, or the long-term matching of food intake to energy expenditure. Reductions from an individual's normal weight owing to a lack of sufficient food lowers levels of adiposity signals (leptin and insulin) reaching the brain from the blood, activates anabolic hormones that stimulate food intake, and decreases the efficacy of meal-generated signals (such as cholecystokinin) that normally reduce meal size. A converse sequence of events happens when individuals gain weight, adiposity signals are increased, catabolic hormones are stimulated, and the consequence is a reduction in food intake and a normalization of body weight. The brain also functions as a fuel sensor and thereby senses nutrients and generates signals and activation of neuronal systems and circuits that regulate energy...

Drugs No Longer Under Investigation or Withdrawn

Hibernating and migratory animals change their ability to store and burn fat based on circadian rhythms these circadian rhythms are controlled by prolactin secretion. It has been postulated that obese and diabetic individuals have abnormal circadian rhythms. These abnormal rhythms favor fat storage and insulin resistance. Rapid-release bromocriptine (Ergocet ), given at 8 00 am, has been postulated to reverse this abnormal circadian rhythm and effectively treat diabetes and obesity. An uncontrolled trial of quick-release bromocriptine given orally for 8 wk significantly decreased 24-h plasma glucose, free fatty acid, and triglyceride levels from baseline (121). This was followed by a controlled trial in which 22 diabetic subjects were randomized to quick-release bromocriptine or placebo. The hemoglobin A1c fell from 8.7 to 8.1 in the bromocriptine group and rose from 8.5 to 9.1 in the placebo group, a statistically significant difference (122). In an uncontrolled trial, 33 obese...

Ciliary Neurotrophic Factor and Axokine

Ciliary neurotrophic factor (CNTF) is a neuronal survival factor shown to induce weight loss in rodents and humans (222,223). CNTF leads to a reduction in food intake and body weight apparently via activating pathways that mimic leptin, though unlike leptin, CNTF is active in leptin-resistant diet-induced obese mice (224). Interestingly, CNTF-treated rodents and humans lose weight and maintain the reduced body weight for a long period after cessation of treatment. The implication of these observations suggests that CNTF resets the body weight set point, or changes the weight the body defends. But the reason was not understood, although recent data from the Flier laboratory shed light on a potential mechanism for the maintenance of the weight loss (225). Flier and colleagues showed that CNTF induces neuronal cell proliferation in hypothalamic feeding centers. The new cells show functional leptin responsiveness. The data provide an explanation for the prolonged weight loss maintenance...

Review of the medical records

Brain trauma results in a severe physiological stress to the body and elevates adrenocorticotropic hormone (ACTH) release. This secondarily increases cortisol secretion. Brain injury to the frontal brain parts may damage the hypothalamus and pituitary. If the injury is severe, the result is usually death. Rarely, the patient develops a syndrome of inappropriate antidiuretic hormone secretion (SIADH) or panhypopituitarism. Infrequently, loss of thermoregulation may occur due to hypotha-lamic damage. These are usually low-likelihood events occurring in less than 1 of brain-injured persons but when they do occur, they can cause significant difficulty to the patient.109 An endocri-nologist may be required to manage some patients following brain injury, and, depending on the particular releasing factor deficiency, adjunctive hormonal replacements may be needed.117


The action of leptin, and possibly insulin, on feeding behavior is transduced by the melanocortin signaling pathway in the hypothalamus (227). The arcuate nuclei in the hypothalamus contain two distinct populations of neurons that highly express the leptin receptor. These neurons are the POMC and agouti-related protein (AgRP) NPY neurons, which project onto neurons in the paraventricular and lateral hypothalamic area known to express the melanocortin receptors. The POMC-containing neurons secrete the melanocortin agonist a-MSH, whereas the AgRP NPY-containing neurons secrete the melanocortin antagonist AgRP. Leptin appears to reciprocally regulate these nuclei. Low leptin levels lead to increased expression of AgRP and reduced expression of POMC and a-MSH. In contrast, high leptin levels lead to increased expression of POMC and reduced expression of AgRP.


Regulation of feeding behavior by syndecan-3 is likely modulated by cleavage of its extracellular domain by shedding (244). Transgenic expression of syndecan-1, a homolog of syndecan-3, in the hypothalamus leads to hyperphagia and obesity in mice (240). Notably, the hypothalamic expressed syndecan-1 cannot be shed, suggesting loss of feeding regulation. In fact, injection of shedding inhibitors into the hypothalamus of normal rodents leads to hyperphagia. Syndecan-3 is poised to play a role in the hypothalamic regulation of feeding behavior modulated by synaptic plasticity. Recent data from the Horvath and Simmerly laboratories indicate that rewiring of the arcuate nuclei in the hypothalamus occurs in response to leptin (245,246). The data indicate that excitatory and inhibitory synapses on the POMC and AgRP NPY neurons can rapidly change in response to adiposity signals such as leptin. Syndecan-3 has been implicated in synaptic plasticity changes involved in hippocampus-dependent...

Peripheral Signals

Insulin from the pancreas, leptin from adipose tissue, and gut peptides (PYY3-36, GLP-1, CCK, and OXM) from the gastrointestinal tract (GIT) are known anorexigenic hormones peptides. They directly inhibit NPY AgRP and stimulate POMC CART in the arcuate nucleus (11). Reciprocal to this is the orexigenic gut peptide ghrelin. Ghrelin stimulates NPY AgRP and inhibits POMC CART (discussed in Ghrelin Mechanism of Action), thereby promoting meal initiation and increasing food intake. Whereas leptin and insulin are known to be long-term regulators of adiposity and energy expenditure, gut peptides are short-lived signals controlling food intake. They are sensed by the hypothalamus on a meal-to-meal and or day-to-day basis along with other neural, mechanical, and nutrient gut sensing signals. Here we discuss the anorexigenic and orexigenic gut peptides.

Cushings Syndrome

Psychotic symptoms such as delusions and hallucinations occur only rarely. When the syndrome occurs secondary to other causes, depressive symptoms are far more common. It appears that a depressive mood secondary to Cushing's syndrome is intermittent rather than chronic and irritability is reported to be heightened beyond what is typically found in major depression 107, 109 . The onset of the affective symptoms has been reported to occur both preceding and following the onset of the medical signs and symptoms of Cushing's disease. Depressive symptoms subside following successful treatment of the endocrine disorder. Several symptoms are not dependent on cortisol plasma levels 109,110 .

Neuroendocrine Tests

The hypothalamic-pituitary-adrenocortical axis. The DST was the first, and is to date the most studied, putative biological marker in research on depressive disorders. In 1968 Carroll et al 136 showed that while depressed, patients fail to suppress plasma cortisol. This led Carroll to claim that a positive DST is a specific laboratory test for melancholia or severe forms of depression 46 . Subsequent studies confirmed the high specificity vs. normal or non-psychiatric controls (91 -93 ) but not vs. dysthymic and other severe or acute psychiatric disorders as well as vs. apparently healthy individuals who had experienced a recent stressful event 137 . Moreover, high and low cortisol suppressors were found not to differ in depressive symptoms among participants in population studies 138 . However, cortisol secretion was found to be related to temperament dimensions 139 . A recent meta-analysis to determine the significance of differences in non-suppression of cortisol across studies,...

Adipose Tissue

White adipocytes express CB1 receptors (16,17,20), and in vitro experiments demonstrate that the CB1 agonist WIN-55,212 stimulates adipocyte differentiation and increases the activity of lipoprotein lipase both actions are blocked by pretreatment with SR 141716 (16). These findings imply that EC activity in white fat has the potential to facilitate growth of new fat cells as well as an enhanced ability to remove fat from circulating lipoproteins and deposit it into fat cells. Furthermore, as adipocytes mature, they express a greater amount of CB1, and CB1 expression is higher in adipocytes of obese as opposed to lean animals (17). Studies in humans also indicate that mature adipocytes have increased CB1 expression as compared to preadipocytes. However, in contrast with the observations reported in obese animals, obese humans have decreased CB1 expression in their adipose tissue relative to lean humans (20).


Higher concentrations of adipose tissue IL-6 are associated with insulin resistance (96). In a study that carefully examined adipose tissue and systemic insulin sensitivity, including measures of serum fatty acids, IL-6, and TNF-a in the lean and obese, insulin resistance was most highly correlated with serum measures of IL-6. Additionally, serum IL-6 correlated with serum measurements of fatty acids (69). However, it is currently unclear as to whether this is merely a reflection of the correlation between insulin resistance and inflammation, or is in fact a causal relationship. One possible effect of IL-6 may be indirect in the sense that IL-6 has been reported to decrease adiponectin levels (96). Additionally, IL-6 can increase lipolysis (97). Another possibility is that IL-6 can inhibit insulin by increasing the cellular expression of suppressor of cytokine signaling (SOCS)-3, a negative regulator of both leptin and insulin signaling. IL-6-induced SOCS-3 expression has been...


Although historically adipocytes have been thought of basically as a reservoir of triglyceride, it is clear that AT can synthesize and secrete local as well as systemic mediators of metabolism. Thus, AT can be viewed as an endocrine organ. In lean individuals small adipocytes secrete adipokines, such as leptin and adiponectin, which promote healthy metabolic homeostasis. However, with the onset of obesity, a macrophage-mediated profile is observed in AT. Multiple cytokines, such as TNF-a and IL-6, are secreted, with some acting locally in AT and some being released into the circulation to act at distal sites. In addition, these cytokines can act locally to increase adipocyte release of fatty acids and to reduce adiponectin levels. Chronically, this altered adipokine secretion that accompanies obesity significantly contributes to the development of insulin resistance, metabolic syndrome, atherosclerosis, and diabetes.

Barry E Levin md

Epidemiological studies suggest that maternal undernutrition, obesity, and diabetes during gestation and lactation can all produce obesity in offspring. Animal models provide a means of assessing the independent consequences of altering the pre- versus postnatal environments on a variety of metabolic, physiologic, and neuroendocrine functions that lead to the development of offspring obesity, diabetes, hypertension, and hyperlipidemia. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological, immunological, and pharmacological stressors can all promote offspring obesity. Normal postnatal nutrition can sometimes reduce the adverse impact of some of these prenatal factors but may also exacerbate the development of obesity and diabetes in offspring of dams that were malnourished during gestation. The genetic background of the individual is also an important determinant of outcome when the perinatal environment is perturbed. Individuals...

Intercostal veins

Respiratory distress syndrome is caused by a deficiency of surfactant (composed of phosphatidylcholine mainly dipalmitoyl lecithin and proteins). This condition can be associated with premature infants, infants of diabetic mothers, and prolonged intrauterine asphyxia. Thyroxine and Cortisol treatment increase the production of surfactant.

Sf1 Knockout Mice

Involved in steroidogenesis, including 3 -hydroxysteroid dehydrogenase, the ACTH receptor, StAR, and the high-density lipoprotein receptor SR-B1 (reviewed in 10). Analyses of reporter genes driven by the M llerian-inhibiting substance (MIS) promoter region in transfected Sertoli cells and transgenic mice suggest that SF-1 also regulates expression of the MIS gene (11-13). Thus, SF-1 regulates the production of both essential hormones in male sexual differentiation androgens and MIS.


A history of sudden emergent severely high blood pressure, alcohol abuse or kidney disease, and or a physical examination that showed signs of end-stage damage or Cushing's syndrome, including striae, truncal obesity, a hump, and bruising, would suggest that a more extensive evaluation is needed. Similarly, abnormal electrolytes, especially potassium levels, might indicate the need to evaluate for endocrinopathies. An elevated blood urea nitrogen or creatinine level or an abnormal urine analysis would indicate the need to examine renal functions with 24-hour urine tests, serum levels of metanephrines, urine culture, morning and or afternoon cortisol levels, and intravenous pyleograms and renal ultrasounds.

Novel Therapeutics

Other novel substances are on the horizon which, when administered parenterally, have insulin-sparing or insulin-like effects. Leptin, also known as the obesity gene product, has been linked to lower glucose levels, improved insulin sensitivity, regulation of adipose stores, myocardial antihypertrophic effects, and enhanced P-cell function. Leptin can delay the onset of type 2 diabetes, inhibiting fat formation and speeding its depletion. Deficiency of leptin or leptin insensitivity has caused obesity and altered metabolic rates in humans and animals. When administered via infusion in mice, leptin has reversed myocardial wall thickness and partially reversed myocyte hypertrophy. These effects were not produced by calorie restriction alone. Leptin does not only affect fat cells it is also responsive to cells that express leptin receptors, which are found in adipose and nonadipose cells in the liver, pancreas, and skeletal muscle.


In patients with type 1 insulin-dependent diabetes melhtus not adequately treated with insulin, fatty acid release from adipose tissue and ketone synthesis in the liver exceed the ability of other tissues to metabolize them, and a profound, life-threatening ketoacidosis may occur. An infection or trauma (causing an increase in Cortisol or epinephrine) may precipitate an episode of ketoacidosis. Patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM) are much less likely to show ketoacidosis. The basis for this observation is not completely understood, although type 2 disease has a much slower, insidious onset, and insulin resistance in the periphery is usually not complete. Type 2 diabetics can develop ketoacidosis after an infection or trauma. In certain populations with NIDDM, ketoacidosis is much more common than previously appreciated.

IOral Contraceptives

This side effect is seen most often in patients taking high estrogen and or progestin products. (e) Nausea and vomiting. This side effect is most often observed in patients taking high estrogen products. (f) Skin reactions. Increased pigmentation can be aggravated by sunlight. This side effect is more common in individuals who have darker skin. This type of side effect is observed most often in patients who are taking high estrogen products.

Neuropeptide Y NPY

NPY, a 36-amino-acid neuromodulator that is widely distributed throughout the peripheral and CNS and coreleased with norepinephrine, is one of the most potent stimulators of food intake, and exerts a plethora of other physiological effects (131). Overexpression of rat NPY in transgenic rats produced increases in food intake, body wt, fat deposits, and reduction in plasma leptin levels in males (132). Surprisingly, effects of NPY overexpression on the same parameters in transgenic females were either less pronounced or opposite. These differences could be related to a more pronounced downregulation of NPY-receptors in NPY transgenic females (Y. Dumont, M. Michalkiewicz, and R. Quirion, unpublished observations). In NPY-transgenic rats of both sexes, spontaneous locomotor activity (wheel running) was reduced, and systolic blood pressure was elevated (132). However, overexpression of the mouse NPY gene in transgenic mice did not affect body wt (133). These differences between the mouse...

Brown Adipose Tissue

To test this hypothesis, several lines of transgenic mice with selective ablation of the brown adipose tissue have been generated. In these mice, the regulatory elements of the brown adipose tissue-specific UCP protein gene were used to drive expression of DTA transgene resulting in specific ablation of brown adipose tissue. These mutants are characterized by reduced energy expenditure (lower body temperature but not locomotor activity), marked obesity, increased food intake, hyperglycemia, hyperlipidemia, and increased susceptibility to a high-fat diet induced obesity (151,158-160). These abnormalities are associated with insulin resistance and non-insulin-dependent diabetes mel-litus (NIDDM) with both receptor and postreceptor components (161,162). Interestingly, in this model, increased body wt, hyperlipidemia, late hyperphagia, and glucose homeo-stasis are leptin-resistant, while hypothalamic NPY and the hypothalamic-pituitary-adrenal axis remain under leptin control (151,163)....


Though accounting for a relatively small portion of obesity in the pediatric age group, a number of endocrine disorders and genetic syndromes can be causally linked to childhood obesity. Of note is that these disorders are generally accompanied by poor linear growth and developmental delay. Recent studies of large family pedigrees have also identified a number of genetic loci that appear to be associated with severe obesity (103). One such genetic locus found in some obese individuals is that which encodes for the melanocortin 4 receptor (104). It is also possible that alterations in the genes that control production of leptin and ghrelin may play a role in some cases of human obesity (105). Leptin is a hormone secreted from adipocytes that moderates food intake and energy expenditure. Circulating levels correlate with body fat and BMI. Leptin increases in boys and girls from 5 to 15 yr of age, before the appearance of other pubertal hormones. Ghrelin is a gastric hormone that...

Review Questions

As part of a study to quantify contributors of stress to hyperglycemia and ketosis in diabetes, normal hepatocytes and adipocytes in tissue culture were treated with Cortisol and analyzed by Northern blotting using a gene-specific probe. The results of one experiment are shown below. Hepatocytes Cortisol (nM) 0 100 500 1000 Adipocytes Cortisol (nM) Hepatocytes Cortisol (nM) 0 100 500 1000 Adipocytes Cortisol (nM)

Questions 450452

460, A 27-year-old female is diagnosed with hypercortisolism. To determine whether Cortisol production is independent of the pituitary gland, you decide to suppress ACT11 production by giving a high-potency glucocorticoid. Which glucocorticoid is the best for this indication 462, A 48-year-old female is diagnosed with small-cell lung carcinoma with ectopic production of ACTH. An adrenocortical antagonist (drug X) is given. and Cortisol levels decrease significantly. Following treatment, the patient complains of excess hair growth and swelling of the legs. What is drug X

Localized Disease

Microscopically, there is an ulcer with undermined reep-ithelializing edges. Adjacent epidermis is often hyperplastic. In the ulcer base and surrounding tissue there is contiguous coagulation necrosis down to and including the fascia (Fig. 37-5). In the panniculus the fat cells are swollen and dead, but their ghost outlines are retained. The interlobular FIGURE 37-6 Subcutaneous tissue of a major ulcer. There are islands of dead fat cells (ghosts) and massive numbers of acid-fast bacilli in an area of coagulation necrosis. Ziehl-Neelsen stain, x25.


After synthesis of the steroid pregnenolone from cholesterol, sex steroid production relies on four important enzymes. First, the cytochrome p450 enzyme CYP17 converts pregnenolone and progesterone to dehydroepiandrosterone (DHEA) and androstenedione, respectively. Second, the steroid dehydrogenase 3PHSD converts A5 steroids (such as pregnenolone and DHEA) to A4 steroids (progesterone and androstenedione, respectively). Third, 17p-hydroxysteroid dehydrogenase (17PHSD) metabolizes androstenedione to testosterone. Finally, the aromatase enzyme CYP19 converts androstenedione and testosterone to estrone and estradiol, respectively.


Adiponectin, also called gelatin-binding protein (GBP)28 (19), adipocyte complement-related protein (Acrp30) (20), AdipoQ (21), and adipose most abundant gene transcript 1 (apMI) (22), was discovered at approximately the same time as leptin, in 1995. Similar to leptin, adiponectin is expressed exclusively by mature adipocytes, and increases dramatically with differentiation of preadipocytes to adipocytes (23). However, unlike leptin, its expression does not increase with obesity, but as will be discussed later, it decreases. Adiponectin circulates in plasma in the microgram-per-milliliter range, which is the highest plasma concentration of any of the adipose-secreted proteins, most of which are in the nanogram-per-milliliter range (24). Production of both leptin and adiponectin production is higher in subcutaneous fat than the deeper visceral depots (25), and similarly, the concentration of this hormone tends to be higher in females than in males (26). Adiponectin, like leptin, has a...

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