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My Beta Switch Program Review

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All of the information that the author discovered has been compiled into a downloadable pdf so that purchasers of Beta Switch Program can begin putting the methods it teaches to use as soon as possible.

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.

Implications of leptin signal transduction

As mentioned earlier, the fall in leptin during fasting is a potent signal to the brain to increase feeding, reduce energy expenditure, and mediate changes in hormone levels designed to conserve energy (10,17). Low leptin level directly stimulates the expression of NPY and AGRP in the Arc, and indirectly increases MCH in the lateral hypothalamus, leading to hyperphagia and restoration of body weight (10,52). Concurrently, low leptin disinhibits POMC neurons in the Arc, thereby decreasing the synthesis and release of the anorectic peptide a-MSH (10,52). a-MSH normally acts on melanocortin 3 and 4 receptors (MC3 4-R) in the PVN and various hypothalamic nuclei to mediate the satiety effect of leptin (52). a-MSH is antagonized by AGRP, resulting in hyperphagia and weight increase (52). CART, another potent inhibitor of feeding, is directly suppressed by low leptin level during fasting (52). NPY AGRP and POMC CART neurons in the Arc send extensive projections to the PVN, perifornical, and...

Leptin action in peripheral tissues

Ablation of the Arc, Lep db db, or loss of LEPRb in neurons and specifically in POMC neurons have all confirmed that leptin acts primarily in the brain (36,87-90). Nonetheless, numerous studies have demonstrated leptin signaling in blood cells, pancreatic P-cells, pituitary, kidney, hepatocytes, muscle, and adipocytes (18,91-100). Apart from immune cells, most of these tissues lack functional LEPRb or at best express very low levels, suggesting that short-form leptin receptors may mediate leptin signaling (91-100). Ex vivo studies of isolated T-lymphocytes from mice and humans indicate that leptin promotes cellular survival and enhances immunity, especially during starvation (91). Leptin inhibits insulin secretion from isolated pancreatic islets, although the opposite effect has been reported (92,93). Furthermore, leptin induces LH and follicle-stimulating hormone (FSH) release from pituitary explants and sympathetic nerve activity to the kidneys (94,97). Kim et al. (95) found that...

Leptin modulation of innate immunity

The primary amino acid sequence of leptin indicated that it could belong to the long-chain helical cytokine family (11), such as IL-2, IL-12, and growth hormone (GH). In fact, leptin receptor (Ob-R) shows sequence homology to members of the class I cytokine receptor (gp130) superfamily (12), which includes the receptor for IL-6, LIF, and granulocyte colony-stimulating factor (G-CSF). Moreover, Ob-R has been shown to have the signalling capabilities of IL-6-type cytokine receptors (13) this is detailed later in this chapter. In this context, a role for leptin in the regulation of innate immunity has been proposed (10,14). Figure 1 summarizes the role of leptin modulating the function of cells involved in both innate and adaptive immunity. Consistent with this role of leptin in the mechanisms of immune response and host defense, circulating leptin levels are increased upon infectious and inflammatory stimuli such as lipopolysaccharide (LPS), turpentine, and cytokines (15,16). On the...

Leptin Regulation of Monocytes Macrophages

Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflamma-tory cytokines both in vivo and in vitro, whereas exogenous leptin upregulated both phagocytosis and the production of cytokines (18). Furthermore, phenotypic abnormalities in macrophages from leptin-deficient, obese mice have beeen found (19). More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production (16). More specifically, murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. In this context, leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation (20). Human leptin was found to stimulate proliferation and activation of human circulating monocytes in vitro, promoting the...

Mechanisms of leptin action in immune cells

Leptin receptor (Ob-R) belongs to the family of class I cytokine receptors, which include receptors for IL-2, IL-3, IL-4, IL-6, IL-7, LIF, G-CSF, growth hormone-releasing hormone, prolactin, and erythropoietin (12). As mentioned in the previous section, Ob-R expression is present in hematopoietic cells as well as the cells that participate in the innate and adaptive immune response. Leptin signaling has recently been reviewed (47,48), and we have previously reviewed leptin signaling in mononuclear cells (10). Most members of the cytokine family of receptors stimulate tyrosine phosphorylation of signal transducers and activators of transcription (STAT) proteins by activating JAK kinases, which are associated with the intracellular part of the transmembrane receptor (49,50). Tyrosine phosphorylation of the activated leptin receptor has already been reported in other systems (51,52). In human blood mononuclear cells, we have also found that human leptin stimulates tyrosine...

Leptin and pathophysiology of the immune system

It seems to be generally accepted that leptin may be an important signal that connects energy stores with the immune system (3,5,10). In fact, leptin has been considered an indicator of nutritional status. Thus, falling leptin levels in starvation may alert the organism to avoid energy wasting and to seek energy storing. Therefore, the lack or decrease of leptin levels may play a role in the immunosuppression of starvation. In this context, leptin may serve to signal the organism to conserve energy by shutting down nonessential systems. Moreover, leptin might be not only a signal for the adaptation of starvation, but in addition, leptin could have played a role in selection, helping the better nourished to survive under starving conditions, allowing the defense against infection to those better prepared. The same immune deficiency observed in starvation has been found in human obesity syndromes caused by a deficiency of leptin production or leptin action (46). In addition, leptin...

Leptin in liver and kidney immunemediated disorders

Protection of ob ob mice from autoimmune damage is also observed in experimentally induced hepatitis (EIH). Activation of T-cells and macrophages is one of the initial events during viral or autoimmune hepatitis. Activated T-cells are directly cytotoxic for hepatocytes and release proinflammatory cytokines, which mediate hepatocyte damage in several models. A well-described mouse model of T-cell-dependent liver injury is the iv injection of the T-cell mitogen concanavalin A (Con A), which results in fulminant hepatitis. During Con A-induced hepatitis, TNF-a is a crucial cytokine, as specific neutralization of this cytokine reduces liver damage. The injection of TNF-a causes acute inflammatory hepatocellular apoptosis followed by organ failure, and TNF-a appears to cause hepatoxicity in several experimental models. Siegmund et al. (30) showed that leptin-deficient ob ob mice were protected from Con A-induced hepatitis. Moreover, TNF-a and IFN-y levels, as well as expression of the...

BHydroxysteroid dehydrogenase1 11PHSD1 inhibitors

In humans, the circulating levels and activity of cortisol and cortisone are tightly regulated. The enzyme 11-b-HSD-l catalyzes the conversion of cortisone to cortisol, using NADPH as co-factor, while the reverse reaction is catalyzed by 11-p-HSD-2. Cortisol is the ligand for glucocorticoid receptors and modulates numerous biological functions, including the HPA axis. Studies using transgenic mice lacking either 11-b-HSD-l or ll-b-HSD-2 indicated the desirability of selective inhibition of 11-b-HSD-l to reduce hepatic glucose production, and improve glucose homeostasis. Numerous steroid based inhibitors have been discovered including glycyrrhetinic acid and carbenoxolone 42,43 . Recently, 2-aminothiazole based rat- and human-selective 11-b-HSD-l inhibitors, 45 and 46 respectively were disclosed 44,45 . Compound 46, was found to lower circulating glucose levels by 50- 88 and insulin by 52-65 of control in ob ob and KK-Ay mice after dosing at 200 mg kg b.i.d for 4 days. BVT.3498,...

Leptin as pivotal mediator of intestinal inflammation

In several experimental colitis models, such as trinitrobenzene sulfonic acid (TNBS) as well as indomethacin-induced colitis and in spontaneously developing colitis in IL-2- - mice, serum leptin concentrations are increased (27,28). However, the elevated serum concentration of a mediator during active colitis does not necessarily imply its key function in the inflammatory process. To prove a critical role, neutralization experiments or the use of knockout animals is required. Thus, we compared disease severity in wild-type (WT) and leptin-deficient ob ob mice using the model of DSS-induced colitis, which represents a model of chemically induced intestinal inflammation. The exposure of the colon to DSS results in disruption of the epithelial barrier, followed by phagocytosis of otherwise unavailable antigen from the normal mucosal microflora by antigen-presenting cells located in the lamina propria. Presentation of these antigens subsequently results in activation of T-cells (29-31)....

Direct role of leptin on tcell activation in intestinal inflammation

Leptin has primarily been described as a regulator of appetite that exerts its regulatory function via a negative feedback mechanism in the hypothalamus (31). Because of this systemic effect of leptin it was necessary to evaluate whether the alterations in the immune system in ob ob mice are induced by a central effect of leptin or whether leptin can directly act on cells in the periphery. The in vitro data described in the introduction strongly suggested that leptin in fact can directly stimulate T-cells as well as epithelial cells (14,25). In line with these results, data from our own group indicated that leptin exerts direct stimulatory effects on intraepithelial lymphocytes as well as LPMC in vitro (32). However, in vivo data were lacking. In order to approach this question in vivo, the CD4+CD45Rbhigh transfer model of colitis was chosen. In this model, na ve T-cells, characterized by the CD4+CD45Rbhigh phenotype, are transferred into mice with severe combined immunodeficiency...

Biological significance of leptin produced at the site of inflammation

Adipocytes represent the primary source of leptin (38). However, several studies have reported local leptin production by lymphocytes and other cells at inflamed areas. The first of these studies demonstrated local leptin production in inflammatory infiltrates around neurons in the brain and spinal cord of mice with experimental autoimmune encephalomyelitis (39). Another study showed leptin production of colon epithelial cells at the sites of inflammation (34). Our own group demonstrated leptin production by LPMC as well as T-cells from mesenteric lymph nodes in the CD4+CD45Rbhigh transfer model of colitis (37). However, it remained unclear whether or not leptin released by these activated lymphocytes is of significance for the inflammatory process itself. In order to address this question, the CD4+CD45Rbhigh transfer model of colitis was used. Cells isolated from either WT or leptin-deficient ob ob mice were transferred into scid mice and were compared for their ability to induce...

Influence of leptin on antigen processing and presenting cells

Although T-cells are key players in the development and persistence of intestinal inflammation, these cells from the adaptive immune system rely on support by antigen processing and presenting cells for activation. As mentioned previously, OB-R isoforms are expressed on a variety of cell types, including macrophages monocytes. A study using ob ob mice in the experimental infection model of Gram-negative pneumonia has shown that in the absence of leptin signaling the phagocytic capacity, as well as the production of leukotrienes, is reduced in alveolar macrophages (43). Furthermore, in vitro studies have demonstrated that leptin enhances survival of monocytes in a concentration-dependent manner (44,45). Macrophages monocytes are sensitive to leptin stimulation, and because their activity is increased by this mediator, their efficacy as antigen-presenting cells might be affected by leptin levels in vivo as well. In addition, a stimulating effect of leptin on dendritic cells was recently...

Regulation of Leptin Levels in the Elderly

Leptin and Adiposity Does Aging Change the Association Between Leptin and Fat Content and Distribution The main mechanism regulating circulating leptin levels is represented by the amount of adipose tissue itself. As leptin is synthesized mainly by white adipose tissue and then secreted into the bloodstream, its circulating levels are strongly associated with amount of body fat 2-5 . Several studies have described this significant association from young to middle age, between leptin and different surrogates of adiposity as body weight, BMI, waist and hip circumferences, and fat mass directly evaluated by computed tomography (CT) and dual energy X-ray absorptiometry (DXA) or indirectly measured by skin-fold thickness or bioelectrical impedance analysis (BIA) 2-5 . Aging is associated with substantial body composition changes in both sexes with a progressive decrease in muscle mass and increase in body fat, with central redistribution of adipose tissue 14-16 . Irrespective of body...

Clinical Implications of Leptin Physiology in the Elderly

Based on the above, it is certain that leptin physiology remains not particularly well understood in older patients. This confusion is, however, further exacerbated in older patients with different disease states typically found in aging. In recent years, investigators have hypothesized that leptin may be involved in the pathogenesis of chronic disease states including diabetes, metabolic syndrome, dyslipidemia, anorexia, and malnutrition as well as hypertension, atherosclerosis, osteoporosis, and osteoarthritis 2-5 . Although these diseases are highly prevalent in old age, existing data on the role of leptin in a specific disease state has not been unequivocal. Furthermore, the available literature data were not always obtained in an elderly population. Because of this limitation, the second part of the review addresses those diseases in which the role of leptin has been supported by relevant and unequivocal findings from data collected in elderly populations.

Leptin and Glucose Metabolism

A number of epidemiological studies have examined circulating leptin level in diabetic and nondiabetic subjects with discrepant results 52, 90, 91 . It is still debated whether different degrees of glucose tolerance may affect plasma leptin level. In elderly overweight patients, plasma leptin did not differ between diabetic and nondiabetic men and women after accounting for age and fat mass 90 . Among US Pima Indians, subjects with type 2 diabetes had lower leptin concentration than nondiabetic subjects independent of body fat percentage 91 . However, there is clear evidence demonstrating a strong relationship between leptin, insulin, and indices of insulin resistance independent of body fat in both men and women with or without diabetes mellitus. A number of studies have been published in recent years on leptin and its relationship to body fat and insulin resistance 2-4 . However, only a few of these were performed in older subjects 34, 92-94 . In a group of 107 nondiabetic women...

Leptin Leptin Resistance and the Metabolic Syndrome

The prevalence of the metabolic syndrome increases with aging, rising from about 4 at the age of 20 years to almost 50 at the age of 60 years 104 . Concomitant with increased prevalence of metabolic syndrome is increased body fat 105, 106 and particularly visceral fat. Visceral fat has been recognized as a main factor in the pathogenesis of the metabolic syndrome 107 . Body fat distribution is associated with several components of the metabolic syndrome in the elderly 108 . In addition to the role of total visceral fat, it was hypothesized that peptides produced by adipocytes might also explain the higher prevalence of metabolic syndrome in older age groups 109 . Leptin can modulate many of the metabolic changes that are characteristic of aging 2-4, 95, 96, 110 . Aging has been considered the most common cause of impaired leptin sensitivity at both hypothalamic and peripheral levels 111 . Unger et al. 111 suggested that the physiological role of hyperleptinemia might be to permit the...

Leptin and ghrelin in cachexia

Leptin is secreted by adipocytes and regulates adiposity and metabolic rate by reducing food intake and increasing energy expenditure. Leptin is also a member of the IL-6 superfamily of cytokines. Experimental elevation of leptin within the physiological range produces weight loss and relative anorexia. Leptin secretion is increased by both central and systemic immunological challenge and has been proposed as a potential mediator of inflammation-induced anorexia. The mechanism of how leptin expression and secretion is enhanced during inflammation is complex, but there is evidence for mediation by both IL-1 and TNF-a. Conversely, leptin induces production and release of IL-1 in the brains of normal rats and the release of both IL-1P and TNF-a from mouse macrophages. Collectively, these observations suggest a complex interplay between leptin and other cytokines in the regulation of metabolism and appetite during acute and chronic illness (49). Leptin is cleared from the circulation...

Role of leptin resistance in obesity and insulin resistance

Leptin is produced by adipocytes and secreted into the blood. In the healthy state, the circulating leptin concentration varies in proportion to adipose mass. Activation of leptin receptors in the hypothalamus decreases food intake and increases energy expenditure via uncoupling proteins (UCPs) in fat and muscle. UCPs are mitochondrial proteins that allow for oxidation of substrates with the production of heat, rather than storage of energy in the form of ATP. Thus leptin serves as part of an adipostat mechanism, whereby increased adiposity sets in motion responses that will eventually reduce adiposity. In 1994, Friedman et al. discovered that ob ob mice are leptin-deficient and lose weight following leptin treatment (15). However, obese humans are typically leptin-resistant and have higher-than-normal circulating concentrations of leptin. Leptin resistance in humans has two components impaired transport of leptin across the blood-brain barrier and impaired signaling via hypothalamic...

Leptin in rheumatoid arthritis

AIA is a model of immune-mediated joint inflammation induced by administration of methylated bovine serum albumin (mBSA) into the knees of immunized mice (21). The severity of arthritis in leptin- and leptin receptor-deficient mice was reduced in this model (22). The milder form of AIA seen in ob ob and db db mice, as compared with their controls, was accompanied by decreased synovial levels of interleukin (IL)-1P and TNF-a, decreased proliferative response to antigen of lymph node cells in vitro, and a switch toward production of Th2 cytokines (22). Serum levels of all isotypes of anti-mBSA antibodies were significantly decreased in arthritic ob ob mice as compared with controls. Thus, in AIA leptin probably contributes to joint inflammation by regulating both humoral and cell-mediated immune responses. However, joint inflammation in AIA depends on the adaptive immune response, which is known to be impaired in ob ob and db db mice, so recent studies investigated the effect of leptin...

Leptin in type 1 autoimmune diabetes

Leptin is involved in other autoimmune conditions (17). Leptin accelerates autoimmune diabetes in female NOD LtJ mice (18). Fluctuations in serum leptin levels have also been observed in a study performed by our group in an animal model of CD4+ T-cell-mediated autoimmune disease, such as T1D. Nonobese diabetic (NOD LtJ) female mice, spontaneously prone to the development of -cell autoimmunity, have higher serum leptin levels, as compared with NOD LtJ males and nonsusceptible strains of mice, and show a serum leptin surge preceding the appearance of hyperglycemia (19). Furthermore, leptin administration early in life significantly anticipated the onset of diabetes and increased mortality and inflammatory infiltrates in beta-islets this phenomenon correlated with increased secretion of IFN-y in leptin-treated NOD mice (20). More recently, it has been found that a natural leptin receptor mutant of the NOD LtJ strain of mice (named NOD LtJ-db5J) displays reduced susceptibility to T1D...

Leptin in multiple sclerosis

Leptin is involved in both the induction and progression of EAE in mice (11-13). Analysis of the disease susceptibility in naturally leptin-deficient ob ob mice before leptin replacement revealed resistance to both active and adoptive EAE that was reversed by leptin administration. Leptin replacement converted Th2- to Th1-type response and shifted IgG antibodies from IgG1 to IgG2a. In addition, leptin administration to susceptible wild-type C57BL 6J mice worsened the disease by increasing proinflammatory cytokine release and IgG2a production (11). In addition, it has also been recently observed that a serum leptin surge precedes the onset of EAE in susceptible strains of mice (12). This peak in serum leptin is correlated with inflammatory anorexia, weight loss, and development of a pathogenic T-cell response against myelin (12). In animals with EAE, inflammatory brain infiltrates have also been shown to be a source of leptin, attesting to an in situ leptin production in active lesions...

Leptin and Bone Metabolism

Mice Leptin Level

Leptin has been proposed as mediating the protective effects of obesity on the skeleton similarly to traditional factors, such as mechanical loading and increased levels of estrogens and insulin 117 . Leptin shows both a peripheral and positive action on bone as well as a central and negative control of bone metabolism 118-122 . Considering the conflicting and sometimes contradictory data published in the literature, it remains difficult to draw a clear picture harmonizing these dual eVects of leptin on bone metabolism. 9.1. Peripheral Effect of Leptin on Bone Metabolism The expression of both short and long forms of leptin receptor was first recognized in human marrow stromal cells 123 and more recently in primary cultures of normal human osteoblasts 124 . In different cell models, leptin stimulates human osteoblastic cell diVerentiation 123, 125 , bone matrix mineralization 123-125 , and collagen synthesis 125 with protective effects against osteoblastic apoptosis 125 . Leptin could...

Leptin in endometriosis

Many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, TNF-a, and vascular endothelial growth factor (VEGF) (34,36,37). These molecules, together with other angiogenic factors, are thought to be of fundamental importance in the pathogenesis of the disease. Leptin may be one of these factors, as it promotes angiogenesis and proinflammatory cytokine production and induces the expression of intercellular adhesion molecule 1 (ICAM-1) and matrix metalloproteinases (34,36,37). Evidence from the literature demonstrates that serum and peritoneal fluid leptin is significantly higher in endometriosis patients and correlates with the stage of disease (38). Interestingly, endometrial cells of women with endometriosis have altered expression of ICAM-1, matrix metalloproteinases, and increased secretion of TNF-a, IL-1, and IL-6 (34). Eutopic endometrium from patients with endometriosis might be more invasive and prone to peritoneal implantation, as a consequence of altered production of...

Leptin and the Anorexia of the Elderly

Anorexia has multiple causes including alterations in taste, flavor and palatability of food, increased gastrointestinal satiations signals, and decline in central feeding drive 80-83 . A role for leptin has been advanced in this multifactoral pathway due to its ability to decrease food intake and increase resting metabolic rate 80-83 . Thus, increased leptin level with age could play a role in anorexia of aging. Increased circulating leptin level in aging humans is largely due to increased fat mass. Adjustment for fat mass, however, eliminates this relationship in most 20-23, 25, 29 but not all studies 18, 24, 27 . Some investigators have speculated that increased leptin in males is due to the age-related decrease in testosterone that ultimately leads to decline in food intake. A second hypothesis linking leptin to anorexia of aging is that aging may be associated with alteration in leptin sensitivity. Little information on this topic, however, is currently available. Ma et al. 85...

Leptin modulation of adaptive immune response

Faggioni et al. (16) have reviewed the role of leptin in cell-mediated immunity, from data obtained working with ob ob mice. These mice have a decreased sensitivity of T-cells to activating stimuli. Furthermore, these animals show atrophy of lymphoid organs (4-6), with a decrease in the number of circulating T-cells and an increase in the number of monocytes. In addition, ob ob mice have a decrease in TNKCD4+ in the liver (39). The ability of leptin to prevent thymic atrophia is due to a direct antiapoptotic effect on T-cells (6). Acute deficiency of leptin has a potent effect in the immune system, which is even higher than that observed in ob ob mice (genetic defect). Acute hypoleptinemic mice show a higher decrease in the total number of thymocytes, and double the number of apoptotic cells, than ob ob mice. Moreover, the acute deficiency of leptin also causes a decrease in splenic cellularity, which does not occur in ob ob mice, even though they have a smaller spleen than control...

Leptin and the hygieneaffluence hypothesis in autoimmunity

Insulin Resistance Images

Fewer infections and more autoimmunity, observed in affluent countries, lead us to postulate the so-called leptin hypothesis to explain this phenomenon (42). During the past century, in the industrialized world, the incidence of infections has diminished greatly because of improved hygienic conditions, better nutrition, vaccination, and the use of antibiotics (42). Interestingly, in affluent and more-developed societies, epidemio-logical studies have revealed a parallel increase in the incidence of autoimmune diseases, whereas these diseases have become less common in less-developed nations. Thus, susceptibility to infection and autoimmunity appear to be inversely related (42). Several factors other than nutrition might contribute to this relationship, such as the environment, genetic background, other hormones, stress, and exposure to specific pathogens (Fig. 1). Nevertheless, changes in diet and calorie intake and, subsequently, serum leptin concentrations should be taken into...

Leptin

Recent evidence has shown that adipose tissue is an active participant in maintaining energy and glucose homeostasis and plays crucial roles in controlling neuroendocrine, autonomic, and immune functions. Leptin is a hormone secreted by adipose tissue. Deficiency of leptin or its receptor results in hyperphagia, morbid obesity, insulin resistance, hyperlipidemia, hypothalamic hypogonadism, and immunosuppression. These abnormalities are reversed by leptin treatment in patients with congenital leptin deficiency or lipodystrophy. In contrast, diet-induced obesity is associated with elevated leptin levels and blunted response to leptin. Leptin resistance has been ascribed to the reduced entry of leptin into the brain or impairment of leptin signal transduction. This chapter focuses on the current understanding of leptin's actions, with particular emphasis on transport across the blood-brain barrier, signaling via JAK-STAT and PI3-kinase, neuropeptide targets, and electrophysiological...

Anxiety and depression

In a study of men suffering from major depression with a history of childhood trauma, it was shown that these patients exhibited higher increases in ACTH and cortisol responses when dosed with CRF after pretreatment with dexamethasone (dexamethasone CRF test) as compared to non-depressed men, or to depressed men with no history of childhood trauma 62 . In another study, patients diagnosed with unipolar depressive disorder with melancholic features showed an attenuated ACTH and increased cortisol response to CRF administered alone (CRF test) as compared to healthy controls 63 . Interestingly, however, there was no significant difference in response between depressed patients at different stages of illness (current depressive episode vs. recovery). This may suggest that alterations to the HPA axis in depressed patients may remain after recovery.

The development of oxidative rancidity in foods

Lipids occur in nearly all food raw materials with the major classes being triglycerides (also known as triacylglycerols), which occur in fat storage cells of plants and animals, and phospholipids, which occur in biological membranes. In the processing of a wide range of foods, fats may be added as part of the food formulation. The added fats are a major component of many foods including mayonnaise, margarine, and frying oils. These fats are almost completely triglycerides, and it is these components that are of most significance as potential sources of oxidative off-flavours in these foods. In plant or animal tissues used as foods, the phospholipids present in all biological membranes may be an important substrate for oxidative deterioration.

Adipokines with vasoactive or inflammatory effects

IL-6 and TNF-a are among the well-known cytokines consistently found to be increased in obesity, comprising elevations both at the adipose tissue expression level and the bloodstream (11,27). The list of factors shown to be implicated either directly or indirectly in the regulation of vascular homeostasis through effects on blood pressure, inflammation, atherogenesis, coagulation, fibrinolysis, angiogenesis, proliferation, apoptosis, and immunity has increased at a phenomenal pace (5-12,14-18,21,24). By definition, adipocytokines are cytokines produced by adipocytes. Although adipose tissue secretes a variety of factors, strictly speaking, not all of them can be contemplated as cytokines. Therefore, the less strict term of adipokines has been coined to include a wider range of factors. Leptin, adipsin, resistin, adiponectin, and visfatin fall within the category that satisfy the more strict requirements to be properly classified (11).

Are there other substances that affect bone development What about hormones

Cortisol Secreted by the adrenal glands (located by the kidneys), is needed in small amounts for bone growth. Large amounts of cortisol can interfere with bone growth. The synthetic form of cortisol, or steroids, used in the treatment of some diseases, can cause bone loss. Cortisol, secreted by the adrenal glands (located by the kidneys), is needed in small amounts for bone growth. Large amounts of cortisol can interfere with bone growth. The synthetic form of cortisol, or steroids, used in the treatment of some diseases (see Question 16), can cause bone loss. Insulin, a hormone secreted by the pancreas to help the body use carbohydrates and sugar, and leptin, a newly identified hormone that is found in fat cells, both have effects on bone growth.

Potential Therapeutic Applications

Bone Formation - NPY is a down stream modulator of leptin action. Chronic central administration of NPY and leptin both have a similar inhibitory effect on bone mass. By comparing bone phenotypes of germline and selective hypothalamic Y2 receptor -deficient mice, it was reported that hypothalamic Y2 receptors are involved in a tonic inhibition of bone formation by alteration of autonomic activity in the bone (30). Y2 receptor deficient mice have an increased rate of bone mineralization, as well as stimulated osteoblast activity which leads to a two fold increase in bone volume. This

And Jos Santos Alvarez

Adipose tissue is no longer considered as a mere energy store, but an important endocrine organ that produces many signals in a tightly regulated manner. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. Leptin's modulation of the immune system is exerted at the development, proliferation, anti-apoptotic, maturation, and activation levels. The role of leptin in regulating the immune response has been assessed in vitro as well as in clinical studies. Both the innate and adaptive immune responses are regulated by leptin. Every cell type involved in immunity can be modulated by leptin. In fact, leptin receptors have been found in neutrophils, monocytes, and lymphocytes, and the leptin receptor belongs to the family of class I cytokine receptors. Moreover, leptin activates...

Discuss the concerns for the use of etomidate in the critically ill patient

Etomidate decreases serum cortisol levels by blocking two enzymes in the cortisol pathway 11-p-hydroxylase and 17-a-hydroxylase. Clinically significant adrenal suppression and increased morbidity and mortality have been documented in critically ill patients and those with septic shock after receiving even a single dose of etomidate. Annane and associates reported that 68 of the 72 patients (94 ) who received etomidate for the induction of anesthesia did not respond to a high-dose cosyntropin stimulation test. This is consistent with other reports of adrenal insufficiency 12 to 24 hours after the administration of etomidate. The results seem to indicate a significant mortality for etomidate anesthetic induction in septic patients. However, the stable hemodynamic properties of etomidate make it a desirable induction agent for patients with shock. As the debate continues and further data are collected, some authors are advocating the use of etomidate in conjunction with exogenous...

Physical and Emotional Health How They Interact

However, when a person is under constant stress, the body steadily releases a hormone called cortisol, which can cause long-term damage to the brain and other organs. The harmful effects of this hormone include an increased tendency for blood to clot, a surge in the pressure on coronary arteries, increased blood pressure, and other demands on the heart and blood vessels.

Spontaneous intestinal inflammation

Despite the important observations described above, the role of leptin in regulating inflammatory or autoimmune responses developing spontaneously as a result of alterations in the immune system a situation that more closely reflects human autoimmune disease has not been studied in great detail. The only published study about this topic demonstrates that in the nonobese diabetic model of type 1 diabetes, administration of exogenous leptin accelerates destruction of insulin-producing P-cells and promotes an increased production of IFN-y (47). Concerning intestinal inflammation, it has been demonstrated that IL-2- - mice that develop colitis spontaneously have increased leptin serum concentrations (28). IL-10-deficient mice spontaneously develop chronic intestinal inflammation, which is mediated by CD4+ T-cells and is associated with enhanced Th1 responses in the early course of disease, with Th2 cytokines progressively increasing later on (48). As colitis in IL-10-deficient mice is...

Infectious colitis models

The role of leptin in infectious colitis models is not very well defined. There is only one study that examined the role of leptin in Clostridium toxin A-induced intestinal inflammation, the causative agent of antibiotic-related colitis (50). It could be demonstrated that Clostridium toxin A-induced colitis in WT mice resulted in an increase of circulating leptin concentrations. Furthermore, OB-Rb expression in the mucosa could be induced by Clostridium toxin A at the mRNA as well as at the protein level. Thus, to further explore the function of leptin in this model of intestinal inflammation, WT mice were compared to leptin-deficient ob ob as well as leptin receptor-deficient db db mice. Remarkably, in the absence of leptin or leptin signaling mice were partially protected against Clostridium toxin A-induced colitis. By including studies with adrenalec-tomized db db as well as WT mice it could be demonstrated that corticosteroid-depend-ent as well as -independent mechanisms are...

Human inflammatory bowel disease

Abnormalities of adipose tissue in the mesentery, including adipose tissue hypertrophy and fat wrapping, have been long recognized on surgical specimens as characteristic features of Crohn's disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Desreumaux and colleagues evaluated this phenomenon and quantified intra-abdominal fat in patients with CD vs UC by using magnetic resonance imaging (51). By applying this technique they were able to demonstrate a significant accumulation of intraabdominal fat in patients with CD. This mesenteric obesity, present from the onset of disease, is associated with overexpression of PPARy as well as TNF-a mRNA, as evaluated by RT-PCR studies (51). In a subsequent study, the same group could demonstrate an overexpression of leptin mRNA in the mesenteric adipose tissue in inflammatory bowel disease, whereas no difference could be detected between UC and CD. The...

Potential Therapeutic Indications

Initial studies showing higher expression of MCH in hypothalami of leptin deficient (Lepob ob) and hypoleptinemic (fasted) mice, and that i.c.v. administration of MCH to rats stimulates food intake, established a role for MCH in feeding 37 . Several groups have since confirmed the hyperphagic effect of acute central administration of MCH in both mice and rats 38-41 , as well as the over-expression of MCH in genetic models of leptin resistance 42,43 . Sub-chronic (7-14 days) central infusion of MCH to mice on a high fat diet induced persistent hyperphagia accompanied by increased adiposity, hyperinsulinemia and hyperleptinemia 44,45 while i.c.v. infusion of a potent MCH1-R peptide agonist to rats produced similar effects 46 . Consistent with these findings, transgenic eutopic over-expression of MCH produces an obese, insulin resistant and hyperphagic phenotype in mice on a high fat diet 47 . Deletion of the pmch gene, which generates an animal null for MCH as well as NEI and NGE,...

Adipocyte Dysfunction And Insulin Resistance

Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue recruits macrophages for reasons that are not entirely clear. However, the local inflammatory milieu is thought to (a) increase adipocyte lipolysis as cytokines downregulate insulin signaling and (b) change the secretion of adipokines such as leptin and adiponectin. Photomicrograph courtesy of Barbara Kozak, PhD Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue recruits macrophages for reasons that are not entirely clear. However, the local inflammatory milieu is thought to (a) increase adipocyte lipolysis as cytokines downregulate insulin signaling and (b) change the secretion of adipokines such as leptin and adiponectin. Photomicrograph courtesy of Barbara Kozak, PhD our understanding of fat and carbohydrate metabolism and their interaction. In particular, a large body of...

Triglyceride Synthesis

Two enzymes that display DGAT activity have been characterized to date DGAT-1 (acylCoA diacylglycerol O-acyltransferase type 1) 24 and DGAT-2 (acylCoA diacylglycerol O-acyltransferase type 2) 25 . DGAT-1 and DGAT-2, which share only 12 sequence identity, are both ubiquitously expressed, but the highest expression levels are in tissues typically associated with triglyceride synthesis and storage. DGAT-1 is predominantly expressed in small intestine, liver, and white adipose, while DGAT-2 is most highly expressed in liver and white adipose tissue, and, to a lesser extent, in the small intestine. Significant impetus for pursuing small molecule inhibitors of DGAT-1 was provided by the phenotype of DGAT-1mice. These animals are resistant to diet-induced obesity and have increased sensitivity to insulin and leptin 26,27 . Additionally, DGAT-1 deficient mice are protected against hepatic steatosis, demonstrate increased energy expenditure, and decreased levels of tissue triacylglycerides. In...

AMPactivated protein kinase AMPK

AMPK is directly activated by physical exercise 61 and by the adipokines adiponectin and leptin 62,63 . AMPK is also activated by treatment with antidiabetic drugs metformin 64 and thiazolidinediones (TZDs) 65 . However, these compounds may not act on AMPK directly. The AMP analog 5-amino-imidazole-4-carboxamide 1 p-D-ribofuranoside (AICAR, 17) is phosphorylated within cells to yield a potent but non-specific activator of AMPK. Chronic treatment of obese Zucker fa fa rats with AICAR produces effects very similar to those of metformin 66 . The biological effects of AICAR are confounded by the dual ability of AICAR to stimulate glycogen phosphorylase (GPPase) and to inhibit fructose-1,6-bisphosphatase (FBPase), both of which can lead to the lowering of blood glucose levels and an increase in insulin sensitivity 67,68 . Despite the intense interest in this target, there are very few publications describing direct activators of AMPK. A series of thienopyridones has been identified as...

StearoylCoA desaturase SCD

SCDl-deficient asebia mice bred onto a leptin-deficient (ob ob) background show reduced adiposity despite higher food intake and have a corrected hypo-metabolic phenotype, suggesting that down-regulation of SCD1 is an important component of leptin's metabolic actions 79 . SCD1 knockout mice are viable and

Energy Balance and Immune Function

Leptin was first identified as an adipocyte secretion that acts on the brain to regulate energy balance and lipid storage and was later shown to act on lymphoid cells in vitro (156). More recently, other appetite regulators, including adipophilin (157) and ghrelin (158), have been shown to act on various kinds of leukocytes, at least in vitro. The possibility of using leptin or other appetite regulators as antiobesity drugs has prompted intensive study of the interactions between mechanisms of energy storage and immune function (159,160). Unfortunately much of the data come only from depots of pure adipose tissue that do not incorporate lymphoid structures. In describing observations on the effects of deficiencies in the secretion and reception of leptin on immune function, Matarese et al. mention the presence of adipocytes associated with lymph nodes, thymus, and bone marrow, and implicate them in these effects, although no evidence is presented that these adipocytes secrete leptin...

Compounds In Human Clinical Trials

Early clinical results for two nonpeptide GnRH compounds, TAK-013 and NBI-42902 46 , have been reported at scientific meetings although reports have not appeared in a peer-reviewed journal as of this writing 47-50 . NBI-42902 showed good exposure following oral administration to post-menopausal women and dose-dependent suppression of LH 46 . TAK-013 was shown to suppress testosterone in healthy young men following a single oral dose 49 . In a 14-day study, premenopausal women receiving oral TAK-013 each day showed dose-dependent suppression of LH and estradiol, but no significant effect on FSH 48 . Comparison of day 1 and day 14 pharmacokinetics, as well as urinary 6-hydroxycortisol cortisol ratios, suggested that the compound was inducing CYP3A4. A multiple dose study in post-menopausal women confirmed the potential for CYP3A4 induction, but in this population FSH, as well as LH, was suppressed 47 .

Division of Geriatric Medicine University of Verona Piazzale Stefani 1 37126 Verona Italy

Regulation of Leptin Levels in the 4.1. Leptin and Adiposity Does Aging Change the Association Between Leptin and Fat Content and 4.2. Leptin and Gender Is a Sexual Dimorphism in Leptin Levels Still Present 4.3. Leptin and Aging Does Aging have an Independent Effect on Leptin 4.4. Leptin and Hormonal Changes During 4.5. Leptin and Nutritional 4.6. Leptin and Lifestyle 5. Clinical Implications of Leptin Physiology in the 6. Leptin and the Anorexia of the 7. Leptin and Glucose 8. Leptin, Leptin Resistance, and the Metabolic 9. Leptin and Bone 9.1. Peripheral Effect of Leptin on Bone 9.2. Central Effect of Leptin on Bone

Orbital Adipose Tissue and Thyroid Associated Ophthalmopathy

Thyroid-associated (Graves') ophthalmopathy (TAO) has an autoimmune pathogenesis possibly related to the thyrotropin receptor (50-53). The symptoms of TAO result from inflammation, fibrosis, and accumulation of orbital adipose tissues. Immunohistochemical analysis of orbital tissue biopsies from patients with TAO demonstrates that the thyrotropin receptor is expressed in fibroblast-like cells, accompanied by mast cell infiltrates (50,51). Whether these mast cells, via their fibrogenic (34-36) and or angiogenic (37) potential, may contribute to TAO-associated fibrosis and orbital adipose tissue hypertrophy, respectively, remains to be evaluated. Further, transforming growth factor- inhibits, whereas IL-6 stimulates, thyrotropin receptor expression (52), suggesting that the pathogenesis of TAO may be influenced by competing inhibitory (yin) and stimulatory (yang) adipokine effects within the orbit. One study examined 2686 genes, of which 25 known genes were upregulated in TAO orbital...

Patrick Laharrague and Louis Casteilla

Bone marrow (BM) adipose tissue should no longer be considered simply as a filling material for bone cavities that is not needed for hematopoietic activity. In addition to its potential role as an energy store, BM adipose tissue exhibits a considerable adaptive plasticity and secretes a broad spectrum of hormones, cytokines and growth factors whose receptors are present on different cells of the stromal microenvironment. BM adipocytes, originating like osteoblasts from mesenchymal stem cells, display a marked metabolic and secretory activity. Among the various secreted adipokines, leptin, and adiponectin have opposite effects on hematopoiesis, immunity, inflammation, and bone remodeling. As a whole, a counterbalance exists between adipogenesis and erythropoiesis, and between adipose and bone formation. The better knowledge of the different paracrine and endocrine agents involved in the subtle and complex regulation of hematopoiesis and its osseous environment suggests that BM adipose...

Morphological and functional characterization of bm adipocytes

In the rabbit, palmitate turnover per gram triglyceride is fivefold greater in BM adipose tissue than in subcutaneous or perinephric adipose tissues however, when expressed on the basis of individual cells, incorporation of the free fatty acid in marrow and in nonmedullary fat cells appears similar (55). Gas chromatography reveals that marrow fat contains a higher concentration of unsaturated fatty acids. As a whole, these studies and those performed during stimulation of erythropoiesis indicate that there is greater lipolysis and lesser storage in BM fat than in nonmedullary fat pads (55). Our opinion is that, contrary to white adipose tissues, fat storage and energy conservation are probably a secondary function of marrow fat.

Animal Models of Osteoporosis or Increased Bone Formation

Studies by Hamrick et al. reveal that the bone phenotype of the ob ob mouse is more complex than has previously been appreciated. It is characterized by short femora with reduced cortical thickness and reduced trabecular bone volume. In the spine, however, although cortical thickness is still reduced, vertebral length, bone mineral density, and trabecular bone volume are all increased. These results indicate that the effects of altered leptin signaling on bone differ significantly between axial and appendicular regions. Few adipocytes are observed in BM from lumbar vertebrae, whereas in the femur the number of marrow adipocytes per unit area is increased 235-fold. Leptin treatment induces loss of BM adipocytes and increases bone formation in these leptin-deficient ob ob mice (153). Transgenic mice expressing A-FosB not only develop a severe and progressive osteosclerotic phenotype characterized by increased bone formation, but also show pronounced decrease in adipogenesis with...

Primary Human BM Adipocytes

What are the hematopoietic effects of the products more specifically secreted by adipocytes, namely cytokines, leptin and adiponectin We first reported that human BM adipocytes secrete large quantities of leptin (63), which appears to play a part in the regulation of hematopoietic progenitors and their differentiation into granulocyte and monocyte precursors. The concentration of leptin required for this effect in vitro (50-100 ng mL) is rather high, but is within the range of plasma leptin levels observed in obese subjects (64). As leptin concentrations in bone marrow and plasma are highly correlated in humans (64), is leptin involved in the leukocytosis associated with obesity and, more broadly, is there any correlation between leptin levels and blood cell counts Wilson et al. observed that in obese Pima Indians most of the variance in the leukocyte count attributable to body fat could be accounted for by plasma leptin concentration (204). We confirmed that leptin and leukocyte...

Posttraumatic Stress Disorder

There are several identifying symptoms of PTSD, including intrusive recollections of the traumatic event even when it is not occurring, hyper-vigilance, fear and anxiety about one's safety, and a numbing of emotions and avoidance of people or places that remind the person of the original trauma. These emotions are being moderated by cortisol-releasing factors and the neurotransmitters released by the ANS to try to reregulate and stabilize our emotions. It is not known exactly how these emotional

Infant Overnutrition Pathway

Although there are conflicting data, recent systematic reviews concur that breastfeeding confers some protection against the development of childhood and adult obesity (67,68). In turn, these studies imply that feeding infant formula or cow's milk results in a greater risk of obesity. This could reflect the greater caloric and protein load of cow's milk, which can lead to overnutrition in infancy, or as yet unidentified beneficial effects of other breast milk components, such as growth factors or hormones such as leptin. In rats, high nutrition in infancy can induce both peripheral and central components of obesity, involving changes in both local depots and hypothalamic neuroendocrine pathways (69,70). The effect is apparent in both premature and term infants, suggesting that it is early feeding that is particularly sensitizing to the development of later obesity (71). A recent long-term cohort study identifying an association between adult obesity and rapid weight gain in the first...

Prevalence ofObesity Too Low During Periods Between Famines to Be a Strongly Selected Trait

Although hunting-gathering has largely died out as a lifestyle, there are still many tribal communities in the third world subsisting on agriculture, using practices effectively unchanged for thousands of years. If the model in Fig. 1 is realistic, all the individuals in these populations should carry thrifty genes conferring efficient fat storage capabilities. Table 1 summarizes some estimates of body mass index (BMI) in hunting-gathering and subsistence-farming populations. Only one of the papers from which

Obesity Therapeutics Prospects and Perspectives

Cannabinoid Receptors ( ), Leptin Receptors, Melanocortin Receptors, NPY Receptors, CART, Corticotropin-Releasing Factor Receptors, Serotonin Receptors, Cannabinoid Receptors ( ), Leptin Receptors, Melanocortin Receptors, NPY Receptors, CART, Corticotropin-Releasing Factor Receptors, Serotonin Receptors, Cortisol Leptin, Uncoupling Proteins, B3-Adrenergic Receptors,

Selective Glucocorticoid Receptor Modulators

Introduction - Glucocorticoids (GCs) have a pervasive role in human health and physiology. The endogenous members of this family, Cortisol and corticosterone, are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance as well as maintenance of immunological, renal and skeletal homeostasis (1-4). Synthetic GCs have long been recognized as effective treatments for inflammatory conditions and immunomodulation. The overriding mode of action of GCs involves regulation of gene expression through the glucocorticoid receptor (GR). Unfortunately, the widespread changes in gene regulation also potentiate GC-mediated homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. Clinical use is further complicated by the cross-reactivity of most commonly used GCs with other steroid hormone receptors resulting in ancillary pharmacology. Consequently, the...

Neuropeptides in cachexia

A current hypothesis of cachexia in chronic illness is that cytokines released during cancer, CKD, or chronic inflammation act on the central nervous system to alter the release and function of a number of key neurotransmitters, thereby altering both appetite and metabolic rate (54,55). The melanocortin system is critical in mediating the effect of cytokines, such as leptin, on metabolism. There are distinct local counterparts of the pro-opiomelanocortin (POMC) cells agouti-related protein (AgRP) and neuropeptide Y (NPY) producing cells in the arcuate nucleus. Activation of POMC neurons by leptin triggers the release of a-melanocyte-stimulating hormone (a-MSH) from POMC axon terminals, which in turn activates the type 4 melanocortin receptor-4 (MC-4R), leading to suppressed food intake and increased energy expenditure. Simultaneously, leptin suppresses the activity of arcuate nucleus NPY AgRP neurons, which otherwise would antagonize the effect of a-MSH on MC-4Rs through the release...

Neuropsychiatry Disorders

Affective Disorders - Many patients with major depression are hypercortisolemic and exhibit an abnormal dexamethasone suppression test (23,24). Given the primary role of CRF in stimulating pituitary-adrenocortical secretion, the hypothesis has been put forth that hypersecretion hyperactivity of CRF in brain might underlie the hypercortisolemia and symptomatology seen in major depression. The concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free depressed individuals (25-27), and a significant positive correlation is observed between CRF concentrations in the CSF and the degree of post-dexamethasone suppression of plasma Cortisol (28). Furthermore, the observation of a decrease in CRF binding sites in the frontal cerebral cortex of suicide victims compared to controls is consistent with the hypothesis that CRF is hypersecreted in major depression (29). The increased CSF concentrations of CRF seen in depressed individuals are decreased following...

Exclusion of Specific Disorders

Approximately 6 of androgen excess patients suffer from a specific disorder, including classic and nonclassic 21-hydroxylase deficiencies, the HAIR-AN syndrome, or an ASN, among others (12). In patients clinically suspected of having an ASN, a computed tomography or magnetic resonance imaging scan of the adrenals and transvaginal ovarian ultrasonography should be obtained to assess for adrenal or ovarian masses, respectively. Importantly, measurement of a basal 17-hydroxyprogesterone serum level should be obtained in the follicular phase of the menstrual cycle, preferably in the morning, to exclude 21-hydroxylase-deficient NCAH (39). In patients suspected of having Cushing's syndrome, it will also include a 24-hour urinary free cortisol level or a cortisol level following an overnight dexamethasone (1.0 mg at 11 pm) test. If the HAIR-AN syndrome is suspected, a basal or preferably a glucose-stimulated insulin level should be obtained. Growth hormone levels should be obtained in...

Animal Models of Human Prostate Cancer

Documented in 20-40 of CaP cases 164-166 , Both LNCaP and the CWR22 xenografts bear AR mutations that enable the receptor to be activated by nonandrogenic steroid hormones such as progesterone and estrogen. In addition, in a patient who had failed androgen ablation, it was recently demonstrated that his CaP-cells possessed a mutated AR with altered lig-and affinity. Essentially, the mutant AR functioned as a high-affinity Cortisol receptor, enabling the CaP cells to circumvent the androgen requirement for growth 167 . Another emergent theme is that some hormone refractory cancers have activated the AR signaling pathway through a ligand-independent mechanism. For example, in LAPC-4 cells expressing wild-type AR, the overexpression of Her-2 neu has been shown to activate AR 168 . Not surprisingly, the LAPC-4 xenograft progresses to androgen-independence after androgen ablation and differential gene expression studies reveal a consistent increase in Her-2 neu protein expression in...

Ancha Baranova and Zobair M Younossi

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopathological conditions in patients who do not consume excessive amounts of alcohol these conditions are characterized by hepatic steatosis with or without other pathological changes observed in liver biopsy. The pathogenesis of NAFLD and its progressive form (non-alcoholic steatohepatitis NASH ) appears to be multifactorial and is the subject of intense investigation. Increasing evidence indicates that the pathogenesis of NAFLD and NASH is hastened by a disturbance in adipokine production. Decreased serum adiponectin and increased tumor necrosis factor-a, which are characteristic of obesity, appear to contribute to the development and progression of NASH. The role of leptin in the pathogenesis of NASH remains controversial and the involvement of serum resistin is primarily documented only in animal models, which may or may not be applicable to the human form of NAFLD. Finally, other adipokines such as vaspin,...

Adipose tissue adipokines and nafld

White adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including adipokines (leptin, adiponectin, resistin, apelin, vaspin, visfatin, and zinc-a2-glycoprotein), cytokines (such as tumor necrosis factor TNF -a and interleukin IL -6), and chemokines (21). In addition to adipocytes, white adipose tissue contains several other cell types, including macrophages and monocytes. It is likely that macrophages are retained within adipose tissue in response to both monocyte chemoattrative protein (MCP)-1 and macrophage migration inhibitory factors released by adipocytes in amounts proportional to body mass index (BMI) (22). Cytokines produced by adipose tissue contribute to the increased systemic inflammation associated with obesity (23). The exact contribution of each component of white adipose tissue in the proinflammatory state of obesity is not entirely clear. Some studies indicate that more than 90 of the adipokines released from adipose...

Adipokines in the experimental models of nafld

Common experimental models of NAFLD include mice or rats fed high-fat or high-carbohydrate diets, or mice that exhibit a genetic deficiency in leptin, a satiety factor (15). These animal models spontaneously develop steatosis, and some progress to steatohepatitis. Animal models of NAFLD point to adipokine and cytokine abnormalities in the patho-genesis of NAFLD. For example, leptin-deficient ob ob mice are important animal models of NAFLD because they are obese, insulin-resistant, hyperglycemic, and hyperlipidemic. Similarly, leptin receptor-deficient fa fa rats and db db mice are phenotypically similar to ob ob mice, with the addition of hyperleptinemia. It is noteworthy that NAFLD occurs in both leptin-deficient and hyperleptinemic animals with impaired leptin signaling. However, leptin restoration leads to NAFLD reversal in leptin-deficient animals (15). TNF-a is another important cytokine involved in the pathogenesis of NAFLD serum levels are high in all animal models of NAFLD....

Clinical Examples Of Enzyme Induction Measurement Time Of Onset And Types Of Protein Induced

Clinical Assays for CYP3A Induction - Measuring the urinary 6p-hydroxycortisol to Cortisol ratio (6P-OHC C) has been reported to be an effective and efficient method for evaluating the potential of investigational agents to induce CYP3A4 (63, 64). Disadvantages of using this ratio as a marker of endogenous CYP3A activity are reported as including variability of the response due to stress or circadian rhythm, and daily interindividual variability (65). Despite these limitations, this assay has been used to characterize rifampicin, antipyrine, phenobarbital, troglitazone, phenytoin, and carbamazepine as CYP3A inducers in clinical studies (Table 1). Midazolam has likewise been used to probe for CYP3A induction in the clinic, where the magnitude of the response is typically 10-fold higher than that observed for the 6P-OHC C ratio. Regardless of the specific probe substrate used, there are benefits to standardizing on a single probe substrate to calibrate enzyme inducers in the clinic as...

Adipokines and Steatosis

Leptin protects against lipotoxicity in nonadipose tissues (68), possibly by a peripheral mechanism. Studies of pair-fed controls receiving the exact amount of food ingested by leptin-treated animals show that controls remain steatotic despite caloric restriction (73,74). In cultured pancreatic islets, leptin lowers TG content by increasing FA oxidation and preventing its esterification (73). A similar mechanism may be at work in the liver, because liver tissue expresses leptin receptors. Indeed, tissue-specific overexpression of wild-type leptin receptors in steatotic livers reduces TG accumulation in the liver but nowhere else (75). Furthermore, leptin dramatically suppresses the expression of the hepatic stearoyl-CoA desaturase (SCD)-1, the rate-limiting enzyme in the biosynthesis of monounsatu-rated fats (74). SCD-1 suppression, in turn, supports resistance to both hepatic steatosis and obesity owing to a marked increase in energy expenditure. Two proposed mechanisms for these...

Adipokines in Hepatic Fibrosis

Leptin enhances liver inflammation and fibrogenesis, in part, by upregulating TGF- . Leptin has a profound positive influence on a(2)(I) collagen mRNA expression in HSCs (125). In addition, leptin augments PDGF-dependent HSC proliferation. Taken together, these studies indicate that leptin is a potent promoter of hepatic fibrosis. Observations in lipodystrophic patients treated with recombinant leptin support this conclusion (57).

Can Stable Isotope Methods Provide New Insights Into Open Questions In Brain Metabolic Regulation And Neurological

An open question in which SIDMAP can provide new insights is in the understanding of the effect of GLP-1 in the brain. GLP-1 is produced in the brain and transported along axonal networks to diverse central nervous system regions 65 . It has been suggested that GLP-1 could be downstream of leptin action in the brain whereas it is still an open question whether GLP-1 needs to enter the brain to affect gut motility and food intake 66 . Taking into account that increased evidence has been provided recently on the relationship between enhanced glucose metabolism and resistance to apoptosis 67 , and that fatty acids induce apoptosis in b-cells 68 we hypothesize that SIDMAP characterization of GLP-1 effect on the neuronal metabolic network can help to illuminate the molecular basis of the described neuroprotective effect of GLP-1, which activates different anti-apoptotic signaling pathways in specific neurons 69 . This hypothesis is supported by the recent evidence provided on the effect of...

How are MS attacks treated Why are there different drugs to treat attacks of MS

ACTH (or corticotrophin) is a hormone that is made in the brain and is stored in the pituitary gland, which is situated at the base of the brain. This hormone is normally released in miniscule amounts during the early hours of the morning to stimulate the adrenal glands' production of steroid hormones. Cortisol, the active form of cortisone, is one product of ACTH stimulation. Dr. Leo Alexander began using ACTH a half-century ago at Harvard Medical School. He showed in a series of studies that it speeded recovery from MS attacks. Later, a national study, published in 1970, proved that it did indeed significantly speed the recovery for patients with acute exacerbations of MS. glands secrete steroid hormones that are important in the body's response to stress. Cortisol the stored form of cortisol produced by the adrenal cortex.

Large scale structural studies on human proteins in the private sector

In the end of the 1990's, companies were formed to provide novel protein structures of drug targets to pharmaceutical companies. Examples are Syrxx, recently acquired by Takeda Inc. (http www.syrrx.com), which was focused on various human targets of therapeutic interest, e.g. Dipeptidyl Peptidase IV, protein kinases and 11b-hydroxysteroid dehydrogenase type 1) Structural GenomiX (http www.stro-mix.com focused on e.g. protein kinases) Integrative Proteomics (now Affinium Pharmaceuticals, http www.afnm.com) Plexxicon (http www.plexxicon.com focused on e.g. protein kinases and phosphodiesterases) and Astex Technology (http www.astex-technology.com focused on e.g. protein kinases as well as drug metabolism in relation to structural data on cytochrome P450's). Although initially set out as structural genomics (or high throughput structural chemistry) operations, these companies have now developed into more classical drug discovery companies with focus on structure-based drug design...

Effects of prolonged exposure of A b peptide on cholinergic neurons

The mechanisms by which Ab peptides are toxic to cholinergic neurons are still unclear, but may involve, as indicated from other studies, alterations in intracellular calcium and or the production of free radicals (Behl et al., 1992 Mattson et al., 1992 Hensley et al., 1994 Mattson and Pedersen, 1998). A variety of experimental data from different cell lines and primary cultured neurons suggest that Ab toxicity might be mediated either by interaction with a hydroxysteroid dehydrogenase enzyme or by the plasma membrane RAGE, SR, p75NTR and or nicotinic receptors (El Khoury et al., 1996 Yan et al., 1996, 1997 Kuner et al., 1998 Wang et al., 2000a,b). Whether Ab peptides induce toxicity in cholinergic neurons by interacting with any of these receptor subtypes remain to be established. However, it has been demonstrated that 24 h exposure to pM Ab1-40 can increase choline fluxes from PC12 cells (Allen et al., 1997). If pM Ab peptide does so in cholinergic neurons, it is likely that the...

Class II the Metabolic Sensors

The first nuclear hormone receptors to be identified as metabolic sensors were members of the PPAR subfamily. Although the PPARs were named based on their activation in response to molecules that promote peroxisome proliferation in rodents, the PPARs are potently activated by fatty acids, especially polyunsaturated fatty acids such as specific ecosanoids derived from aracadonic acid.46,48,81,83,86 The PPAR response element is a direct repeat separated by one nucleotide (DR-1). There are three forms of PPAR PPARalpha, PPARbeta-delta, and PPARgamma.36 PPARalpha coordinates fat mobilization by enhancing the genes involved in beta oxidation.35,138 PPARgamma promotes fat storage by promoting adipocyte differentiation and fatty acid uptake.11,38,145 PPARbeta was discovered in Xenopus.36 The third form of PPAR identified in the mouse was named PPARdelta due to insufficient homology to Xenopus PPARbeta.72 However, the third PPAR isotype in chickens shares substantial homology with both PPAR...

Impact of Obesity on Metabolism

Adipose tissue produces metabolically active proinflammatory molecules called adipocytokines such as tumour necrosis factor (TNF)-a, interleukins (IL), leptin, adiponectin (18-20), and some newly identified molecules such as visfatin (21) and omentin (22). The cytokines within adipose tissue originate predominantly from in situ macrophages (23-25) but also from adipocytes and preadipocytes (26). The altered production of these molecules has characterized obesity as a state of chronic, low-grade inflammation (27), which may contribute to the development of insulin resistance and endothelial dysfunction (28-30). It is postulated that paracrine and endocrine communication between macrophages and adipocytes, mediated by cytokines and fatty acids, creates a positive feedback loop to aggravate inflammatory changes in adipose tissue (31). Although the adipocytokines are reviewed in detail in previous chapters in this book, it is important to briefly highlight these compounds here, as they...

Obstructive Sleep Apnea Syndrome

OSAS is thought to be both a systemic and local inflammatory condition (118). Inflammatory processes associated with OSAS may contribute to cardiovascular morbidity in these patients. Indeed, it is the presence of systemic inflammation, characterized by elevated levels of certain proinflammatory mediators, such as C-reactive protein (119), leptin (120), TNF-a, IL-1 , IL-6 (37), reactive oxygen species, and adhesion molecules, that may predispose people to the development of cardiovascular complications observed in patients with OSAS. Interestingly, both TNF-a and IL-6 have been found to be significantly elevated in OSAS independent of obesity (121). To date it is unclear how the cytokines directly mediate OSAS (122).

Liposuction and Abdominoplasty

Liposuction, the most common cosmetic surgery procedure performed on men, is a procedure that can improve the contour of your body by removing stubborn pockets of fat that you have not been able to remove through exercise or diet. During the procedure, the plastic surgeon uses a vacuum device to suction these unwanted fat deposits from specific areas of the body. For men, these areas are usually the abdomen, the flanks (love handles), or the chest. Other possible neck. The best candidates for liposuction are men of normal weight with firm Cosmetic skin who have excess fat deposits in certain areas of the body. Liposuction is not Surgery a weight-loss method you should be at or near your ideal weight before surgery.

Interpretation of the Beneficial Actions of CR Based On the Adaptive Response Hypothesis

The characteristics of animals subjected to long-term CR are summarized in Fig. 13. These CR effects could differ in several aspects of physiology from those of fasting (starvation), but the hormonal profile of CR (lower plasma leptin, insulin, growth hormone and gonadotropins, and higher plasma free corticosterone) is similar to that of fasting 83 . Based on studies examining the respiratory quotient or respiratory exchange ratio, carbohydrate is the major fuel after feeding in CR animals, and fuel utilization shifts from carbohydrate to fat before feeding 21, 42 . Fasting also shifts the fuel utilization from carbohydrate to fat. The role of leptin in the altered hormonal profile and metabolic shift in CR animals has yet to be determined, but several lines of evidence indicate that it has an important role in metabolic adaptation during CR. When leptin is administered intraventricularly in fasting rats, the reduced respiratory quotient and fasting-induced hormonal profile are almost...

Evidence For Monoamine Contributions To Adhdne And 5ht Activity

The results for the 5-HT system are more limited, reflecting in part the methodological issues (see Section 7). However, if one brings the separate findings together, there is an indication of an increase of 5-HT turnover, largely reflecting decreases in 5-HT levels (Table 1). Nonetheless, as with NE, it must be recognized that there will be subgroups, however defined, for which the effects associated with the core symptoms will be masked by other features. One such example is shown by the contrast between ADHD boys brought up in families with or without alcoholic fathers (164). Those with this experience showed a larger cortisol response to a challenge dose of fenfluramine than those without an alcoholic father. This was interpreted as reflecting increased 5-HT receptor sensitivity.

Metabolic Mechanism for OA

Despite these inconsistent findings, it may be that unexamined or unidentified metabolic factors mediate the association between obesity and OA. For example, there is emerging evidence that leptin may be important in the pathogenesis of OA (63). In particular, the discovery that osteoblasts and chondrocytes are capable of leptin synthesis and secretion (64,65), as well as existence of leptin receptors at articular cartilage (66), may have significant implications for future studies examining the metabolic link between obesity and OA. Indeed, significant levels of leptin were observed in the cartilage and osteophytes of people with OA, yet few chondrocytes produced leptin in the cartilage of healthy people (64).

StearoylcoA Desaturases

Criture Cursive Flech

Deletion, mutation, or inhibition of SCD1 in mice and rats results in decreased hepatic TGs 7-11 , resistance to weight gain, and improvements in insulin sensitivity and glucose uptake. In one study, naturally occurring lean, hypermetabolic SCD-deficient asebia mice were crossed with obese leptin-deficient ob ob mice and the resulting offspring were lean, hyperme-tabolic and had normal liver histology 8 . Thus, SCD inhibition may offer a novel approach to treating obesity, insulin resistance, and diabetes, as

Computed Tomography of ARVCD

Motion Artifact Animated

Hamada et al. 56 imaged four ARVC D patients who had abnormalities on electrocardiography and angiography using electron bean CT (EBCT). With contrast enhanced volume mode scanning they were able to demonstrate morphologic abnormalities in ARVC D (a) abundant epicardial fat, (b) low attenuation trabeculations, (c) scalloping of RV free wall, and (d) intramyocardial fat deposits. Quantification of ventricular volumes was performed on cine mode scanning, which showed regional dysfunction and depressed global RV function respectively. Tada et al. 57 added ten more ARVC D patients to the above series and compared electron beam CT findings in 16 age-matched, non-ARVC D patients with RV dilation dysfunction with 13 control subjects. Intramyocar-dial fat was defined based on tissue attenuation values. The attenuation value for epicardial adipose tissue is approximately 65 10 Hounsfield units (HU), and 5 to -17 HU for intramyocardial fat, which is far less than that of myocardium. Using the...

Body Fat Distribution

Figure 3.4 There is strong evidence suggesting adipose tissue has a central role in contributing to insulin resistance. New evidence suggests that insulin resistance is partly the result of the inability of the adipose organ to expand to accommodate excess calories. Increased fat cell size may represent the failure of the adipose tissue mass to expand, i.e. proliferate and differentiate, resulting in a reduced ability to accommodate an increased energy influx. When combined with reduced fat oxidation in adipose tissue, these pathophysiologic changes will contribute to a decrease in fat storage in adipocytes and an increase peripheral deposition of lipids in tissues, i.e. increased 'ectopic fat'. Individuals who have a low capacity for proliferation and or differentiation of precursors into mature fat-storing adipocytes are susceptible to hypertrophy of the existing adipocytes under conditions of energy excess. Thus, adipocyte hypertrophy (i.e. large fat cells) is indicative of a...

Clinical Findings With Crfr1 Antagonists

The next report of the effects of a CRF-R1 antagonist in human subjects did not appear until 2007 90 . The tricyclic pyrazolopyridine NBI-34041 (38), a potent CRF-R1 antagonist (human CRF-R1 Ki 4.0 nM) 39,91 , was evaluated in a Phase 1 proof-of-concept study in 24 healthy male volunteers for its effect on psychosocial stress and the responsiveness of the HPA axis. Subjects received 10, 50, or 100 mg of 38 or placebo for 14 days. At day 9, subjects underwent the Trier Social Stress Test (TSST), which is a public speaking task involving a mock job interview and mental arithmetic. The responsiveness of the HPA axis to exogenous CRF stimulation was not affected by treatment with NBI-34041, indicating that 38 does not impair basal regulation of the HPA system. By comparison, in subjects undergoing the psychosocial stress test, the cortisol response was significantly lower in the 100mg day treatment group than in the placebo group. These results suggest that CRF-R1 antagonists such as 38...

The Interactions Between Stress Lipid Profiles Cortisone HPA Axis and Inflammation Immunity

In an earlier study, Francis investigated the correlations between serum uric acid, cortisol, HDL cholesterol, LDL cholesterol, and psychometric indices of stress, including anxiety, hostility, and depression, in 20 students over a 2.5-month academic quarter. The students' serum cholesterol and the LDL cholesterol levels were significantly elevated above control levels. The ratio of HDL cholesterol total cholesterol was significantly lower 102 . Agarwal et al. also estimated the serum cholesterol, triglycerides, and total lipids in 12 students exposed to a varying degree of examination stress. Serum cholesterol and triglycerides exhibited a rise proportional to the degree of examination stress, whereas other lipids exhibited an initial rise followed by a fall. The rise in serum cholesterol and triglycerides seems to be caused by stress-induced changes in hormonal levels and peripheral lipolysis, respectively 103 . The HPA axis, the mediator of cortisol, also plays a central role in...

Counterregulatory Hormones

Hypoglycemia or stress can trigger the secretion of several hormones, including glucagon, the catecholamines such as epinephrine, growth hormone and Cortisol. These act to counter insulin's action in stimulating peripheral glucose disposal and inhibiting hepatic glucose output (89,90). Modulation of these counterregulatory hormones can impact glycemic control and or insulin action in diabetic patients.

Metformin Weight Loss and PCOS

High concentrations of serum LH in the follicular phase are associated with PCOS and with decreased reproductive function (22). Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing problems with fertilization and miscarriage. Van Dam et al. (23) noted that 7 days of calorie restriction on a very-low-calorie diet (VLCD) (471 kcal day) paradoxically increased basal and pulsatile LH secretion, despite reductions in plasma glucose, insulin, leptin, and testosterone concentrations, which decreased by 18, 75, 50, and 23 , respectively. Serum estrone, estradiol, SHBG, and androstenedione concentrations remained unchanged.

Venous Sinus Obstruction in Pseudotumor Cerebri Syndrome Cause or Effect

There are various other pathological entities that may be represented in the spectrum of obstructive intrinsic venous sinus lesions. Fat deposits in the dural sinuses on CT was reported by Tokiguchi et al. 173 . These authors reported 8 cases in which macroscopic, non-obstructing fat deposits were demonstrated in the walls of the sinuses. In 5 cases fat was located at the torcular while in 3 it was located in the SSS. Anatomical proof that these lesions did indeed consist of fat was supplied in a later report where 2 of these patients had later undergone autopsy 174 . Finally, nodules of cavernous tissue have been identified in the sinuses, especially at the junction of the straight sinus and vein of Galen 13, 95 . The nodules, distinct from arachnoid granulations, were common at autopsy and were composed of endothelium lined sinusoids resembling erectile tissue.

Ayurvedic Tips Fot Controling Troponin

Not come into play giving the skeleton more weight bearing strength 120 . It may be concluded that there is a balance between these two pathways, with a predominance of peripheral and positive effects of leptin only in conditions of central leptin resistance, as in obesity, or when serum leptin levels rise above a threshold. This hypothesis appears supported by recent observations in hemodialysis patients in which bone mineral density (BMD) was positively associated with leptin only when circulating levels were higher than the threshold for blood-brain transport saturation 134 . However, it must be kept in mind if data obtained from mice models is relevant to humans. This question particularly needs to be addressed because leptin-deficient mice and humans are phenotypically different 118 . As such, further clinical studies are clearly required to better define the effect of leptin on bone metabolism in humans. Several cross-sectional studies have been published reporting conflicting...

Enhancers Of Insulin Action

Fta Adrenergic Receptor (SaARs) Agonists - Agonists of P3ARS increase the release of energy stores as heat in brown adipose tissue, increase lipolysis in white adipose tissue, suppress food consumption, suppress leptin gene expression and serum leptin levels. Uncoupling proteins (UCPs) in the inner mitochondrial membrane generate heat without effecting other energy-consuming processes (76). After treatment with the P3AR agonist CL316,243 35 (0.2 mg kg day), KK-Ay mice showed increased UCP expression in adipose tissue, but not in muscle and heart. Furthermore, the concentration of plasma insulin and free fatty acids were significantly reduced (77). CL316,243 has also been prepared in ester form to

Mice with Reduced Atg16L1 Expression Reproduce Aspects of Crohns Disease Pathology and Reveal a Cellular Target for the

Crohn Disease Model

Histological examination of the small intestine from Atg16L1HM mice led to the identification of a previously unknown human Crohn's disease pathology striking morphological, functional, and transcriptional abnormalities in the Paneth cell. Interestingly, like macrophages from Atg16L1 KO mice (Saitoh et al. 2008), Paneth cells from Atg16L1 -deficient mice display gain-of-function properties in that they overproduce transcripts associated with PPAR signaling, acute phase reactants, adipocytokine signaling, and lipid metabolism. The proteins encoded by many of these transcripts are directly implicated in inflammation. However, the increased expression of IL-1P in macrophages from Atg16L1 KO mice is due to post-translational changes in IL-1P, while increases in the cytokine leptin noted in Paneth cells from Atg16L1HM mice are due to altered transcriptional regulation. Fig. 2a-g Crohn's disease patients homozygous for the disease risk allele of ATG16L1 display Paneth cell abnormalities...

V1b Receptor Antagonists

Beta-lactams 23-24 represent a new class of Vib receptor antagonists (23 rVib Ki 70 rM, 24 rVib K, 30 nM no selectivity data against the Via receptor reported). Compound 24 was found to restore both biochemical (testosterone cortisol levels) and behavioural (seed finding) markers in hamster at the dose of i mg kg i.p. with activity comparable to that of fluoxetine, buspirone and chlordiazepoxide 6i . Interestingly, this chemotype is related to a previously discussed class of selective Via receptor antagonists represented by 4 and 5.

Gpr119 Agonists Medicinal Chemistry

Further pharmacological characterization demonstrated that sulfox-ide 34 elicited a dose-responsive effect on GLP-1 secretion in murine GLUTag cells (EC50 153 7 70 nM). This was confirmed in a meal tolerance test using P32 98 (50mg kg, po) in combination with 34 (100mg kg) in rats. In addition, 34 (30mg kg, po) inhibited gastric emptying in rats in a manner similar to the antiobesic agent HMR1426 (50 mg kg, po). Subchronic daily dosing of 34 to high fat diet-fed rats for 21 days (100mg kg qd po) significantly lowered plasma glucose and insulin levels during an oGTT test performed on day 21 and also decreased fat pad mass and plasma leptin levels 53,54 . In addition, subchronic once daily oral administration (100 mg kg day) slowed the progression of diabetes in a study in young db db mice, as highlighted by the ability of 34 to maintain normal fed blood glucose levels and glucose tolerance following an oGTT on day 21 of the experiment.

Mechanisms of Kidney Damage in Adiposity

Leptin, and transforming growth factor TGF - 1) (11). The following discussion elaborates on these mechanisms. White adipose tissue can be considered as the largest secretory organ in the body. It releases a wide range of protein signals and factors, termed adipokines (27). A number of adipokines including leptin, adiponectin, tumor necrosis factor (TNF)-a, inter-leukin (IL)-ip, IL-6, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin are linked to inflammation and the inflammatory response. This leads to a low-grade inflammatory condition that is important in the causation and progression of hypertension and endothelial dysfunction. Leptin is a proinflammatory adipokine. Leptin is cleared by the kidney (29-31), and its concentration increases in renal impairment. In glomerular endothelial cells, leptin stimulates cellular proliferation, TGF- 1 synthesis,...

Androgen Metabolism Within the Skin

Androgens within sebaceous glands (9). Such insights may be of benefit in the design of new acne therapies. The skin and sebaceous gland are capable of producing and metabolizing androgens (9). DHEAS is the major adrenal androgen precursor. It circulates in the blood stream in relatively high levels compared with other hormones with the exception of cortisol. In fact, in for review, see Ref. postmenopausal women, all sex steroids made in the skin are from adrenal steroid precursors, especially DHEA. Secretion of this precursor steroid by the adrenals decreases progressively from age 30 to less than 50 of its maximal value at age 60 (10). The enzyme 3 -hydroxysteroid dehydrogenase (3 -HSD) acts on DHEA to convert it to androstenedione (Fig. 1). This conversion may take place in the adrenal gland and tissues such as the sebaceous gland, where activity of the 3 -HSD enzyme has been identified by several investigators (11-13). The reversible conversion of androstenedione into testosterone...

Adipokines and Oxidative Stress

Leptin increases markers of lipoperoxidation in the liver while decreasing antioxidant GSH levels and the activities of glutathione-S-transferases (GSTs), superoxide dismutase (SOD), and catalase (107). Similar observations have been made in non-NAFLD patients with other chronic liver diseases (108). Intravenous leptin injections induce the release of nitric oxide (NO) (109) by both endothelial and inducible nitric oxide synthases (eNOS and iNOS). As uncoupled eNOS changes from a protective enzyme to a contributor to oxidative stress, leptin-induced stimulation of eNOS and iNOS is a pro-oxidative event (110). Leptin also stimulates cytochrome CYP2E1 expression, responsible for the oxidation of alcohol and the production of ROS. Paradoxically, CYP2E1-dependent production of ROS inhibits apoptosis but accelerates necrosis stimulated by polyunsaturated FA (111). This latter observation is consistent with the necroinflammatory features seen in patients with NASH. Finally, CYP2E1 activity...

Recruitment of monocytes to adipose tissue in obesity

Although recent studies have established that obesity is associated with the accumulation of macrophages in adipose tissue of rodents and humans, the mechanisms that regulate this process are just being studied. The first step in the recruitment of mono-cytes to a tissue is the adhesion to endothelial cells. In human studies, obesity and impaired insulin sensitivity are associated with elevated circulating concentrations of cellular adhesion molecules, including ICAM-1, VCAM-1, and E-selectin (103-107). In vitro adipocyte-conditioned medium can directly u pregulate the expression of ICAM-1 and platelet-endothelial cell adhesion molecule (PECAM), and increase adhesion, migration, and chemotaxis of monocytes (97). Recently leptin and adiponectin have been shown to have opposing effects on endothelial cells leptin increases mono-cyte adhesion to endothelial cells, and adiponectin reduces expression of adhesion molecules and other proinflammatory molecules by endothelium (97,108).

Adipokines Inhibitory Yin and Stimulatory Yang Signals in Inflammation

Celsus's description (first century AD) of inflammation signs includes rubor et tumor cum calor et dolor. Inflammation is an essential biological response aiming at recovering from injury, wound healing being a paradigm of such a homeostatic phenomenon. However, what begins as a protective response becomes a damaging process in excess hence, inflammation is increasingly recognized as the underlying basis of a significant number of diseases. Recent studies based on a pangenomic approach in human subcutaneous WAT revealed that a panel of inflammatory molecules was upregulated in obese compared to lean subjects (ref. 12and references therein). Of note, a calorie-restriction diet improved the anti-inflammatory profile of obese subjects via increase of antiinflammatory and decrease of proinflammatory molecules (12). Further, weight loss resulted in decrease of adipose macrophage number and an increased production of interleukin (IL)-10, a well-known anti-inflammatory cytokine (13). These...

What is the physiologic response to electroconvulsive therapy

Heart rate of 20 or more and increases in blood pressure of 30 to 40 or more. Ventricular arrhythmias and ST-segment changes may be noted and tend to be self-limited. The duration of the tachycardia tends to correlate with the seizure duration as measured by electroencephalography (EEG), although hypertension often persists and requires therapy. Increases in adrenocorticotropic hormone, cortisol, epinephrine, vasopressin, prolactin, and growth hormone are noted. Intraocular pressure and intragastric pressure also transiently increase.

What are the neurohumoral responses associated with laparoscopy

Plasma concentrations of dopamine, vasopressin, epinephrine, norepinephrine, renin, angiotensin, and cortisol all significantly increase. The increases correspond to the onset of abdominal insufflation. Serum levels of vasopressin and norepinephrine most closely parallel the changes noted in CO, MAP, and SVR. Hypercarbia, the mechanical effects of the pneumoperitoneum, and stimulation of the autonomic nervous system have all been implicated as possible causes of these observed changes. Preoperative a2-adrenergic agonists (clonidine dexmedetomidine) have been shown to decrease the stress response.

What are the alleged benefits and risks of ginseng

Ginseng is a general tonic for improving well-being and stamina and may increase resistance to environmental stress. The active constituents of ginseng are ginsengosides these compounds may raise blood pressure and act as a central nervous system stimulant. Adrenal function and cortisol release may increase. Ginsengosides are reported to interfere with platelet aggregation and coagulation in vitro, but this effect has not been demonstrated in humans. Ginseng is also associated with hypoglycemia, interferes with warfarin, and may increase partial thromboplastin time.

Congenital generalized lipodystrophy from mutations in BSCL2 and AGPAT2

Patients also develop significant metabolic abnormalities very early in life. Extreme insulin resistance is a striking feature of this syndrome. Most patients have high fasting and postprandial insulin levels. Onset of DM is usually seen during pubertal years, but, occasionally, neonates may also develop hyperglycemia. Severe hypertriglyceride-mia leading to recurrent pancreatitis, low HDL cholesterol levels, and chronic steatohep-atitis are other associated features. These patients have very low levels of serum leptin and adiponectin (16). Administering recombinant leptin to these patients as a replacement therapy helped to control hyperglycemia, hypertriglyceridemia, and hepatic steato-sis (17), suggesting that hypoleptinemia may be partly responsible for the metabolic abnormalities.

Arvind Batra and Britta Siegmund

Leptin is a 16-kDa protein, predominantly produced by adipose tissue with serum leptin concentrations correlating to body fat mass. Initially described as a regulator of appetite, it is now well established that this mediator exerts pro-inflammatory effects on various immune as well as nonimmune cells. In vitro as well as in vivo studies suggest an involvement of leptin in the regulation of intestinal inflammation. The data leading to this finding are the subject of discussion in this chapter. In particular, the various effects of leptin on different cell populations that are involved in the induction and persistence of intestinal inflammation, i.e., T-cells, antigen presenting cells, and epithelial cells, are outlined in detail. In addition, we propose a significant role for the potential interaction of the adipose tissue and the mucosal immune system in the pathophysiology of inflammatory bowel disease. Key Words Leptin adipokines cytokines inflammatory bowel disease experimental...

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