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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent cloning of the leptin (obese, ob) gene has determined fundamental insight into the understanding of the regulation of food intake, basal metabolism and reproductive function. Leptin, mainly secreted by adipocytes, belongs to the helical cytokine family and its plasma concentrations correlate with fat mass and respond to changes in energy balance. Initially, leptin was considered as an anti-obesity hormone, but experimental evidence has also shown pleiotropic effects of this molecule on hematopoiesis, angiogenesis, lymphoid organ homeostasis and T lymphocyte functions. More specifically, leptin links the pro-inflammatory T helper (Th)-1 immune response to the nutritional status and the energy balance. Indeed, decreased leptin concentrations during conditions of food deprivation lead to impaired immune capabilities. This review focuses on the potential therapeutic utilities for agents that manipulate the leptin-adipocyte axis and discusses novel strategies for an immune intervention in pathologic conditions.
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PMID:Leptin as a novel therapeutic target for immune intervention. 1456 Dec 3

Adiponectin, an adipocyte-derived hormone, is attracting considerable interest as a potential drug for diabetes and obesity. Originally cloned from human s.c. fat, the protein is also found in bone marrow fat cells and has an inhibitory effect on adipocyte differentiation. The aim of the present study is to explore possible influences on lymphohematopoiesis. Recombinant adiponectin strongly inhibited B lymphopoiesis in long-term bone marrow cultures, but only when stromal cells were present and only when cultures were initiated with the earliest category of lymphocyte precursors. Cyclooxygenase inhibitors abrogated the response of early lymphoid progenitors to adiponectin in stromal cell-containing cultures. Furthermore, PGE(2), a major product of cyclooxygenase-2 activity, had a direct inhibitory influence on purified hematopoietic cells, suggesting a possible mechanism of adiponectin action in culture. In contrast to lymphopoiesis, myelopoiesis was slightly enhanced in adiponectin-treated bone marrow cultures, and even when cultures were initiated with single lymphomyeloid progenitors. Finally, human B lymphopoiesis was also sensitive to adiponectin in stromal cell cocultures. These results suggest that adiponectin can negatively and selectively influence lymphopoiesis through induction of PG synthesis. They also indicate ways that adipocytes in bone marrow can contribute to regulation of blood cell formation.
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PMID:Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells. 1460 7

GH and PRL are both implicated in adipose tissue development. Whilst direct effects of GH have been clearly demonstrated, direct effects of PRL have been subject to considerable debate. Recent studies have however provided compelling evidence for PRL receptors on adipocytes and in vitro effects on leptin and lipoprotein lipase activity have been demonstrated. Quantitatively however these effects of PRL are less significant than those of GH and the most pronounced effects of PRL on adipose tissue are indirect, for example, during lactation, when prolactin drives milk synthesis which results in a homeorhetic shift towards lipid mobilization from adipose tissue to support milk production. GH also exhibits such homeorhetic effects, most notably in ruminants, but also clearly has direct, insulin-antagonistic, metabolic effects. The roles of GH and PRL on adipocyte proliferation and differentiation have also been controversial, with GH stimulating adipocyte differentiation in vitro in cell lines whilst stimulating proliferation and inhibiting differentiation of primary cell cultures. Examination of adipose tissue development in PRLRko and GHRko mice has revealed roles for both hormones. PRLRko mice show impaired development of both internal and subcutaneous adipose tissue due to decreased numbers of adipocytes. In contrast, GHRko mice exhibit major decreases in the number of internal (parametrial) adipocytes whereas subcutaneous adipocytes develop almost normally. This leads to major changes in the sites of adipose tissue accretion and bears interesting parallels with the adipose tissue redistribution which occurs in HIV-induced lipodystrophy. Such individuals exhibit a central obesity which can be partially corrected by GH treatment. However, recent studies suggest that this may be a physiological response in which adipose tissue sites containing lymphoid tissue (such as mesenteric) show preservation of adipose tissue perhaps to support augmented immune responses.
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PMID:Effects of growth hormone and prolactin on adipose tissue development and function. 1470 19

Leptin is an adipocyte-derived hormone that acts as a major regulator for food intake and energy homeostasis. Leptin deficiency or resistance can result in profound obesity, diabetes, and infertility in humans. Since its discovery, our understanding of leptin's biological functions has expanded from anti-obesity to broad effects on reproduction, hematopoiesis, angiogenesis, blood pressure, bone mass, lymphoid organ homeostasis, and T lymphocyte systems. Leptin orchestrates complex biological effects through its receptors, expressed both centrally and peripherally. Leptin receptor belongs to the class I cytokine receptor superfamily. At least five isoforms of leptin receptor exist, primarily because of alternate splicing. The longest form is capable of full signal transduction. The short forms may serve as leptin binding proteins and play a role in leptin transporting across the blood-brain barrier. In this review, we present the crystal structure of leptin and the structural comparison with other four-helical cytokines, discuss the leptin-receptor binding models based on other cytokine-receptor complex structures, and summarize the most recent progress on leptin signal transduction pathways--especially its link to peripheral lipid metabolism through AMP-activated protein kinase and hepatic stearoyl-CoA desaturase-1 pathways. Furthermore, we propose the structure based design of leptin analogs with increased stability, improved potency, enhanced blood-brain barrier transport, and extended time action for future therapeutic application.
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PMID:Leptin: structure, function and biology. 1611 74

Ancestral lymphoid cells reside in adipose tissues, and their numbers are highly altered in obesity. Leptin, production of which is correlated to fat mass, is strongly involved in the relationships between adipose tissues and immune system. We investigated in epididymal (EPI) and inguinal (ING) fat pads to determine whether 1) lymphocyte phenotypes were correlated to the tissue weight and 2) leptin was involved in such relationships. Immunohistological analyses revealed a tight relationship between the T and NK lymphocytes of the stromal vascular fraction and adipocytes. We identified a significant negative and positive correlation between EPI weight and the percentage of NK and total T cells respectively by cytofluorometric analyses. The NK and ancestral gammadelta T cell contents were directly dependent of leptin since they increased significantly in high-fat (HF) diet mice but not in leptin-deficient (ob/ob) mice as compared to control. By contrast, the alphabeta T cell content seemed independent of leptin because their percentages increased significantly with the EPI weight whatever the type of mice (control, HF, ob/ob). The present study suggests that adipose tissues present, according to their localization, different immunological mechanisms that might be involved in the regulation of adipose cells functions and proliferations.
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PMID:Weight-dependent changes of immune system in adipose tissue: importance of leptin. 1665 Aug 47

Glucocorticoids are important endocrine regulators of a wide range of physiological systems ranging from respiratory development, immune function to responses to stress. Glucocorticoids in cells activate the cytoplasmic glucocorticoid receptor (GR) that dimerizes, translocates to the nucleus and functions as a ligand-dependent transcriptional regulator. Synthetic glucocorticoids such as dexamethasone and prednisolone have for decades been the cornerstone for the clinical treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, and in some lymphoid cancers, yet its prolonged use has undesirable side effects such as obesity, diabetes, immune suppression and osteoporosis. Detailed knowledge on the mechanism of GR action has led to the development of novel selective glucocorticoid receptor modulators (SGRMs) that show promise of being efficacious for specific treatments of disease but with fewer side effects. SGRMs promote specific recruitment of transcriptional co-regulators that elicit specific gene responses and show promise of greater efficacy and specificity in treatment of inflammatory diseases and type-2 diabetes.
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PMID:Glucocorticoid action and the development of selective glucocorticoid receptor ligands. 1704 97

Obesity results from disturbances of tightly regulated interactions between the nervous, endocrine, and metabolic systems that can be caused by external factors, such as viral infections. A mouse model of obesity induced by brain infection with a morbillivirus, canine distemper virus, allowed us to identify obesity-related genes. Using a subtractive library for the hypothalamus, the main brain structure regulating energy homeostasis, we identified a new gene on mouse chromosome 19 which we named upregulated obese product (Urop) 11 and, which has no homology with any known mRNA. A step-by-step molecular approach allowed us to isolate the full-length mRNA, predict the protein sequence, and identify consensus sites. Urop11 was mainly detected in the hypothalamus and adipocytes, and was dramatically upregulated in these central and peripheral structures in obese mice. Urop11 was also expressed in human neural and lymphoid samples and its expression seemed to be regulated by the state of lymphocyte activation. Interestingly, Urop11 expression was strongly upregulated both in vivo in mouse hypothalamus and in vitro in mouse neural cell lines, after leptin treatment. Taken together, our data show that Urop11 is a target of leptin, the satiety factor produced by adipocytes, in physiological and pathological conditions, including obesity. This new gene can be considered a key molecule in the hypothalamic integration pathway and demonstrates the importance of Urop11 as a target of leptin action.
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PMID:Identification of Urop11, a novel leptin-modulated gene that is upregulated in the hypothalamus of mice with virus-induced obesity. 1724 66

Both hypergonadotropic hypogonadism and myasthenia gravis can be parts of type II autoimmune polyendocrine syndrome and association between the two disorders has been reported in few cases. A 14 year old male patient with a personal history of bilateral cryptorchidism and ptosis was referred for delayed puberty. Clinical examination revealed eunuchoid habitus, small, soft testes, gynecomastia, ptosis, a myasthenic deficit score of 22.5 points and an IQ of 84 points. Decreased testosterone (0.064 ng/mL) and elevated LH (64.5 mUI/mL) were consistent with hypergonadotropic hypogonadism and karyotype was normal: 46,XY. Thyroid function, haematologic evaluation, BUN, electrolytes, and glycemia were in the normal range. Therapy consisted of anticholinesterase inhibitors, immunosuppressants, corticotherapy, testosterone; thoracoscopic thymectomy was performed showing thymic lymphoid hyperplasia on histopathologic examination. Myasthenic score improved (12.5 points), progressive virilization occurred, and a year later the patient presented with cushingoid features and obesity.
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PMID:46,XY hypergonadotropic hypogonadism and myasthenia gravis. 1730 92

Metabolic and immune systems are very important for a living organism to survive. Since they play crucial roles in maintaining homeostasis, both systems work interdependently. In metabolic disorders like obesity and related diseases, lot of reports have been published about immune system impairment. In addition, in the case of malnutrition and calorie restriction, immune system is affected through several mechanisms. Different from the current point of view, I propose an unusual way of thinking about the relationship between immune and metabolic systems. The nutrient-based ecosystemic balance; the simple desires and rules like feeding or reproduction underlying very complex relations among species; the beneficial effects of caloric restriction; and the similarities between the pathways contributing obesity and infection made me look from a different perspective. Based on ecology and systems thinking, the present hypotheses suggest that pathologic organisms could be a kind of dietary source for lymphoid cells. If it is true, it will bring new and hopeful insights to all events related to metabolic and immune systems. At first, new mechanisms could be improved to defeat unbeatable organisms like Mycobacterium tuberculosis or HIV. The unphagocytosed organisms could be unknown tastes for our body's defenders. For example, the lymphoid cells could be classified as virovores, bacterivores, or fungivores like herbivores, and carnivores. Secondly, this basic relation could be used to solve huge problems caused by obesity related disorders like diabetes, because insulin would play more important roles for lymphoid cells while regulating the blood glucose level if the hypothesis is true. And the persistence of hyperglycemia would mainly effect lymphoid cells according to the current hypothesis.
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PMID:Could pathogens be nutrients for lymphoid cells? 1744 12

Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan.
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PMID:Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span. 1857 54


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