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

Leptin and its receptor are involved in endocrine and paracrine regulation of metabolism, obesity and reproduction. Here, we describe the detection of the functional long isoform receptor of leptin in human endometrium. The leptin receptor protein was shown to be expressed in glandular and luminal epithelium and is periodically regulated throughout the menstrual cycle, demonstrating main expression in follicular and mid-luteal phase. In contrast, leptin receptor mRNA is detectable by reverse transcription-polymerase chain reaction (RT-PCR) as a constitutive component. Since RT-PCR analyses showed that leptin is not expressed in this tissue, the present study suggests that the human endometrium is a novel target for leptin. Therefore, we investigated 11 subfertile patients who underwent two biopsies in one menstrual cycle. The patients presented with a repetitive endometrial maturation defect, but showed adequate serum hormone concentrations and normal steroid hormone receptor expression and down-regulation in the endometrium. These patients were, however, deficient for expression of the functional leptin receptor. These analyses provide evidence that the lack of the leptin receptor in an ovulatory cycle may contribute to subfertility by a yet undefined 'endometrial factor'.
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PMID:The endometrium as a novel target for leptin: differences in fertility and subfertility. 1087 46

This article reviews the fetal endocrine system in sheep, a species that has a long gestation and primarily produces a singleton fetus. Attention is focused on information that is applicable to humans. The endocrinology of metabolic homeostasis in sheep fetuses is well adapted to respond to a range of metabolic challenges, including placental restriction and maternal undernutrition. A small placenta results in hypoxaemia, hypoglycaemia, reduced abundance of anabolic hormones, and fetal growth restriction. Fetuses with restricted growth are characterized by tissue-specific reductions in hormone receptor mRNA, for example mRNA for the long form of prolactin receptor is reduced in adipose tissue. In contrast, the adipose tissue of fetuses with accelerated growth, stimulated by increasing maternal nutrition in the second half of gestation, has more protein for the long form of the prolactin receptor and more uncoupling protein 1, by which large amounts of heat are generated at birth. Maternal undernutrition in early gestation, coinciding with the period of rapid placental growth, initially restricts placental growth, but when mothers are fed to requirements, a longer fetus results with a disproportionately large placenta. This nutritional manipulation replicates, in part, epidemiological findings from the Dutch famine of 1944-1945, for which the offspring are at increased risk of adult obesity.
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PMID:Fetal endocrinology and development--manipulation and adaptation to long-term nutritional and environmental challenges. 1137 71

A large response range can be observed in both behavioral and neuroendocrine responses to environmental challenges. This variation can arise from central mechanisms such as those involved in the shaping of general response tendencies (temperaments) or involves only one or the other output system (behavioral vs. endocrine response). The participation of genetic factors in this variability is demonstrated by family and twin studies in humans, the comparison of inbred strains and selection experiments in animals. Those inbred strains diverging for specific traits of stress reactivity are invaluable tools for the study of the molecular bases of this genetic variability. Until recently, it was only possible to study biological differences between contrasting strains, such as neurotransmitter pathways in the brain or hormone receptor properties, in order to suggest structural differences in candidate genes. The increase of the power of molecular biology tools allows the systematic screening of significant genes for the search of molecular variants. More recently, it was possible to search for genes without any preliminary functional hypothesis (mRNA differential expression, nucleic acid arrays, QTL search). The approach known as quantitative trait loci (QTL) analysis is based on the association between polymorphic anonymous markers and the phenotypical value of the trait under study in a segregating population (such as F2 or backcross). It allows the location of chromosomal regions involved in trait variability and ultimately the identification of the mutated gene(s). Therefore, in a first step, those studies skip the 'black box' of intermediate mechanisms, but the knowledge of the gene(s) responsible for trait variability will point out to the pathway responsible for the phenotypical differences. Since variations in stress-related responses may be related to numerous pathological conditions such as behavioral and mood disorders, drug abuse, cardiovascular diseases or obesity, and production traits in farm animals, these studies can be expected to bring significant knowledge for new therapeutic approaches in humans and improved efficiency of selection in farm animals.
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PMID:Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses. 1196 55

Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor-defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor-positive than hormone receptor-negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor-defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.
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PMID:Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. 1546 70

Breast cancer patients who are obese have a higher risk of lymph node metastases and a poorer prognosis than those who are slim. It has been claimed that estrogens derived from fat are important for these associations. If estrogens are important, these relationships must be stronger in the hormone receptor-positive than in the hormone receptor-negative groups. Body mass index (BMI) was used as a measure of obesity. The second, third, and fourth quintiles of BMI were treated as one group and termed 'medium'. Patients in the fifth quintile were termed 'obese' and those in the first quintile 'slim'. The number of women with unilateral disease treated with modified radical mastectomy and included in the study was 1211. Of all patients included, obese patients had a 1.53 higher risk of lymph node metastases compared to slim patients (p=0.02). In the PgR-negative group, obesity gave a 3.08 times higher risk of lymph node metastases (p=0.03). The risk of dying of breast cancer tended to be higher in obese than in slim patients when all patients in the study were compared (relative risk=1.38, p=0.06). BMI did not show a statistically significant relationship with prognosis if only hormone receptor status was considered. However, if lymph node status and hormone receptor status were taken together, the association was strong and reversed in the lymph node-positive group with ER-negative tumours. The adjusted relative risk was 0.33, showing that slim patients had a 3.03 (1.0/0.33) times higher risk of dying of breast cancer compared to obese patients (p=0.002). These results indicate that non-hormonal mechanisms could be important.
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PMID:The associations of obesity, lymph node status and prognosis in breast cancer patients: dependence on estrogen and progesterone receptor status. 1551 Dec 72

We identified a glycoprotein hormone beta-subunit (OGH, also called GPB5) that, as a heterodimer with the alpha-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH-/-) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop approximately 2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates. Moreover, when OGH-TG mice are challenged with a high-fat diet, they gain significantly less weight and body fat than their WT littermates. The OGH-TG mice also have reduced blood glucose, insulin, cholesterol, and triglycerides. In contrast to other approaches in which the thyroid axis is activated, OGH-TG mice exhibit only minor changes in heart rate and blood pressure. Our findings suggest that constitutive low-level activation of the thyroid axis (via OGH or other means) may provide a beneficial therapeutic approach for combating diet-induced obesity.
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PMID:Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5. 1569 48

Hypogonadotrophic hypogonadism (HH) is characterized by delayed or absent pubertal development secondary to gonadotrophin deficiency. HH can result from mutations of the gonadotrophin-releasing hormone receptor 1, the gonadotrophin beta-subunits, or various transcription factors involved in pituitary gland development. HH occurs in DAX1 mutations when associated with adrenal insufficiency (adrenal hypoplasia congenita), and is also linked with obesity in patients with mutations of leptin and its receptor, as well as mutations in prohormone convertase 1. Rarely, HH has resulted from kisspeptin receptor (GPR54) mutations, a gene implicated in the regulation of pubertal onset. When occurring with anosmia (a lack of sense of smell), HH is referred to as Kallmann's syndrome (KS). Two KS-related loci are currently known: KAL1, encoding anosmin-1, responsible for X-linked KS, and KAL2, encoding the fibroblast growth factor receptor 1 (FGFR1), mutated in autosomal dominant KS. Anosmin-1 is an extracellular glycoprotein with some unique structural characteristics; it interacts with both urokinase-type plasminogen activator and FGFR1. It has previously been shown that anosmin-1 enhances FGFR1 signalling in a heparan sulphate-dependent manner, and proposed that anosmin-1 fine-tunes FGFR1 signalling during olfactory and GnRH neuronal development. Here, we review the known normosmic causes of HH, and discuss novel developmental and molecular mechanisms underlying KS; finally, we introduce three novel genes (NELF, PKR2, and CHD7) that may be associated with some phenotypic features of KS.
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PMID:Molecular pathogenesis of Kallmann's syndrome. 1719 Oct 30

To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)alpha (V1q) or monocyte/macrophage-expressed EGF-like module-containing mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFalpha- and anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFalpha therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting "activated" TNFalpha-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.
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PMID:Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. 1746 Jul 30

Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R), are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin(-/-) mice but not in Ghsr(-/-) mice. Under caloric restriction, the weight loss of ghrelin(-/-) and Ghsr(-/-) mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin(-/-) and Ghsr(-/-) mice are not resistant to diet-induced obesity but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than directly regulate energy intake and energy expenditure.
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PMID:Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. 1800 36

Complement-C1q TNF-related protein 1 (CTRP1), a member of the CTRP superfamily, is expressed at high levels in adipose tissues of obese Zucker diabetic fatty (fa/fa) rats, and CTRP1 expression is induced by proinflammatory cytokines, including TNF-alpha and IL-1beta. In the present study, we investigated stimulation of aldosterone production by CTRP1, since it was observed that CTRP1 was specifically expressed in the zona glomerulosa of the adrenal cortex, where aldosterone is produced. Increased aldosterone production by CTRP1 in cells of the human adrenal cortical cell line H295R was dose-dependent. Expression levels of aldosterone synthase CYP11B2 were examined to investigate the molecular mechanisms by which CTRP1 enhances the production of aldosterone. The expression of CYP11B2 was greatly increased by treatment with CTRP1, as was the expression of the transcription factors NGFIB and NURR1, which play critical roles in stimulation of CYP11B2 gene expression. It was also revealed that angiotensin II-induced aldosterone production is, at least in part, mediated by the stimulation of CTRP1 secretion, not by the increase of CTRP1 mRNA transcription. In addition, the levels of CTRP1 were significantly up-regulated in hypertensive patients' serum. As CTRP1 was highly expressed in obese subjects as well as up-regulated in hypertensive patients, CTRP1 may be a newly identified molecular link between obesity and hypertension.
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PMID:A novel adipokine CTRP1 stimulates aldosterone production. 1817 93


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