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

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (<or=1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months' treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p<0.001), with >or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.
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PMID:Pharmacotherapy for obesity. 1597 70

Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate." The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their coregulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Additional elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.
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PMID:New modes of action for endocrine-disrupting chemicals. 1603 29

Despite the well-established role of liver X receptors (LXRs) in regulating cholesterol homeostasis, their contribution to lipid homeostasis remains unclear. Here we show that LXR null mice are defective in hepatic lipid metabolism and are resistant to obesity when challenged with a diet containing both high fat and cholesterol. This phenotype is dependent on the presence of dietary cholesterol and is accompanied by the aberrant production of thyroid hormone in liver. Interestingly, the inability of LXR-/- mice to induce SREBP-1c-dependent lipogenesis does not explain the LXR-/- phenotype, since SREBP-1c null mice are not obesity resistant. Instead, the LXR-/- response is due to abnormal energy dissipation resulting from uncoupled oxidative phosphorylation and ectopic expression of uncoupling proteins in muscle and white adipose. These studies suggest that, by selectively sensing the cholesterol component of a lipid-rich diet, LXRs govern the balance between storage and oxidation of dietary fat.
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PMID:LXRs regulate the balance between fat storage and oxidation. 1605 68

Resting oxygen consumption and energy expenditure is sensitive to slight alterations in thyroid function. This means that timing and magnitude of cold adaptation would to some extent depend on thyroid function. Local thyroid hormone metabolism is important for energy expenditure and dissipation of heat in special tissues. Recruitment of brown adipocytes and upregulation of uncoupling protein 1 in mitochondria depends on high tissue T3 concentrations. Most of this T3 is derived from local 5' deiodination of T4. Brown fat is vital for cold exposed mice and rats, and may be important for temperature adaptation in human neonates. The role of thyroid hormone metabolism in adult human cold adaptation has not been finally clarified. Hypothetically, cold exposure may enhance T3 production by deiodination of T4 in skeletal muscle, which may enhance heat production in muscle via a change in muscle fiber type. Another hypothetical possibility is recruitment of brown adipocytes embedded in white adipose tissue in human adults. Understanding cold adaptation in human adults may lead to development of new drugs against obesity.
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PMID:Cold adaptation and thyroid hormone metabolism. 1617 91

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.
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PMID:Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. 1643 98

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via interaction with the thyroid hormone nuclear receptors (TRs). Recently, a small class of halogen-free high-affinity thyroid hormone agonists has been developed that are highly selective for the TRbeta subtype. Because of the selective hyperthyroidism generated by one of these agonists, GC-1, this compound has the potential to be developed as a new therapeutic agent for the treatment of a variety of metabolic disturbances, including lipid disorders and obesity; thus, it becomes important to determine whether GC-1 has other unknown effects on potential target organs. The purpose of this study was to investigate the effect of GC-1 on cell proliferation in rat liver and pancreas. Rats treated with GC-1 (50 or 100 mug/100 g body weight) were killed at different time points. Hepatic and pancreatic cell proliferation was monitored by immunohistochemical determination of bromodeoxyuridine incorporation. The expression of cell cycle-related genes was analyzed by Northern and Western analysis. The results show that GC-1 strongly stimulates rat hepatocyte proliferation in the absence of tissue injury. Although GC-1-induced hepatocyte proliferation was associated with a rapid increase in cyclin D1 mRNA levels, no change in the expression of c-jun and c-fos was observed. GC-1 also induced massive pancreatic cell proliferation. The results indicate that the TRbeta-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells. Furthermore, they suggest that the TRbeta receptor is the mediator for the mitogenic activity of thyroid hormone and other thyromimetics.
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PMID:The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas. 1657 85

This paper will suggest that the Down syndrome phenotype would have been well suited, physiologically, for a deprived environment and that it may represent a predictive, adaptive response to severe maternal deprivation. A trisomy of the 21st chromosome, prior to, or at conception is responsible for Down syndrome and is known to increase in incidence with advanced maternal age. One out of 11 mothers over the age of 50 conceives a Down syndrome baby, compared to one in one thousand at age 30. This article emphasizes that an older mother is more likely to die before she is able to provide the parental investment necessary to produce an ecologically self-sufficient offspring. Prolonged maternal investment is known to be essential for hunter-gatherers to master the skill intensive food procurement techniques that they will need in order to become independent of their mothers. Because Down syndrome individuals are much more likely to be born to older mothers, they must have been routinely deprived of maternal investment in the human environment of evolutionary adaptedness. This consistent paring of maternal deprivation to trisomy 21 conceptions, over time, may have caused natural selection to favor genes responsible for the energy conserving traits seen in modern day Down syndrome. These traits include muscle hypotonia, decreased cerebral metabolism, decreased hippocampal volume, a strong propensity for obesity and growth hormone and thyroid hormone paucity. Such a "thrifty phenotype" may have allowed Down syndrome individuals to become independent of their mothers at a far earlier age and allowed them to forgo the skill intensive ecological niche that non-trisomic humans are phenotypically suited for in order to take up a less cognitively and physically rigorous one.
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PMID:Evolutionary neuropathology and Down syndrome: an analysis of the etiological and phenotypical characteristics of Down syndrome suggests that it may represent an adaptive response to severe maternal deprivation. 1673 81

White adipose tissue (WAT) represents a reservoir of lipophilic environmental pollutants, especially of those which are resistant to biological and chemical degradation - so-called persistent organic pollutants (POPs). Large amounts of different congeners and isomers of these compounds exhibit a variety of adverse biological effects. Interactions among different classes of compounds, frequently with opposing effects, complicate hazard evaluation and risk assessment. WAT is the key organ for energy homeostasis and it also releases metabolites into the circulation and adipokines with systemic effects on insulin sensitivity and fuel partitioning in muscles and other tissues. Its beneficial role is lost in obesity when excessive accumulation of WAT contributes to severe diseases, such as diabetes. POPs may crossroad or modulate the effect of endogenous ligands of nuclear transcription factors, participating in differentiation, metabolism and the secretory function of adipocytes. These mechanisms include, most importantly: i) endocrine disrupting potency of POPs mixtures on androgen, estrogen or thyroid hormone metabolism/functions in WAT, ii) interference of dioxin-like chemicals with retinoic acid homeostasis, where impact on retinoid receptors is expected, and iii) interaction with transcriptional activity of peroxisome proliferator-activated receptors is likely. Thus, the accumulation and action of POPs in WAT represents a unitary mechanism explaining, at least in part, the effects of POPs in the whole organism. By modulating WAT differentiation, metabolism and function, the POPs could affect not only the physiological role of WAT, but they may also influence the development of obesity-associated diseases.
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PMID:White adipose tissue: storage and effector site for environmental pollutants. 1692 64

Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.
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PMID:Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases. 1706 80

Mechanisms by which the hypothalamus senses nutritional status are important for many metabolic diseases, including obesity and diabetes. Now, report that hypothalamic neurons sense nutritional deficit through a cascade of events involving leptin, corticosterone, and glial production of thyroid hormone, leading to neuronal induction of uncoupling protein.
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PMID:The "domino theory" of hunger: the hypothalamus is hot. 1718 4


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