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

This work was undertaken to examine the relationship between thyroid hormone and serum leptin concentration. This study included 368 Japanese female subjects (27 were affected with pretreatment hyperthyroidism, 68 with hyperthyroidism during treatment, 19 with pretreatment hypothyroidism, 57 with hypothyroidism during treatment and 197 euthyroid control subjects) and 60 control male subjects. In the control group, serum leptin levels in males were lower than those recorded in females (mean +/- SD; 4.6 +/- 4.1 vs 9.5 +/- 6.4 ng/ml, p < 0.001). The leptin values correlated well with body mass index (BMI) and body fat mass (BFM) in both control male and female subjects (p < 0.001 for each). The serum leptin levels in pretreatment female patients with hyperthyroidism were significantly lower than those in the pretreatment patients with primary hypothyroidism and control female subjects (6.4 +/- 3.0 vs 9.7 +/- 6.3, 9.5 +/- 6.4 ng/ml; p < 0.05, 0.02, respectively), but after adjusting for BMI and BFM, the difference was mainly due to the significantly different BMI and BFM. Furthermore, serum leptin did not change significantly during the treatment in hyper and hypothyroidism. There was no correlation between serum leptin and thyroid hormones or lipids levels in female patients with thyroid disorders. Adiposity and gender were the major determinants of leptin concentration, but thyroid hormones did not appear to play any relevant role in leptin synthesis and secretion in human.
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PMID:Serum leptin and lipids in patients with thyroid dysfunction. 1142 45

Fifty obese subjects with body weight above 120% of the ideal weight for that height or body mass index greater than 27.8 kg/m2 in men or 27.3 kg/m2 in women were studied for thyroid hormone profile. Nearly three-fourths obese subjects had body mass index of 30-40 kg/m2. Eighty-six per cent subjects were clinically and biochemically euthyroid. Fourteen per cent of the subjects had hypothyroidism; out of them, 8% were clinically and biochemically hypothyroid while 6% were only biochemically hypothyroid. None of the hypothyroid subjects had morbid obesity (greater than 40 kg/m2 body mass index). Duration of obesity in hypothyroid subjects was less than 10 years in nearly three-fourths of cases.
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PMID:Thyroid hormone profile in obese subjects--a clinical study. 1167 11

We report a 43 years old female, admitted due to fatigability, asthenia and diffuse abdominal pain. On admission, obesity, slowness of thinking, bradycardia, distention of jugular veins and ascites were observed on physical examination. Laboratory showed undetectable thyroid hormone levels, a chest X ray showed bilateral pleural effusion and an enlarged heart. An echocardiography showed a massive pericardial effusion with collapse of the right atrium and dilatation of both caval veins. A pericardial tap was performed, draining 350 ml. Thyroid hormone substitution was started and after 12 months of follow up, the heart size decreased and a control echocardiogram showed a minimal pericardial effusion.
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PMID:[Massive pericardial effusion and cardiac tamponade as the presentation form of hypothyroidism]. 1177 48

The identification of a mutation at the tubby (Tub) locus, which causes obesity and neurosensory degeneration, led to the discovery of the tubby-like proteins (TULPs). Tub and the genes that encode three tubby-like proteins (TULP1- TULP3) form a novel, small gene family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Although exploration of the molecular function of these genes is still in its infancy, recent biochemical studies have provided 'entry points' into pathways whose elucidation will further our understanding of TULP action. In addition, mRNA expression and translocation of the TUB protein have been shown to be regulated by thyroid hormone and by G-protein-coupled receptor signaling, respectively. These latter findings may help to link the cellular function of TUB to known mechanisms for energy homeostasis.
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PMID:The tubby-like proteins, a family with roles in neuronal development and function. 1180 19

Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.
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PMID:Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. 1205 88

A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.
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PMID:Leptin signaling, adiposity, and energy balance. 1207 65

The thyroid hormone (TH; 3,3',5,5'-tetra-iodothyronine and 3,3',5'-triiodothyronine) regulates growth, development, and critical metabolic functions. Thyroid diseases are among the most prevalent group of metabolic disorders in the Western world. TH exerts effects through complex biological pathways, which offer a wealth of opportunities to pharmacologically intervene in TH signalling at numerous steps. These include biosynthesis, cell-specific uptake or export (involving L-type amino acid transporter, organic anion transporter, organic cation transporter, or multidrug resistance transporter), as well as nuclear targeting and actions (the latter including TH receptor binding and histone acetylation/deacetylation). Such processes represent potentially important pharmacological targets for the design of novel or improved therapies for TH disorders, obesity, and cardiovascular diseases.
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PMID:Complex regulation of thyroid hormone action: multiple opportunities for pharmacological intervention. 1211

Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.
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PMID:Mitochondrial uncoupling as a target for drug development for the treatment of obesity. 1211 96

Most often, low-renin hypertension in the child or adolescent has a clearly definable hormonal cause; thus while each of its numerous forms is moderately rare, a specific hormonal basis is to be expected. An endocrine evaluation is indicated after exclusion of cardiologic pathology or renovascular or portal abnormality in a hypertensive child. The evaluation should include analysis of catecholamine and of thyroid hormone plasma levels, and plasma renin activity (PRA) level. Hormonal hypertension with high or normal renin conditions is rare. Elevated blood pressure with high or normal renin levels may be in fact within normal range in the context of growth at upper percentile limits, possibly in conjunction with simple obesity. Diagnosis may be made at any age in most forms of low-renin hypertension.
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PMID:Hypertension in congenital adrenal hyperplasia and apparent mineralocorticoid excess. 1238 49

Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.
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PMID:Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. 1269 76


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