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Query: UMLS:C0028754 (obesity)
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This chapter summarises the results of a recent study which investigated the role of the hypothalamo-pituitary relay system in mediating the effects of photoperiod on seasonal cycles in: (a) body weight; (b) pelage growth; and (c) reproduction in Soay rams. Hypothalamo-pituitary disconnected (HPD) and the control rams were housed indoors under an artificial lighting regimen of alternating 16-weekly periods. These periods consisted of long (16L:8D) and short days (8L:16D) and lasted for more than 2 years. The: (i) body weight; (ii) voluntary food intake; (iii) pelage and horn growth; and (iv) variations in testicular diameter were measured routinely every 2-4 weeks. Twice-weekly blood samples were collected to monitor long-term changes in the blood concentrations of: (1) pituitary; (2) metabolic; and (3) reproductive hormones (prolactin, GH, alpha-MSH, beta-endorphin, ACTH, TSH, LH, FSH, cortisol, insulin, IGF1 and testosterone). In control rams there were clearly defined photoperiod-induced cycles in blood concentrations of prolactin, alpha-MSH, beta-endorphin, LH, FSH, insulin and testosterone and associated morphological changes consistent with causal relationships (e.g. prolactin versus wool and horn growth, alpha-MSH, beta-endorphin and insulin versus body weight/food intake, LH and FSH versus testis size). In the HPD rams there were no photoperiod-induced cycles in the concentrations of any of the pituitary hormones with the exception of prolactin which varied as in controls (10-fold higher under long days). There was a permanent increase in blood concentrations of alpha-MSH, beta-endorphin and insulin in the HPD animals and a decrease in the concentrations of GH (loss of pulsatility) and IGF1. These changes were associated with the development of obesity. The reproductive axis was inactivated (basal LH, FSH and testosterone) although there was residual cyclicity in the size of the testis associated with the changes in prolactin secretion. Overall, the results support the view that the melatonin signal which encodes photoperiod, acts in the hypothalamus to regulate some photoperiodic responses (alpha-MSH and beta-endorphin-body weight axis, gonadotrophin-gonadal axis) but acts in the pituitary gland to regulate other responses (prolactin-pelage axis). However, a functional hypothalamus is required to generate normal seasonal cycles in: (a) body weight; (b) food intake; (c) growth; (d) fattening; and (e) reproduction, to provide the internal coordination between different systems and to facilitate the temporal entrainment to environmental cues.
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PMID:Photo-neuroendocrine control of seasonal cycles in body weight, pelage growth and reproduction: lessons from the HPD sheep model. 982 1

Primary empty sella syndrome (ESS) is an anatomo-radiological picture characterized by the presence of an arachnoid herniation filled with liquor that compresses the pituitary against the sellar wall. ESS occurs particularly in obese, hypertensive, cephalgic women, it is often asymptomatic but it may be associated with ophthalmologic, neurologic and sometime non-characterizing endocrine disorders. We report here 71 cases of primary ESS observed and assessed during the last fourteen years. The following endocrinological diagnostic procedures were carried out: hormonal (RIA) basal profile: FT3, FT4, TSH, PRL, ACTH, FSH, LH, 8.00 a.m. and p.m. cortisolemia, Aldo, PRA, DHEA-S, FTe, E2, P, PTH, CT, and calcemia and phosphoremia; provocative tests: TRH, GnRH, insulin hypoglycemia, etc.; inhibition tests: "overnight" and high dose dexamethasone. Clinical, radiological (skull radiographs, CT and/or MRI) and ophthalmologic (fundus, visual fields) assessment were made. We found principally cephalgia (52/71: 73.2%), hypertension (42/71: 59.1%), obesity (47/71: 66.1%). But we found especially mental disorders (57/71: 80.2%), in our knowledge not previously reported in the literature, as anxiety or dysthymic disorders with behavioural disturbances (chiefly oral compulsion). We found endocrinopathies in 36/71 (50.7%), isolated or coexisting in some patients: hyperPRL (14%), hypopituitarism (10.4%), hypogonadism (7%), diabetes insipidus (2.8%), hyperACTH (1.4%), hypoGH (15.4%), pituitary adenomas (8.4%). Several hypothalamic illness show a clinical picture including mental disorders and obesity. The Authors hypothesize that the ESS may be a "new" hypothalamic syndrome (compression/stretching on hypophysis and/or hypophyseal stalk by arachnoidocele; disorder of some hormones and neurotransmitters as leptin, neuropeptide Y, orexins, POMC-derived peptides, etc).
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PMID:[Primary empty sella syndrome. Observations on 71 cases]. 1020 96

The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and our understanding of energy homeostasis. It is now accepted that leptin is the afferent loop informing the hypothalamus about the state of fat stores, with hypothalamic efferents regulating appetite and energy expenditure. In addition, leptin has a role as a metabolic adaptator in overweight and fasting states. New and previously unsuspected neuroendocrine roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation, and it is a permissive factor for puberty. Relevant gender-based differences in leptin levels exist, with higher levels in women at birth, which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the ovarian cycle, with a regulatory role exerted at the hypothalamic, pituitary, and gonadal levels, and with unexplained changes in pregnancy and postpartum. Leptin is present in human milk and may play a role in the adaptive responses of the newborn. Leptin plays a role in the neuroendocrine control of GH secretion, through a complex interaction at hypothalamic levels with GHRH and somatostatin. Leptin participates in the expression of CRH in the hypothalamus, interacts at the adrenal level with ACTH, and is regulated by glucocorticoids. Since leptin and cortisol show an inverse circadian rhythm, it has been suggested that a regulatory feedback is present. Finally, regulatory actions on TRH-TSH and PRL secretion have been found. Thus leptin reports the state of fat stores to the hypothalamus and other neuroendocrine areas, and the neuroendocrine systems adapt their function to the current status of energy homeostasis and fat stores.
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PMID:Neuroendocrine regulation and actions of leptin. 1056 81

BACKGROUND: Published results of studies of thyroid function in obesity and after weight loss have differed. METHODS: The circulating concentrations of thyroid hormones and TSH were studied in 30 consecutive, euthyroid morbidly obese patients before and after weight loss from vertical gastroplasty, with the aim to determine the relation between body weight loss and pituitary-thyroid axis function. Serum TSH, free T3 (FT3) and free T4 (FT4) were measured before operation and repeated 6 and 18 months postoperatively. RESULTS: A significant increase, but within normal levels, in FT3 value at 6 and, mainly, at 18 months after gastroplasty was observed (p = 0.002). The FT4 value was slightly increased, at the same time and serum TSH was found to, be significantly decreased (p = 0.03 and p = 0.01 respectively). The relative increase in FT4 was negatively correlated with excess body weight and Body Mass Index reduction. This correlation was only moderate with values ranging from r = 0.34 to r = 0.47. CONCLUSIONS: Although there were statistically significant differences in thyroid function tests before and after loss of weight, these were not biologically significant. The hypophyseal/thyroid axis remains always active and contributes to body weight homeostasis and its regulation.
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PMID:Alterations in Thyroid Hormones and Thyrotropin (TSH) in Morbidly Obese Patients before and after Vertical Gastroplasty. 1073 15

Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TRalpha and TRbeta. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRbeta-selective compound GC-1 with T3 at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T3. T3, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the I(f) channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T3 had a larger positive inotropic effect than GC-1. T3, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain alpha and beta and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRbeta-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver vs. the heart probably also contributes to its marked lipid-lowering effect vs. the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.
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PMID:The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. 1096 73

The cornerstone of the evaluation of an obese patient is the medical examination in combination with a few selected obesity specific measurements. Key elements in the obesity specific history are the patient's weight history, the diet history, evaluation of the present and past physical activity pattern and the evaluation of the patient's target weight. Central elements in the examination are the computation of the body mass index (BMI) as well the measurement of the waist circumference. The waist circumference shows a higher degree of correlation with different morbidities than the BMI. A waist circumference of > 80 cm in women and > 94 cm in men is associated with an increased overall morbidity risk. In general a minimal biochemical work-up--including fasting glucose, total cholesterol, HDL and triacylglycerol, urate, electrolytes and TSH--is enough. Special tests (screening examination for e.g. M. Cushing) are only indicated in the case of clinical suspicion; the determination of leptin is presently of no diagnostic nor therapeutic relevance. The indication for weight reduction should be formulated individually. In the long term weight stability has to be regarded as a success for most patients. Presently the prevention of weight gain and obesity is still the safest and most efficient "therapeutic" approach.
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PMID:[Obesity clinic]. 1102 86

The aim of this retrospective study was to investigate the frequency of thyroid dysfunction as assessed by TSH, T3 and T4 in a large cohort of 290 obese and 280 healthy children. In addition, thyroid autoantibodies were measured in random subgroups of 123 obese and 80 control children, iodine excretion in 50 and thyroid volume in 23 of the obese children. Elevated TSH levels (>4 U/l) were found in 22 obese children (7.5%), but only in one control (0.3%). The medians of TSH and T3 concentrations were normal, but significantly higher in the obese group than in the controls, while T4 levels did not differ. The prevalence of positive thyroid autoantibodies was increased in the obese children, for the most part in those with elevated TSH. There was no evidence for iodine deficiency as a cause of the average increase of TSH. We conclude that in childhood obesity TSH and T3 levels are significantly increased; in most cases, however, these increases are not accounted for by thyroid autoimmunity or iodine deficiency. As a consequence, TSH elevations with normal thyroid hormone levels in obese children don't need any thyroxine treatment, if thyroid disorders were definitely excluded beforehand.
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PMID:Thyroid function and obesity in children and adolescents. 1118 30

Thyroid function tests might be affected by diabetes and obesity. To evaluate the influence of these parameters in routine conditions, 72 diabetic and 53 non-diabetic outpatients without known thyroid diseases or severe chronic illness were recruited over a 7-month period. For each patient, dosages of thyrotropin (TSH), total and free thyroxine (TT4 and FT4, respectively), total and free triiodothyronine (TT3 and FT3) and T3 resin uptake (T3RU) were performed by radioimmunoassays. The simultaneous influence of various parameters known to affect thyroid-function tests was evaluated by multivariate linear regression. The studied variables included gender, age, glucosteroids, estrogens, tobacco habits, iodine contacts, body mass index (BMI) and diabetes mellitus. Tobacco habits and iodine contacts did not influence any tests. As expected, estrogens induced an increase in TT4 and TT3 values (p < 0.001 and 0.020, respectively) associated with a decrease in T3RU (p < 0.001). Consequently, females had lower T3RU than males (p < 0.0001). Corticotherapy was associated with decreased TSH values (p = 0.022). TT3 and FT3 decreased with age (p < 0.001), whereas T3RU and FT4 increased (p = 0.020 and 0.004, respectively). In contrast to an increase in TSH (p = 0.006), TT4 and FT4 decreased at higher BMI levels (p = 0.018 and 0.004, respectively), which is consistent with subclinical hypothyroidism. In diabetic patients, TSH was lower than in nondiabetic subjects (p = 0.039). Thus, the present study indicates that besides known parameters such as age and drugs, thyroid-function tests can also be altered by diabetes mellitus and obesity.
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PMID:Minor alterations in thyroid-function tests associated with diabetes mellitus and obesity in outpatients without known thyroid illness. 1138 17

The heterotrimeric G protein G(s) couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G(s) by promoting exchange of GTP for GDP on the G(s) alpha-subunit (G(s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G(s)alpha residues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead to constitutive activation of G(s)-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alpha is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G(s)alpha expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G(s)alpha expression or PTH action. G(s)alpha has recently been shown to be also imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including G(s)alpha, XLalphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G(s)alpha promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease G(s)alpha expression in renal proximal tubules. Studies in G(s)alpha knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.
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PMID:Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. 1158 48

The biological effects of hormones are mediated by plasma membrane receptors which transmit extracellular signals to the cytoplasm and nucleus. Mutations in plasma membrane receptors can affect normal signal transduction with loss-of-function mutations leading to hormone resistance and gain-of-function mutations leading to constitutive activation of signaling pathways. The loss-of-function mutations leading to familial hormone resistance disorders are germline in origin whereas the gain-of-function mutations leading to constitutively active receptors are somatic. G-protein coupled receptors (GPCR) comprise a large superfamily of proteins characterized by seven transmembrane-spanning segments and interaction with GTP-binding(G) proteins. Mutations in GPCRs have been associated with dwarfism, congenital hyperthyroidism or hypothyroidism, nephrogenic diabetes insipidus, obesity, resistance to TSH, LH, FSH and ACTH, Jansen's metaphyseal and Blomstrand's chondrodysplasia, autosomal dominant hypoparathyroidism, and neonatal severe hyperparathyroidism. Mutations in other families of receptors which are characterized into one spanning-transmembrane receptor can result in resistance to insulin, GH, leptin and AMH. This review summarizes the molecular defects in plasma membrane hormone receptors in a large number of clinical disorders.
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PMID:[Molecular defects in plasma membrane hormone receptors]. 1185 9


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