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

The diagnosis of Cushing's syndrome rests on the demonstration of clinical features and biochemical abnormalities that reflect hypercortisolism. If a patient presents with typical clinical features such as weight gain with truncal obesity and supraclavicular fat deposition, wide purple striae, and proximal muscle weakness, the diagnosis is clear-cut and is nearly always substantiated by a 24-hour urine free cortisol excretion value more than four times the normal level. However, many patients present with signs and symptoms that are common in the general population, such as hypertension, generalized weight gain, reproductive abnormalities, and depression. Many of these patients have normal cortisol excretion and do not have Cushing's syndrome. Others have mild hypercortisolism caused by psychiatric disorders, obligate exercise, morbid obesity, sleep apnea, or uncontrolled diabetes mellitus. These patients may be confused with those with the true Cushing's syndrome, and thus are considered to have a "pseudo-Cushing" state. Additional observation over time, and testing with midnight cortisol measurements, the 2-day-2-mg dexamethasone suppression test, or the dexamethasone suppression-CRH stimulation test may be useful to identify true Cushing's syndrome in these patients.
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PMID:Diagnostic tests for Cushing's syndrome. 1238 46

Glucocorticoids are regulated at the prereceptor level by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11 beta-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11 beta-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11 beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11 beta-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9)M (65 +/- 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9) M (65 +/- 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11 beta-HSD-1 mRNA expression. TNF alpha up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (140 +/- 20%; P < 0.001); the same cytokine increased 11 beta-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 +/- 14% of control (P < 0.01). IL-1 beta also up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (160 +/- 33%; P < 0.001) and caused an increase in glycerol levels (159 +/- 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol up-regulated 11 beta-HSD-1 activity maximally at 10(-7) M (162 +/- 46%; P < 0.02), and clonidine down-regulated it at 10(-7) M (82 +/- 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11 beta-HSD-1 might include down-regulation of 11 beta-HSD-1 activity by CRH, ACTH, and alpha 2 sympathetic stimulation, and up-regulation of the enzyme by beta 2 sympathetic stimulation and by the cytokines TNFalpha and IL-1 beta.
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PMID:Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. 1251 81

Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.
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PMID:A review of neuropeptide and neuroendocrine dysregulation in anorexia and bulimia nervosa. 1276 12

Galanin, a 29-30 amino-acid neuropeptide is distributed in the central and peripheral nervous systems, the pituitary gland, the gastrointestinal tract and also in the pancreas. The endogenous and exogenous effects of galanin are mediated by three receptor subtypes, which are termed: GALR1, GALR2, and GALR3. Galanin has a significant role in physiological and pathological processes in adults as well as in children. It has an ability to contract smooth muscles in GI (facilitation and inhibition), stimulates reflexes in the CNS, decreases pancreatic amylase secretion, changes transport of electrolytes Na+ and CL-. It takes part in etiopathogenesis of depression, Alzheimer's disease and diarrhoea, exerts tonic inhibition of nociceptive input to the central nervous system and regulates a function of hypothalamic-pituitary system. Galanin decreases insulin and somatostatin secretion, increases glucagon secretion, takes part in prolactin release, stimulates growth hormone-releasing hormone, hypothalamic gonadotropin releasing hormone and corticotropin releasing hormone. It causes increase of somatotropin secretion, luteinizing hormone and foliculotropin release and adrenocorticotropin secretion. The hypothalamic galanin takes part in etiopathogenesis of obesity not only in human reproductive period, but also in adolescence, increasing the appetite and changing fat metabolism. This variety of actions emphasizes the potential importance of this peptide in the regulation of cells function and the need to understand the mechanism by which they act.
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PMID:[The role of galanin in the endocrine system]. 1281 74

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.
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PMID:Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain. 1461 Feb 51

The present study reports a rare case of full-blown Cushing's disease several years after an episode of pituitary apoplexy. A 60 year-old woman complained of muscular weakness and generalized malaise. Ten years ago she had an episode of pituitary apoplexy. Diabetes mellitus was diagnosed at age 56, and thereafter she had been controlled her plasma glucose with diet therapy and oral hypoglycemic agents. She exhibited cushingoid feature of moon face and central obesity. Both plasma ACTH and serum cortisol levels were elevated to 170 pg/ml and 19.6 microg/dl, respectively. Dexamethasone suppression test showed that a large dose of 8 mg dexamethasone, but not a small dose of 2 mg, suppressed the pituitary-adrenocortical axis. CRH and methyrapone caused increases in plasma ACTH and serum cortisol levels. Brain T(1)-weighted magnetic resonance imaging depicted a low signal of pituitary tumor, which was not enhanced by gadolinium. The pituitary tumor was removed by transsphenoidal adenomectomy, and immunohistochemistry revealed an ACTH-producing adenoma. The evidence suggested the possibility that the two pituitary tumors with dormant period of several years were a recurrence of ACTH-producing tumors in the present patient.
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PMID:Full-blown Cushing's disease after an episode of pituitary apoplexy. 1461 5

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.
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PMID:Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. 1472 56

We report a 45-year-old woman with Cushing's syndrome showing reversible pituitary dysfunction. Left adrenal tumor was incidentally discovered by a screening examination of abdominal computed tomography. Although this patient lacked typical Cushingoid features except hypertension and leg edema, endocrine examinations revealed moderate suppression of plasma ACTH (~6.3 pg/ml) with relatively high levels of serum cortisol (~22.9 microg/dl) without normal circadian rhythm. Plasma ACTH failed to respond to either CRH or metyrapone, and dexamethasone failed to suppress her daily steroid production. Surgical removal of left adrenocortical adenoma and 6-month replacement of hydrocortisone have ameliorated both ACTH and cortisol responses to CRH loading test. Postoperative responses of TSH and GH to TRH and GRH, respectively, were two fold higher than the preoperative levels. In contrast, basal and TRH-induced levels of serum PRL were decreased after surgery although both the basal and stimulated PRL levels were markedly high before surgery. In addition, gonadotropin response to GnRH examined in the same ovarian cycle was decreased in accordance with an increase in serum estradiol and progesterone levels after surgery. Improvement of hypercortisolemia even in a moderate case of Cushing's syndrome not only ameliorates hypertension, obesity and glucose intolerance, but also restores the accompanying dysfunctions of anterior pituitary, suggesting the clinical importance of early discovery and treatment of functioning adrenocortical incidentalomas.
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PMID:Reversible pituitary dysfunction in a patient with Cushing's syndrome discovered as adrenal incidentaloma. 1511 71

Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11beta-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11beta-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11beta-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11beta-HSD-1 activity and induce lipolysis. Tumor necrosis factor-alpha and interleukin-1beta upregulate 11beta-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through beta-adrenergic upregulation and alpha-adrenergic downregulation of 11beta-HSD-1 activity. Inhibition of 11beta-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.
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PMID:Hypothalamic regulation of adiposity: the role of 11beta-hydroxysteroid dehydrogenase type 1. 1524 25

The present case involves a 47-yr-old woman with Cushing's disease due to pituitary macroadenoma. The patient had suffered from hypertension and obesity for two yr. Her serum cortisol levels were moderately elevated throughout the observation period, and dexamethasone failed to suppress the cortisol secretion. Plasma ACTH levels were markedly high (>100 pg/ml) and did not respond to CRH provocation. Gel filtration analysis of the patient's plasma detected the existence of big ACTH molecules, which eluted with a peak of authentic 1-39 ACTH. Cranial magnetic resonance imaging (MRI) revealed a 3 cm pituitary tumor occupying the sellar region and right cavernous sinus with diffuse enhancement by gadolinium. The pituitary mass was removed by transsphenoidal surgery, and was pathologically identified as compatible to ACTH-producing pituitary adenoma by immunohistochemistry. RT-PCR analysis of total cellular RNA extracted from the resected adenoma revealed a relatively high expression level of dopamine D2 receptor (D2R) mRNA. Therefore, a long-acting D2R agonist, cabergoline (0.25 to 0.5 mg/week), was administered for the remnant adenoma, which gradually reduced ACTH levels in 90 days. In addition, cranial MRI exhibited shrinkage of the remnant pituitary mass after a 6-month treatment with cabergoline. This case demonstrates the efficacy of cabergoline to treat Cushing's disease caused by pituitary macroadenoma secreting aberrant ACTH molecules.
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PMID:Effect of cabergoline treatment on Cushing's disease caused by aberrant adrenocorticotropin-secreting macroadenoma. 1575 38


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