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

In 1994, Zhang et al. of Rockefeller University in New York reported the first successful complementary DNA (cDNA) cloning of leptin by the positional cloning method. Leptin was identified as the gene of ob/ob mouse in genetic obesity syndromes. It has very strong food intake control, and body weight and energy expenditure. The name "leptin" derived from the Greek word leptos, meaning "thin." We hereby review major advances leading to our current finding of leptin, leptin receptor and its structure, the outline of homozygote, and also influence of leptin in the pituitary. (The structure of leptin) The mouse obese gene has been localized to chromosome 6. With human leptin gene on chromosome 7q31.3, its DNA has more than 15000 base pairs and consists of three exons and two introns. For bioactivation of leptin the importance of disulfide-binding site is suggested. Human leptin which replaced the 128-th arginine with glutamine has the function of an aldosteron antagonist, which is reported to have the function of athrocytosis inhibition. The resemblance of leptin precursor of human, mouse and rat is very high, i.e., mouse and rat homology is 96% and mouse and human homology is 83%. (The structure of leptin receptor) The mutant gene, which is the cause of obesity, was shown on map on diabetic mouse (db/db) chromosome 4, and it was proven to be the same as the leptin receptor gene cloned by Tartaglia et all. Further studies have found the Zucker fatty rat (fa/fa) to be incorporated into a linkage map of rat chromosome 5, whose region of rat is the equivalent to the region of conserved synteny of the db/db mouse gene. The leptin receptor is glycoprotein consisting of a single transmembrane-spanning component. The primary structure of leptin receptor belongs to the cytokine-class1 family, the single membrane-spanning receptor, and is highly related to the gp130 signal-transducing component of the interleukin-6 (IL-6) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the leukemia inhibitory factor (LIF) receptor. The leptin receptor is known to have at least six existing isoforms (Ob-Ra, b, c, d, e, f) from the difference in splicing. (Homozygote Mutation of Leptin and Leptin Receptor :Hormone Secretion Disorders) The point mutation of ob/ob mouse and the splicing mutation of db/db mouse show remarkable obesity and hyperphagia. These obesity models show a reproduction disorder with both the male and the female, and they develop with homozygote. The cause is thought to be the gonadotropin secretory abnormality in pituitary. Three family lines report the cases of this deficiency, and it is considered that the secretory abnormality in pituitary develops into hypogonadotropic. These patients show low value in plasma FSHbeta (follicle stimulating hormone-beta and LHbeta (luteinizing hormone-beta which are produced from pituitary, and the plasma GnRH (gonadotropin releasing hormone) level is also low. Furthermore, the leptin receptor deficient family line was reported in 1998, in which case only the homozygote developed. The plasma leptin concentration of normal human is about 8.0 ng/ml, and this case with leptin receptor deficiency has high value of 500-700 ng/ml, which is the equivalent to the db/db mouse. (Role of Leptin in Hypothalamus-Pituitary-Periphery Function) The role of leptin which regulates pituitary hormones suggests the promotion the GHRH (growth hormone releasing hormone) secretion in hypothalamus-pituitary axis, with the possibility of the rise in secretion of GH (growth hormone) in pituitary, i.e. effects of icv (intracerebroventricular) infusion of leptin has spontaneously stimulated GHRH, which promotes GH secretion in the normal rats. On the other hand, topical treatment of GH3 (derived from a rat pituitary GH-secreting cell line) with leptin directly inhibits cell proliferation. The obesity model animals (ob/ob, db/db, fa/fa) have equally plump body compared to the normal models, which shows signs of sufficient growth. (Localization and Functional Relevance of Leptin and Leptin Receptor in Rodents Pituitary) Aside from being the food intake inhibitor and the energy control factor, leptin takes part in controlling the pituitary hormones. Promoting the secretion of GH, PRL (prolactin), TSHbeta (thyroid stimulating hormone-beta, FSHbeta/LHbeta, and inhibiting the secretion of ACTH (adrenocorticotropic hormone) are the major changes of pituitary hormones which are brought on by leptin. The expressive localization is specific, and immunohistochemistry (IHC) method recognized leptin in granular state in FSHbeta, LHbeta and TSHbeta positive cells. In our biochemical examination, the bulk of the expression of leptin is recognized in fraction of the secretory granule. In particular, FSHbeta cells had the highest percentage rate of colocalized leptin in rat pituitary. On the other hand, leptin receptor has been reported to be found only in normal rat pituitary, human pituitary adenoma, and respective cell lines in pituitaries by the RT-PCR method until now, but we disclosed for the first time the localization of leptin receptor on the plasma membrane of GH-secreting cells with the IHC method that has not been cleared so far. These findings show that leptin and leptin receptor have been expressed in different cells, and that the rat pituitary glands entertain paracrine mechanism between leptin (FSHbeta/LHbeta cells) and leptin receptor (GH cells). The function of paracrine in this pituitary suggests a new point of view in hypothalamus-pituitary axis, and it shall be concerned with many aspects such as hormone secretions and proliferation/inhibition. (Human Pituitary Adenoma) Preliminary report of leptin and leptin-receptor relationship with pituitary adenoma that has secretion abnormality has been filed, and its manifestation is being observed by the RT-PCR. Leptin and leptin receptor are expressed in most adenoma, and it is thought to function by autocrine and paracrine pathway in the adenomas. Leptin has been located in ACTH-secreting adenoma most frequently, especially in ACTH carcinoma. The leptin receptor is detected in all adenomas with high percentage rate, with both long and short forms, and then many cases of nonfunctioning pituitary adenomas, compared with other adenomas, have been reported to be positive with both long and short forms of leptin receptor as detected by RT-PCR. The HP75 cell line is derived from the nonfunctioning pituitary adenoma, which produces FSHbeta and LHbeta. The expression of leptin receptor in nonfunctioning pituitary adenoma, and the suppression of HP75 multiplication may lead to the possible hypothesis of leptin becoming one factor for the treatment of pituitary adenoma, especially in gonadotropin adenomas.
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PMID:Leptin and the pituitary. 1182 4

The fatty liver Shionogi (FLS) mouse is an inbred strain that develops spontaneous fatty liver (hepatic steatosis) chronically without obesity. Here, we reported that the mice develop spontaneous hepatocellular tumors with high incidences. The mice with age of over 1 year frequently developed whitish protuberant nodules in the livers, which were histologically diagnosed as hepatocellular adenoma and/or carcinoma (HCC). An incidence of HCC was 12/30 (40%) in males at 15-16 months of age, while in females that was 0/36 at 13-16 months and 4/42 (9.5%) at 20-24 months. Furthermore, histological examinations showed that after 2-4 months of age mononuclear cell infiltration and clusters of foamy cells appear in the fatty liver with elevated serum alanine aminotransferase, suggesting presence of inflammatory responses and liver injury. These observations show that the FLS mice develop hepatocellular tumors following steatohepatitis. The mouse might be a good animal model for investigating liver tumor and non-alcoholic steatohepatitis.
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PMID:Spontaneous development of hepatocellular carcinomas in the FLS mice with hereditary fatty liver. 1286 Feb 88

Cushing's disease is uncommon in childhood. It is usually caused by the oversecretion of adrenocorticotrophic hormone (ACTH) by a pituitary corticotroph adenoma. Clinical abnormality is often undetected for long periods of time. The principal clinical features are growth retardation and obesity. We present four patients who were diagnosed with Cushing's disease in a tertiary hospital from January 1995 to December 2002. There were two boys and two girls, aged 10-15 years. The main clinical features at presentation were growth failure and excessive weight gain. The interval between onset of symptoms and diagnosis ranged from 2.5 to 5 years. All patients presented moon face and increased fat around the neck. In all patients, 24-hour urinary free cortisol was high and loss of normal serum cortisol circadian rhythm (3/3) and suppression of cortisol to less than 50 % of the basal level with high-dose but not with low-dose dexamethasone (2/2) were observed. Pituitary microadenoma was detected by magnetic resonance imaging in three patients; no tumor was detected in the fourth patient and inferior petrosal sinus sampling was performed, showing left lateralization of ACTH central secretion. Therapy consisted of transsphenoidal surgery in all patients. Two patients are in remission, one patient presented disease recurrence requiring total hypophysectomy because the tumor could not be completely removed and one patient had persistent disease after a second intervention and required pituitary radiotherapy. Two patients showed pituitary hormone deficiency after therapy.
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PMID:[Diagnosis, treatment and long-term outcome in Cushing's disease]. 1288 47

The levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) peak in human in their twenties, then decrease gradually with age. The physiological importance of DHEA was not clear until recent research reports showing that DHEA has beneficial effects on preventing diabetes, malignancy, inflammation, osteoporosis, and collagen disease. We summarize our results concerning diabetes, hepatitis, and colon cancer. In 1982, Coleman et al. [Diabetes 31 (1982) 830] reported that DHEA decreased hyperglycemia in diabetic db/db mice, which become insulin resistant. We measured hepatic gluconeogenic enzymes in an attempt to elucidate the mechanical mechanism of DHEA action. The activity and gene expression of hepatic gluconeogenic enzyme such as glucose-6-phosphatase (G6Pase) was increased in db/db mice despite hyperinsulinemia compared to control db/+m mice. DHEA, like troglitazone, decreased these levels in db/db mice. We also showed that DHEA improved the insulin resistance caused by aging or obesity using the glucose clamp technique in another animal model. In humans, the serum DHEA concentration was shown to be associated with hyperinsulinemia in diabetes. It also became clear that DHEA increased insulin secretion in old-aged db/db mice. DHEA increases not only insulin sensitivity due to the effects in the liver and muscle, but also insulin secretion. As an effect of DHEA on T-cell mediated hepatitis induced by concanavalin A (ConA), DHEA reduced hepatic injury by inhibiting several inflammatory mediators and apoptosis. As an effect of DHEA on carcinogenesis, DHEA would be a potential chemopreventative agent against colon cancer because it decreases the number of azoxymethane (AOM) induced aberrant crypt foci, which is a possible precursor to adenoma and cancer in a murine model.Thus, since DHEA has many beneficial effects experimentally, we should consider administration of DHEA in the future, and common mechanisms among these actions of DHEA should be elucidated in further studies.
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PMID:Prevention of diabetes, hepatic injury, and colon cancer with dehydroepiandrosterone. 1294 37

The genetic and histopathological backgrounds of adrenocortical tumorigenesis remain poorly characterized. In other tissues, there is conclusive evidence that hyperplasia and adenomas precede cancer. In the adrenal, there are few clinical cases of either hyperplasia or adenoma associated with later development of cancer, and there are few biological studies that attempt to characterize this process molecularly. Current research focuses on the early lesions of the adrenal cortex because of their possible molecular link with carcinogenesis, and evidence of their frequent association with atypical forms of Cushing's and Conn's syndromes, obesity, hypertension and/or diabetes. These studies indicate a model for oncogenesis that is the same as that in other tissues. The rarity of adrenal cancer compared to benign lesions could be a clue to unique features of adrenocortical cells. It might also highlight the function of genes that are associated with endocrine tumors in the context of which the concept of gene 'conductors' is introduced here.
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PMID:Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony. 1458 Jul 59

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

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

We present a unique case of a prolactin (PRL)-producing pituitary adenoma showing incomplete neuronal differentiation without ganglion cells. A 27-year-old man presented with nausea, headaches, and instability over the last 2 months. Clinical examination revealed obesity with no other endocrinological signs. His serum PRL levels were slightly elevated (38 ng/ml), whereas concentrations of the other adenohypophysial hormones were within normal range. Histology revealed an unusual pituitary adenoma containing many hypocellular areas with fibrillar appearance. The sizable tumor cells were polyhedral or elongated harboring an ovoid, vesicular nucleus with prominent nucleolus, lacking, however, the typical features of ganglion cells. By immunohistochemistry, many adenoma cells were positive for PRL. Immunostain for neurofilament protein revealed variable amounts of fibrils dispersed throughout the stroma, mostly in the hypocellular areas. In addition, neurofilament protein and chromogranin were strongly reactive in approximately 15% of the tumor cell population, whereas reactivity for synaptophysin was uniform throughout the tumor. These findings led to the conclusion that part of the tumor-cell population expressed a hybrid immunoprofile of adenoma-neuronal cell. Our case is the first PRL-producing pituitary adenoma showing incomplete neuronal differentiation lacking mature ganglion cells.
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PMID:Prolactin-producing pituitary adenoma with incomplete neuronal transformation: an intermediate adenoma-neuronal tumor. 1517 51

ACTH-independent Cushing's syndrome (CS) usually results from a solitary adrenocortical adenoma. We recently encountered a patient with ACTH-independent CS associated with bilateral adrenal enlargement. The evaluation led us to consider some rare but interesting entities. The patient was a 69 year-old woman who had a 10-15 year history of controlled hypertension, back pain associated with osteoporosis, easy bruising, and truncal obesity. Her medications included conjugated estrogens. Physical examination revealed classical features of CS. She had a raised blue lesion on her buccal mucosa. Plasma cortisol concentrations were elevated at 36 (a.m.) and 38 (p.m.) microg/dL. Urinary free cortisol was normal at baseline (65 microg/24 hours) but failed to suppress adequately in response to the low-dose dexamethasone suppression test (75 microg/24 hours). The plasma ACTH concentration was undetectable. Plasma cortisol concentrations failed to suppress (37 microg/dL) with an 8 mg overnight dexamethasone test. A CT scan of the abdomen revealed bilateral adrenal masses. The possibilities of food-induced CS and primary pigmented nodular adrenal disease were excluded by a lack of marked stimulation in cortisol secretion to a mixed-meal and dermatologic confirmation of the buccal mucosa lesion as an angioma and not a blue nevus. Adrenal venous sampling showed cortisol secretion from both adrenals. The patient underwent bilateral adrenalectomy with pathology confirming bilateral adenomas. This case illustrates an unusual application of selective venous sampling in the CS evaluation and raises questions about the pathogenesis of cortisol-secreting adrenocortical adenomas.
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PMID:Acth-independent Cushing's syndrome: bilateral cortisol-producing adrenal adenomas. 1525 98

Diet has been associated with sporadic colorectal cancer (CRC) risk. The relationship to the growth rate of adenomas is largely unknown. Previous analyses of our cohort of polyp cases have shown 1) indicators of a healthy diet were inversely associated with adenoma occurrence, 2) diet was related to the fecal profile, 3) obesity was positively associated with adenoma growth, 4) familial predisposition of CRC was positively associated with adenoma growth, and 5) intervention with calcium and antioxidants was not associated with adenoma growth. The present aim was to study the effects of diet on growth and recurrence of adenomas. Data were collected from a 3-yr polyp growth and intervention study. Polyps larger than 9 mm were removed, whereas the remainder and newly discovered polyps smaller than 10 mm were left in situ for 3 yr. Diet was assessed by a 5-day dietary record by weighing (DR) and food-frequency questionnaire (FFQ). Weak inverse associations were found only between adenoma growth and fruits and berries (adjusted odds ratio, aOR = 0.3; 95% CI = 0.1-0.9) and carbohydrates (aOR = 0.1; 95% CI = 0.1-0.6; both only DR data) and between adenoma recurrence and vegetables (crude odds ratio, cOR = 0.4; 95% CI = 0.1-0.9; only FFQ data). Taken together, the present and previous findings from this cohort may indicate an early role for dietary factors in CRC development.
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PMID:Dietary habits and growth and recurrence of colorectal adenomas: results from a three-year endoscopic follow-up study. 1548 5


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