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

High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors Type 2 diabetes, and hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated by overexpressing the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in several tissues including muscle, liver, fat, and beta cells. With overexpression of GFA in transgenic animals, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the beta cell secretes excess insulin leading to hyperinsulinemia. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype." Chronically, however, these same adaptive changes result ultimately in obesity, hyperlipidemia, beta cell failure, and Type 2 diabetes. These results suggest a mechanism by which chronic overnutrition leads to the phenotype of Type 2 diabetes.
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PMID:Hexosamines as mediators of nutrient sensing and regulation in diabetes. 1187 72

Adipose tissue glyceroneogenesis generates glycerol 3-phosphate, which could be used for fatty acid esterification during starvation. To determine whether increased glyceroneogenesis leads to increased fat mass and to explore the role of obesity in the development of insulin resistance, we overexpressed PEPCK, a regulatory enzyme of glyceroneogenesis in adipose tissue. Transgenic mice showed a chronic increase in PEPCK activity, which led to increased glyceroneogenesis, re-esterification of free fatty acids (FFAs), increased adipocyte size and fat mass, and higher body weight. In spite of increased fat mass, transgenic mice showed decreased circulating FFAs and normal leptin levels. Moreover, glucose tolerance and whole-body insulin sensitivity were preserved. Skeletal muscle basal and insulin-stimulated glucose uptake and glycogen content were not affected, suggesting that skeletal muscle insulin sensitivity is normal in transgenic obese mice. Our results indicate the key role of PEPCK in the control of FFA re-esterification in adipose tissue and, thus, the contribution of glyceroneogenesis to fat accumulation. Moreover, they suggest that higher fat mass without increased circulating FFAs does not lead to insulin resistance or type 2 diabetes in these mice.
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PMID:Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance. 1187 59

As exemplified in patients with Cushing's syndrome, glucocorticoids play an important role in regulating adipose tissue distribution and function, but circulating cortisol concentrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1 (11 beta-HSD1), which, in intact cells, has been considered to be an oxoreductase, converting inactive cortisone (E) to cortisol (F). Locally produced F can induce ASC differentiation, but the relationship between 11 beta-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omental (om) and sc ASC and adipocytes were prepared from 17 patients undergoing elective abdominal surgery and cultured for up to 14 d. Expression and activity of 11 beta-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. On d 1 of culture, 11 beta-HSD1 activity in intact om ASCs exceeded oxoreductase activity in every patient (78.9 +/- 24.9 vs. 15.8 +/- 3.7 [mean +/- SE] pmol/mg per hour, P < 0.001), and in sc ASCs, relative activities were similar (40.6 +/- 12.2 vs. 36.9 +/- 8.8). Conversely, in freshly isolated om adipocytes, reductase activity exceeded dehydrogenase activity (23.6 +/- 1.5 vs. 6.2 +/- 0.8 pmol/mg per hour, P < 0.01). Following 14 d of culture in serum-free conditions with addition of 10 nM insulin (Ctr) or insulin with 100 nM F (+F), lipoprotein lipase/18S RNA levels increased in both the Ctr- and +F-treated ASCs, but glycerol 3 phosphate dehydrogenase increased only in the +F cultures. In both cases, however, 11 beta-HSD1 oxoreductase activity exceeded dehydrogenase activity (Ctr: 53.3 +/- 9.0 vs. 32.4 +/- 10.5, P < 0.05; +F: 65.6 +/- 15.6 vs. 37.1 +/- 11.5 pmol/mg per hour, P < 0.05), despite no significant changes in 11 beta-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and +F-treated cells. Type 2 11 beta-HSD expression was undetectable in each case. These data show that in intact, undifferentiated om ASCs, 11 beta-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates. Because glucocorticoids inhibit cell proliferation, we postulate that 11 beta-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a "switch" to 11 beta-HSD1 oxoreductase activity generates F, thus promoting adipogenesis. Site-specific regulation of the set-point of 11 beta-HSD1 activity may be an important mechanism underpinning visceral obesity.
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PMID:A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells. 1188 89

Leptin regulates food intake and body weight by acting primarily in the hypothalamus. In humans and rodents, obesity is associated with hyperleptinaemia, suggesting a possible state of leptin resistance. Thus, to begin to examine the mechanisms of leptin resistance, we developed a rat model in which chronic central leptin infusion results in the development of resistance to leptin's satiety action. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or phosphate-buffered saline via Alzet pumps for 28 days, followed by artificial cerebrospinal fluid infusion for 3 weeks. After the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. During leptin infusion, body weight was gradually decreased to reach a nadir on day 12, and thereafter, body weight was sustained at a reduced level throughout the entire 28-day infusion, despite normalization in food intake. Body weight was mostly normalized by day 22 postleptin. Since neuropeptide Y (NPY) neurones are one of the targets of leptin signalling in the hypothalamus, we next examined whether the development of resistance to the satiety action of leptin was due to altered NPY gene expression. On day 3-4 of infusion, hypothalamic NPY mRNA levels, as determined by RNAse protection assay (RPA), were significantly decreased in leptin treated rats compared to controls. By contrast, on day 16 of infusion, NPY mRNA levels in the leptin treated group had returned to control levels. In situ hybridization study confirmed the results obtained with RPA and showed further that the effect of chronic leptin infusion on NPY mRNA levels was restricted to the rostral and middle parts of the arcuate nucleus. Overall, the finding that the action of continuous leptin exposure on NPY neurones was not sustained suggests that NPY neurones may be involved in the development of leptin resistance to the satiety action of leptin in the hypothalamus.
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PMID:Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. 1237 4

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.
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PMID:Progression of chronic renal disease. 1261 42

Our purpose here is to test the hypothesis that Randall's plaques, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers and patients with stones due to obesity-related bypass procedures and obtained papillary specimens from non-stone formers after nephrectomy. Plaque originates in the basement membranes of the thin loops of Henle and spreads from there through the interstitium to beneath the urothelium. Patients who have undergone bypass surgery do not produce such plaque but instead form intratubular hydroxyapatite crystals in collecting ducts. Non-stone formers also do not form plaque. Plaque is specific to certain kinds of stone-forming patients and is initiated specifically in thin-limb basement membranes by mechanisms that remain to be elucidated.
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PMID:Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. 1261 14

Food availability for wild organisms typically varies both in time and space, requiring a mechanism that regulates the storage of excess energy and makes it possible to use stores during energy shortfall. Leptin, a protein hormone encoded by an obesity gene, has been suggested to be the signal mediator for this flux of energy. In a controlled laboratory experiment on caged great tits (Parus major) we evaluated the effect of leptin on food intake and behaviour. Experimental birds were given an intramuscular injection of 10 microg leptin dissolved in phosphate buffered saline (PBS), while the control birds were injected with PBS only at 09:00 h after a night's fasting. Within the first 20 min after injections we observed a significant difference in food intake between groups: control birds initially fed at higher rates compared to leptin treated birds. The cumulative food intake suggested that the effect of leptin disappeared after approximately 40-50 min post-injections. Similar results have previously been found in domesticated chickens. To our knowledge, this is the first study to show that leptin depresses food intake in wild birds.
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PMID:Leptin depresses food intake in great tits (Parus major). 1262 Feb 47

K cells are a subpopulation of enteroendocrine cells that secrete glucose-dependent insulinotropic polypeptide (GIP), a hormone that promotes glucose homeostasis and obesity. Therefore, it is important to understand how GIP secretion is regulated. GIP-producing (GIP/Ins) cell lines secreted hormones in response to many GIP secretagogues except glucose. In contrast, glyceraldehyde and methyl pyruvate stimulated hormone release. Measurements of intracellular glucose 6-phosphate, fructose 1,6-bisphosphate, and pyruvate levels, as well as glycolytic flux, in glucose-stimulated GIP/Ins cells indicated that glycolysis was not impaired. Analogous results were obtained using glucose-responsive MIN6 insulinoma cells. Citrate levels increased similarly in glucose-treated MIN6 and GIP/Ins cells. Thus pyruvate entered the tricarboxylic acid cycle. Glucose and methyl pyruvate stimulated 1.4- and 1.6-fold increases, respectively, in the ATP-to-ADP ratio in GIP/Ins cells. Glyceraldehyde profoundly reduced, rather than increased, ATP/ADP. Thus nutrient-regulated secretion is independent of the ATP-dependent potassium (K(ATP)) channel. Antibody staining of mouse intestine demonstrated that enteroendocrine cells producing GIP, glucagon-like peptide-1, CCK, or somatostatin do not express detectable levels of inwardly rectifying potassium (Kir) 6.1 or Kir 6.2, indicating that release of these hormones in vivo may also be K(ATP) channel independent. Conversely, nearly all cells expressing chromogranin A or substance P and approximately 50% of the cells expressing secretin or serotonin exhibited Kir 6.2 staining. Compounds that activate calcium mobilization were potent secretagogues for GIP/Ins cells. Secretion was only partially inhibited by verapamil, suggesting that calcium mobilization from intracellular and extracellular sources, independent from K(ATP) channels, regulates secretion from some, but not all, subpopulations of enteroendocrine cells.
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PMID:Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent. 1267 50

As the overall survival rate is high in patients with craniopharyngioma, the prognosis in survivors depends mainly on late effects. Late effects such as hypogonadism, growth hormone deficiency, glucocorticoid overreplacement and obesity have a strong impact on volumetric bone mineral density (vBMD). We analyzed vBMD and possible risk factors for reduced vBMD in 61 patients with childhood craniopharyngioma (29 f; 32 m) and in 14 weight, age, and sex-matched controls. VBMD was quantified by peripheral quantitative computed tomography (pQCT). Endocrine status, hormonal substitution therapy and calcium phosphate metabolism were evaluated. VBMD was in the lower normal range in 61 craniopharyngioma patients (total radial z-scores: median - 1.5; range - 3.1 to 1.4; trabecular z-scores: median - 0.4; - 2.4 to 2.3). 23 severely obese patients (body mass index [BMI] > 4 SD) had a higher total radial (p < 0.05) and trabecular (p < 0.05) vBMD when compared with 38 non-severely obese patients and 7 weight-matched controls. Although there was no gender difference in terms of obesity, endocrine substitution therapy or calcium phosphate metabolism, male patients had lower total radial (p < 0.01) and trabecular (p < 0.05) vBMD. Only in male patients' vBMD z-scores showed a positive correlation with BMI standard deviation score (SDS) (total radial z-score: Spearman r = 0.38, p = 0.03; trabecular z-score: Spearman r = 0.35, p = 0.04). We conclude that obesity has a major impact on vBMD in patients with craniopharyngioma. Lean male patients are at special risk for a lower vBMD, whereas female gender and severe obesity seem to have a protective effect regarding vBMD.
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PMID:Volumetric bone mineral density in patients with childhood craniopharyngioma. 1278 91

The authors describe the case of a 14-year old girl with pseudohypoparathyroidism, who showed characteristic phenotypic features of Albright's hereditary osteodystrophy (short stature, round face, mild obesity, abnormal position of teeth, lack of canines, limb valgity) and biochemical disturbances--hypocalcemia, hyperphosphatemia. The nature of pseudohypoparathyroidism consists in a lack of response to the parathormone of effector organs, such as kidneys, bones, alimentary tract. The treatment of choice includes active metabolites of vitamin D3, calcium salts, phosphate-binding components. Pseudohypoparathyroidism is a rare disease. Worth noting is the fact that it can occur in a child with height deficiency.
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PMID:[Pseudohypoparathyroidism in a 14-year old girl]. 1281 2


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