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

Lipogenesis and insulin sensitivity are evaluated in adipose tissue, liver, and diaphragm of ob/ob and non-ob/ob mice. In ob/ob mice, hepatic fatty acid synthesis from [U-14C]glucose is elevated by 4 wk of age, and adipose tissue fatty acid synthesis increases at approximately 7 wk. Hepatic activities in ob/ob mice of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), malate dehydrogenase (EC 1.1.1.40), and alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) are dramatically increased by 7 wk of age. Diminished insulin-stimulated glycogen synthesis is first noted in the diaphragm of ob/ob mice at 7 wk of age. Insulin-stimulated glycogen synthesis in adipose tissue of ob/ob mice is impaired at 3 wk. At 7 wk, insulin-stimulated fatty acid synthesis in adipose tissue of ob/ob mice is markedly increased. Adipose tissue glyceride-glycerol synthesis continues to increase throughout development, whereas fatty acid synthesis decreases after 7 wk. The data suggest that alterations in lipid synthesis occur very early in the development of ob/ob mouse, prior to expression to overt obesity, at which time a major contribution to lipogenesis is made by the liver. The altered de novo lipogenesis does not precede the reported diminution in energy metabolism.
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PMID:Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouse. 678 59

A primary culture of undigested fat tissue fragments was used to obtain fat cells in vitro. On day 2 of culture, immature fat cells, which are fibroblast-like fat cells containing fine lipid droplets, appeared, surrounding the fat tissue fragments, and began to proliferate extensively. Afterwards, these fibroblast-like fat cells grew to become multilocular fat cells containing larger intracytoplasmic lipid droplets, and differentiated further into unilocular fat cells containing a single large intracytoplasmic lipid droplet. Treatment with dibutyryl-cAMP, which is a second messenger of the lipolytic factor, caused the cultured fat cells to retract, and the intracytoplasmic lipid droplets of those fat cells became finely granulated and decreased along with an increase of hormone-sensitive lipase activities. Conversely, administration of insulin caused the lipid droplets in the fat cells to increase and become larger along with an increase of alpha-glycerophosphate dehydrogenase activities. These findings indicate the occurrence of lipolysis and lipogenesis of fat cells in vitro. Immuno-cytochemistry revealed that vimentin surrounded intracytoplasmic lipid droplets, and became distinct with an increase of lipid droplets through lipogenesis in the fat cells. Vimentin seems to be correlated to the behavior of lipid droplets in the fat cells. Fat cells in this study showed the appropriate cellular structures and functions in response to stimulation of lipolysis and lipogenesis under culture conditions. It is expected that in vitro culture of fat cells will facilitate cell biological elucidation of obesity in the future.
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PMID:Cellular structure and function of rat fat cells in the primary culture. 779 65

The mitochondrial FAD-linked enzyme glycerophosphate dehydrogenase plays a key role in the pancreatic B-cell glucose sensing device. In the present study, the activity of this enzyme was examined in islets of fa/fa rats in which inherited diabetes mellitus is associated with obesity, hyperinsulinism and severe insulin resistance. The specific activity of both FAD-linked glycerophosphate dehydrogenase and glutamate dehydrogenase were decreased in islet and liver homogenates prepared from fa/fa, as compared to Fa/Fa, rats, this coinciding with a low ratio between glutamateoxalacetate and glutamate-pyruvate transaminase activity in both islet and liver extracts, islet hyperplasia, hyperinsulinemia and hepatic steatosis in the hyperglycemic fa/fa rats. It is speculated that a low activity of FAD-linked glycerophosphate dehydrogenase in the pancreatic B-cell may participate to the perturbation of glucose homeostasis in fa/fa rats, like in other animal models of non-insulin-dependent diabetes mellitus.
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PMID:Impaired FAD-glycerophosphate dehydrogenase activity in islet and liver homogenates of fa/fa rats. 783 41

Transgenic mice overexpressing transforming growth factor alpha (TGF-alpha) under control of the metallothionein promoter had, on average, 20% reductions in body and carcass weights compared to nontransgenic littermates. This loss resulted from significant decreases in the comparative weights of bone, muscle, and especially fat. Transgenic epididymal fat pads were reduced by 40-80%, and total body fat content by 50%, relative to control animals. Distal hindlimb muscle weights were 20% below normal, and other skeletal muscles were visibly smaller in size. Weight reductions were accompanied by decreases in the cellularity of transgenic fat pads and muscles and by decreases in the number and area of striated muscle fibers. These findings were not obviously attributable to differences in metabolic rates since transgenic and control mice displayed similar levels of energy expenditure per unit lean body mass. The effects of TGF-alpha on the development of these tissues could be mimicked in culture for fat but not muscle. Thus, TGF-alpha did not inhibit the differentiation of the mouse skeletal myoblast cell line C2C12 as evidenced by the expression of muscle-specific actin and fusion to form multinucleated myotubes. However, TGF-alpha repressed the differentiation of the preadipocyte cell line 3T3-F442A in a dose-dependent and reversible manner as judged by morphological conversion and diminished expression of mRNAs encoding the adipocyte-specific markers adipsin and glycerophosphate dehydrogenase. This repression, which occurred without marked stimulation of proliferation, was incomplete even in the presence of high concentrations of growth factor. Despite its effects on adipose development, introduction of the metallothionein-TGF-alpha transgene into the ob/ob genetic background did not suppress the marked obesity characteristic of this mutation. Finally, endogenous TGF-alpha epidermal growth factor receptor mRNAs were detected in normal adipose tissue, suggesting that regulation of adipogenesis by this growth factor may be physiological.
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PMID:Regulation of fat and muscle development by transforming growth factor alpha in transgenic mice and in cultured cells. 846 58

Studies with human adipose tissue have demonstrated the presence of key enzymes of fat synthesis. However, long-term regulation of these enzymes has not been reported. To address this issue, we used human adipocytes in primary culture. Human adipose tissue was obtained from abdominal fat of patients undergoing abdominal surgery. Adipocytes were isolated by collagenase digestion and cultured in media supplemented with 1% fetal bovine serum. To evaluate metabolic activity of cultured cells, we assessed the following during the culture: DNA pattern, cell size, glucose consumption and activities for two lipogenic enzymes, fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH). Analysis of DNA pattern showed that human adipocytes cultured under the above condition did not undergo cell apoptosis. In addition, no significant change in the cell size occurred during 22 d of culture. Glucose consumption by cultured cells was also constant during the culture and was 60% greater in the presence of 10 nmol/L of insulin. Treatment of cultured human adipocytes with insulin for 3-22 d increased GPDH and FAS activity by 60% and 2.8-fold, respectively, compared to cells cultured without insulin. Furthermore, the increase in FAS activity due to insulin treatment was dose dependent and maximal at 10 nmol/L. Our studies show for the first time that human adipocytes can be maintained viable and metabolically active for 2-3 wk in culture. Interestingly, cultured cells remain responsive to insulin. Therefore, this system will allow further characterization of long-term regulation of lipogenesis in human adipocytes and will be useful for developing pharmacological treatments of obesity.
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PMID:Insulin increases lipogenic enzyme activity in human adipocytes in primary culture. 861 89

Hyperinsulinemia accompanies obesity in human patients and experimental rodent models and exacerbates insulin resistance, but the causes of increased insulin secretion remain obscure. This review examines progress in defining biochemical and molecular beta-cell defects that have elucidated in the past 5 years. Some defects, such as decreased glucose transport, decreased mitochondrial FAD-linked glycerophosphate dehydrogenase activity, and altered anomeric specificity for glucose, become evident only after onset of non-insulin-dependent diabetes mellitus. Thus, these defects are unlikely to play a role in the pathogenesis of hyperinsulinemia in obesity. Other biochemical changes, including increased glucokinase and (or) hexokinase function, increased glucose cycling, and altered regulation of intracellular Ca2+ are present in obese nondiabetic animals and may therefore contribute to development of hyperinsulinemia. Few developmental studies have been performed to correlate onset of defects with environmentally and genetically mediated control mechanisms of beta-cell function. However, the availability of new molecular biology techniques should facilitate identification of factors causing hyperinsulinemia in obesity.
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PMID:beta-cell stimulus - secretion coupling defects in rodent models of obesity. 874 32

The enzyme activities of mitochondrial glycerol phosphate dehydrogenase (mGPD) (EC 1.1.99.5) and pyruvate carboxylase (PC) (EC 6.4.1.1) have been reported to be low in the pancreatic islet of several rodent models of NIDDM. The present study was undertaken to discern whether mGPD is abnormal in the Zucker diabetic fatty (ZDF) rat (ZDF/Gmi-fa/fa), an animal model of NIDDM in which insulin secretion is unable to counteract the insulin resistance associated with the obesity that characterizes this model. Experiments were performed in prediabetic 6-week-old ZDF rats in comparison with 12-week-old overtly hyperglycemic animals and, as controls, Zucker lean (ZL) rats (ZDF/Gmi-+/fa or -+/+) and Wistar rats (+/+) of the same ages. The enzyme activity of mGPD was 32 and 18% of normal in islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001 by analysis of variance). The activity of PC, which like mGPD is relatively abundant in the pancreatic islet, was 17 and 10% of normal in the islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001). The activity of mGPD was normal in islets from ZL rats. However, PC activity was slightly lower in islets of 6- (51% of normal, P = 0.007) and 12-week-old (67% of normal, P = 0.01) ZL rats. The amounts of mGPD protein, as judged from Western analysis, and of PC protein, as judged from probing transblots with streptavidin that binds to biotin-containing enzymes, roughly correlated with the enzyme activities. This indicates that the decreased enzyme activities are caused by the decreased net synthesis of these enzymes rather than by the decreased activity of a normal amount of enzyme. The enzyme activity of succinate dehydrogenase, a control for mGPD, was normal in the ZL and ZDF rats. An incidental finding of the current study was the discovery of beta-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in the islet. Levels of these enzymes were also normal. Although reductions in mGPD and PC may contribute to the abnormal insulin secretion present in overt diabetes, they are modest compared with the severe reductions seen in inherited inborn errors of metabolism. Because of this and because more than a single enzyme is affected and the enzymes in the islet are diminished in more than one rodent model of NIDDM, these reductions are unlikely to represent the primary genetic defect in the ZDF rat. Since ZDF rats are euglycemic at 6 weeks of age and ZL animals are euglycemic throughout life and since these animals demonstrate low enzyme activities, this evidence suggests that it is not hyperglycemia but rather some other component of the diabetic syndrome that is responsible for the reductions in these enzymes.
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PMID:Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats. 886 70

Obese subjects with excess intra-abdominal fat deposition suffer greater adverse metabolic consequences than do similarly overweight subjects with a predominantly subcutaneous distribution of adiposity. Little is known about the factors regulating the regional distribution of body fat. Leptin is a recently characterized protein secreted by adipocytes that appears to provide a long-term hormonal feedback signal regulating fat mass. No systematic evaluation of site-related differences in human adipocyte leptin expression has been reported to date. Levels of leptin mRNA were examined by quantitative reverse transcription-polymerase chain reaction in adipocytes isolated from omental and subcutaneous adipose depots of nonobese and mildly obese individuals undergoing elective surgery. In all individuals studied (n = 24), leptin mRNA levels were higher in subcutaneous than in omental adipocytes (P < 0.0001). In contrast, there were no consistent site-specific differences in the expression of glycerol-3-phosphate dehydrogenase mRNA. The subcutaneous-to-omental ratio of leptin mRNA expression was markedly higher in women (5.5 +/- 1.1-fold) than in men (1.9 +/- 0.2-fold) (P < 0.02). A significant relationship between BMI and leptin mRNA expression was demonstrable in the subcutaneous adipocytes of women (P < 0.006). Thus, leptin mRNA appears to be expressed predominantly by subcutaneous adipocytes, particularly in women. These findings suggest a possible role for leptin in the control of adipose tissue distribution and mass.
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PMID:Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. 903 87

Glucocorticoids play an important role in determining adipose tissue distribution and function, with glucocorticoid excess states such as Cushing's syndrome resulting in central obesity. We have investigated the functional significance of local generation of cortisol within adipose tissue from inactive cortisone through the activity of the NADP(H)-dependent enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). In primary cultures of paired omental (om) and sc human adipose stromal cells (ASC; n = 34), 11betaHSD1 oxo-reductase activity was significantly higher in om ASC (median, 40.2 pmol/mg protein x h; 95% confidence interval, 1.8-105) compared with sc ASC (median, 11.4; 95% confidence interval, 0-48.1; P<0.001) despite similar endogenous NADPH/NADP concentrations. Both cortisol and insulin increased the differentiation of ASC to adipocytes (as assessed by glycerol-3-phosphate dehydrogenase expression), but only cortisol increased 11betaHSD1 activity and messenger RNA levels in a dose-dependent fashion. Cortisone (500 nM) was as effective as 500 nM cortisol in inducing ASC differentiation, but this stimulatory effect was inhibited by coincubation with the 11betaHSD1 inhibitor, glycyrrhetinic acid. The higher local conversion of cortisone to active cortisol through expression of 11betaHSD1 in om compared with sc ASC may explain the specific action of glucocorticoids on different adipose tissue depots. 11betaHSD1 expression in om ASC is regulated at a transcriptional level and is increased by glucocorticoids, but is not entirely dependent upon ASC differentiation. Inhibition of 11betaHSD1 within om ASC inhibits cortisone-induced ASC differentiation. These findings indicate that local metabolism of glucocorticoid may control differentiation of adipose tissue in a site-specific fashion. Specific inhibitors of 11betaHSD1 may offer a novel approach for the treatment of patients with central obesity.
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PMID:Differentiation of adipose stromal cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase. 1038 14

Differentiation of precursor cells into mature fat cells is accompanied by enhanced expression of insulin-like growth factor (IGF)-I and is stimulated by multiple hormones including growth hormone, glucocorticoids, IGF-I and insulin. We used transgenic mice that overexpress insulin-like growth factor binding protein-1 to investigate the role of IGF-I in the accumulation of fat tissue. In response to a sucrose-enriched diet, transgenic mice gained significantly less body weight and the epididymal fat mass was significantly reduced compared with wild-type mice. The increase in adipocyte size was also significantly reduced in transgenic mice compared with wild-type mice. Fewer colonies were generated from adipose tissue from transgenic mice and the mitogenic response of these cells to IGF-I was significantly reduced compared with those from wild-type mice. Induction of glycerol-3-phosphate dehydrogenase, a measure of adipocyte differentiation, by IGF-I but not insulin, was reduced in preadipocytes from transgenic mice. These data indicate that IGF-I has a critical role in the proliferation of adipocyte precursors, the differentiation of preadipocytes and the development of obesity in response to calorie excess.
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PMID:Impaired adipogenesis in insulin-like growth factor binding protein-1 transgenic mice. 1046 38


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