Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies on the etiology of obesity have revealed that human adipocytes have the ability to revert or dedifferentiate in culture to a morphology and replicative capacity similar to that of adipocyte precursors. To characterize some of the events of this process, we isolated adipocytes from the greater omentum of 61 morbidly obese and ten normal weight individuals with collagenase, and cultured them for 0, 4, and 7 days. In both lean and obese patients, sn-glycerol-3-phosphate dehydrogenase specific activity decreased significantly after days 4 and 7 compared to day 0. Dedifferentiation was also monitored by phase-contrast microscopy, which revealed that adipocytes from the lean had lost appreciable lipid and had assumed an elongated contour more rapidly than those from the obese. Reversion was also corroborated by reverse transcription-polymerase chain reaction, which indicated a decrease in the expression of sn-glycerol-3-phosphate dehydrogenase mRNA, and an increase in actin and glyceraidehyde-3-phosphate dehydrogenase mRNA over the 7 days. Thus, this work has described some biochemical and molecular genetic characteristics of dedifferentiation. The relative resistance of adipocytes from morbidly obese patients to revert in culture may reflect the inordinately high propensity of fat cells in massively obese persons to preserve the differentiated, triacylglycerol-overfilled state.
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PMID:Relative Resistance of Adipocytes from Massively Obese Persons to Dedifferentiation. 1075 44

We presented a case of a 22-year-old woman with pseudohypoparathyroidism type la. She was a typical congenital Albright syndrome patient with osteodystrophy including hands and feet, accompanied by obesity, strabismum, and retardation growth. Her calcium and phosphate levels were within the normal range which was stated during repeated hospitalisation due to infections. The diagnosis of PHPT was made at the age of 22 when the patient suffered twice from tetany seizure accompanied by numbness and tingling sensation in her hands and around the mouth as well as cramps in her legs. Typical phenotype were found: shortness in stature, obesity, rounded face, small hands and shortening of the third, the fourth and the fifth fingers in both hands and the third and the fourth toes in feet together with trophic disorders of nails and valgity of her knees. Somatic sings were accompanied by hypocalcaemia and hyperphosphatemia, hyperphosphatasia, lower calcium and phosphate urinary excretion and three-fold increased PTH serum level. Computerised tomography of the brain showed extensive evidence of cerebral calcification in basal ganglia as well as in dura mater and in skin covering the skull. X-ray and densitometry examinations revealed osteolytic foci in cranial, humeral and forearm bones as well as osteoporosis in palm and feet bones. The patient presented a typical case of PHPT with resistance of the kidney to PTH, what was confirmed by lower calcium and phosphate urinary excretion, with normal bone receptor sensibility to PTH. Elevated PTH levels resulted in osteoporosis and foci of osteolysis. Treatment with calcium and active form of vitamin D3 caused reversal of hypocalcemia symptoms and normalisation of biochemical features. We also found hormonal symptoms of latent hypothyreosis. No coexistence of PTH with thyroid receptor resistance was found. The case was described because it is rare disorder, difficult to diagnose. Early diagnosis and treatment is necessary to limit the irreversible changes as well as bone and central nervous system injury.
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PMID:[A case of pseudohypoparathyroidism]. 1080 May 89

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.
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PMID:Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. 1080 41

Calorie restriction (CR) has previously been shown to unexpectedly induce a reversal of in vivo insulin action (phosphorylation instead of dephosphorylation) on skeletal muscle glycogen synthase (GS) in four out of six long-term calorie-restricted (CR) monkeys. The purpose of the present study was to determine whether this increase in Ka (concentration of glucose 6-phosphate [G6P] at which GS activity is half-maximal) during insulin is also present in very lean (VL) young adult monkeys maintained on a controlled feeding regimen. Muscle samples from 10 VL monkeys (10 +/- 2% body fat; 7 years old) were obtained before and during a euglycemic hyperinsulinemic clamp and the Ka was determined and compared to the Ka of two other groups of monkeys, one matched in age but fully ad libitum (AL)-fed (n = 9.8 +/- 1 years old, 20 +/- 3% body fat, p = 0.01 vs. VL monkeys), and the other our previously described weight-clamped long-term CR monkeys (n = 6.20 +/- 1 years old, 21 +/- 2% body fat, p = 0.01 vs. VL monkeys). All of the AL monkeys had the expected decrease in Ka with insulin; however, similar to the 4 out of 6 CR monkeys, 7 out of 10 VL monkeys had an increase in Ka with insulin. The 11 monkeys with an increase in Ka (+Ka) (7 VL + 4 CR) were compared to the 14 monkeys with a decrease in Ka with insulin (-Ka) (3 VL + 2 CR + 9 AL). The +Ka monkeys had lower basal Ka (p = 0.0001), higher basal GS fractional activity (p = 0.0003), lower basal G6P content (p = 0.002), lower glycogen phosphorylase fractional activity (p = 0.01), and lower whole-body insulin-mediated glucose disposal rate (p < 0.05) than the -Ka monkeys. We conclude that the condition of steady-state restrained calorie intake (as in the CR monkeys and in the controlled feeding VL monkeys) produces the paradoxical action of in vivo insulin to phosphorylate muscle GS, and raises the possibility that the presence of the unusual response to insulin may serve as a marker in calorie-restrained individuals for the genotype of obesity, insulin resistance and/or Type 2 diabetes.
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PMID:Paradoxical phosphorylation of skeletal muscle glycogen synthase by in vivo insulin in very lean young adult rhesus monkeys. 1084 66

Low plasma leptin levels have been shown to be associated with the development of obesity in mice as well as in humans. The present study was undertaken to determine if raising plasma leptin levels of obesity-prone C57BL/6J (B6) mice to those seen in obesity-resistant A/J mice would prevent the development of diet-induced obesity. Four-week-old B6 (n = 40) and A/J (n = 10) male mice were weaned onto a low-fat (11% kcal) diet. When the animals weighed 20 g, their diets were changed to a high-fat (HF) diet (58% kcal), and a continuous infusion of leptin (0.4 mg x kg(-1) x day(-1)) or phosphate-buffered saline (control) was started using Alzet minipumps. The A/J mice were not treated but were included to monitor the efficacy of the minipumps in raising plasma leptin in B6 mice. The mice were followed for 12 weeks. Chronic treatment with leptin for 4 weeks raised plasma levels in B6 mice to that of A/J mice. Plasma leptin in B6 control mice remained significantly lower than A/J mice through week 4. By week 8, leptin levels in the B6 control group had risen and were similar to A/J mice. Although there were significant weight differences between B6 treated and B6 control groups for 2-3 weeks after pump implantation, these differences were transient. Ultimately, there were no weight differences between the B6 treated and B6 control groups. There were no differences in plasma glucose between B6 treated and control groups. Plasma insulin values were also not different between the 2 groups. There was no effect of leptin supplementation on locomotor activity or food intake in B6 mice. In summary, this study demonstrates that leptin supplementation in animals that show low plasma leptin levels in response to fat feeding may slow but does not prevent the subsequent development of diet-induced obesity.
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PMID:Transient effects of long-term leptin supplementation in the prevention of diet-induced obesity in mice. 1090 79

Several studies have suggested that the activity of nitric oxide synthase (NOS) may be involved in the regulation of food intake in the genetically obese Zucker rats. In the present study, we investigated the expression of NOS in various hypothalamic regions of obese and lean Zucker rats using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Obese Zucker rats showed significantly lower staining intensities of NADPH-diaphorase-positive neurons in the paraventricular nucleus (PVN), lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH) than lean Zucker rats did. The differences in staining intensities between obese and lean Zucker rats were large in both the PVN and LHA, but such differences were relatively small in the VMH.
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PMID:Differential expression of nicotinamide adenine dinucleotide phosphate-diaphorase in hypothalamic areas of obese Zucker rats. 1099 50

The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its d-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([(3)H]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [(3)H]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta-Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormones/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta-amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes.
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PMID:Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. 1111 77

Renal sodium retention, as a result of increased abundance of sodium transporters, may play a role in the development and/or maintenance of the increased blood pressure in obesity. To address this hypothesis, we evaluated the relative abundances of renal sodium transporters in lean and obese Zucker rats at 2 and 4 mo of age by semiquantitative immunoblotting. Mean systolic blood pressure was higher in obese rats relative to lean at 3 mo, P < 0.02. Furthermore, circulating insulin levels were 6- or 13-fold higher in obese rats compared with lean at 2 or 4 mo of age, respectively. The abundances of the alpha(1)-subunit of Na-K-ATPase, the thiazide-sensitive Na-Cl cotransporter (NCC or TSC), and the beta-subunit of the epithelial sodium channel (ENaC) were all significantly increased in the obese rats' kidneys. There were no differences for the sodium hydrogen exchanger (NHE3), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2 or BSC1), the type II sodium-phosphate cotransporter (NaPi-2), or the alpha-subunit of ENaC. These selective increases could possibly increase sodium retention by the kidney and therefore could play a role in obesity-related hypertension.
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PMID:Increased renal Na-K-ATPase, NCC, and beta-ENaC abundance in obese Zucker rats. 1155 10

A simple and convenient high performance liquid chromatographic method with UV detection is described for the determination of mazindol [5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol] and its major metabolite, 2-(2-aminoethyl)-3-(p-chlorophenyl)-3-hydroxyphthalimidine (Met), in human plasma. The analytes were extracted with ethyl acetate from plasma samples and separated on a C18 column using acetonitrile-0.067 mol dm(-3) phosphate buffer (pH 3.5) (24 + 76 v/v) as a mobile phase. The eluates were monitored at 220 nm. Following complete validation and stability studies, the proposed method proved to be sensitive and precise. The limits of detection were 0.07 and 0.08 ng ml(-1) of plasma for mazindol and Met, respectively. The accuracy and recovery were in the ranges 94-102% and 91-102%, respectively, for both compounds. The intra- and inter-assay precisions were less than 7.6 and 9.2%, respectively, for both compounds. The stability of mazindol under different storage conditions, i.e., at room temperature (rt) and 4 degrees C and with freeze-thaw cycles, was also examined. Mazindol was unstable in plasma samples left at rt and 4 degrees C. The method was applied to the determination of mazindol and Met in the plasma of a patient treated for obesity with mazindol.
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PMID:High performance liquid chromatographic determination of mazindol in human plasma. 1176 75

Cholecystokinin (CCK) and gastrin (G) and their receptors (CCK1 and CCK2) are involved in multiple physiological functions. Notably, CCK1R plays a role in the regulation of food intake whereas both CCK1R and CCK2R play a role in the regulation of pancreatic endocrine function. CCK1R and CCK2R may therefore serve as pharmacological targets in diabetes and obesity and genes encoding these receptors may be candidate genes in the pathogenesis of the diseases. In this study, we used single nucleotide polymorphism analysis and allele specific amplification for mutation screening of the CCK2 receptor gene and family linkage study. Mutated receptors were constructed, expressed in COS-7 cells for analysis of their binding and functional properties. V125I-CCK2 receptor variant was found in 2 out of 18 type 2 diabetes mellitus families tested. V125I mutation co-segregated in those 2 initial families, but further association studies showed that this mutation was not associated with diabetes or early age at diagnosis of the disease. V125I-CCK2 receptor high affinity sites exhibited a 2-fold enhanced binding affinity for CCK which was correlated to a slightly increased potency in coupling to inositol phosphate production. Since CCK2 receptor is expressed in pancreatic glucagon-producing cells in humans and is involved in secretion of glucagon, an increase of binding affinity of the mutated CCK2 receptor could enhance glucagon secretion in patients bearing V125I mutation. We also characterized a mutant of the CCK1 receptor which was previously identified in an obese patient. This mutant, V365I-CCK1, demonstrated a decreased level of expression (26%) and efficacy (25%) to stimulate inositol phosphates. It can therefore be expected that in humans bearing V365I mutation, decreases in CCK1 receptor expression and coupling efficiency may affect CCK-induced regulation of satiety. Polymorphism or mutations in the CCK receptors may be involved in type 2 diabetes mellitus and obesity. However, further studies are necessary to precisely evaluate this role in humans.
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PMID:Genetic, pharmacological and functional analysis of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in type 2 diabetes and obese patients. 1177 61


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