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)

Resistin, a small cysteine rich protein secreted by adipocytes, has been proposed to be a link between obesity and type II diabetes by modulating the insulin signaling pathway and thus inducing insulin resistance. Resistin protein, with 11 cysteine residues, was not significantly homologous at the amino acid level to any other known cysteine rich proteins. Resistin cDNA derived from human subcutaneous adipose tissue was expressed in Escherichia coli as an N-terminal six-His-tag fusion protein. The overexpressed recombinant resistin was purified to homogeneity from inclusion bodies, after solubilization in 8 M urea, using a metal affinity column. While MALDI-TOF mass spectrometric analysis of the purified protein generated a single peak corresponding to the estimated size of 11.3 kDa, the protein exhibited a concentration-dependent oligomerization which is evident from size exclusion chromatography. The oligomeric structure was SDS-insensitive but beta-mercaptoethanol-sensitive, pointing to the importance of disulfide linkages in resistin oligomerization. Estimation of free cysteine residues using the NBD-Cl assay revealed a concentration- and time-dependent increase in the extent of formation of disulfide linkages. The presence of intermolecular disulfide bond(s), crucial in maintaining the global conformation of resistin, was further evident from fluorescence emission spectra. Circular dichroism spectra revealed that recombinant resistin has a tendency to reversibly convert from alpha-helical to beta-sheet structure as a direct function of protein concentration. Our novel observations on the biophysical and biochemical features of human resistin, particularly those shared with prion proteins, may have a bearing on its likely physiological function.
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PMID:Human recombinant resistin protein displays a tendency to aggregate by forming intermolecular disulfide linkages. 1296 78

Adipose tissues play a crucial endocrine role in the control of whole body glucose homeostasis and insulin sensitivity. Considering the current substantial rise in obesity and obesity-related diseases, including diabetes, it is important to understand the molecular basis of adipocyte differentiation and its control. In this study, we have analyzed the protein expression inherent to adipogenic differentiation, by 2-DE, MALDI-TOF, and RT-PCR. This study focused on proteins that were differentially expressed by the differentiation of human mesenchymal stem cells (hMSCs) to adipocytes. We conducted 2-DE for each set of proteins in the cytosol of adipocytes that had differentiated from hMSC, in a pH range from 3-10. Thirty-two protein spots were shown to have different expression levels. Among these, eight up-regulated proteins were identified by MALDI-TOF/MS, as the following: syntaxin binding protein 3, OSBP-related protein 3, phosphodiesterase, glycophorin, immunoglobulin kappa chain variable region, peroxisome proliferative activated receptor gamma (PPAR-gamma), bA528A10.3.1 (novel protein similar to KIAA01616, isoform 1), and T cell receptor V-beta 4. Four proteins: syntaxin-3, OSBP-related protein 3, PPAR-gamma and glycophorin were associated with adipogenesis.
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PMID:The proteomic analysis of an adipocyte differentiated from human mesenchymal stem cells using two-dimensional gel electrophoresis. 1642 33

C75 is a potential drug for the treatment of obesity. It was first identified as a competitive, irreversible inhibitor of fatty acid synthase (FAS). It has also been described as a malonyl-CoA analogue that antagonizes the allosteric inhibitory effect of malonyl-CoA on carnitine palmitoyltransferase I (CPT I), the main regulatory enzyme involved in fatty acid oxidation. On the basis of MALDI-TOF analysis, we now provide evidence that C75 can be transformed to its C75-CoA derivative. Unlike the activation produced by C75, the CoA derivative is a potent competitive inhibitor that binds tightly but reversibly to CPT I. IC50 values for yeast-overexpressed L- or M-CPT I isoforms, as well as for purified mitochondria from rat liver and muscle, were within the same range as those observed for etomoxiryl-CoA, a potent inhibitor of CPT I. When a pancreatic INS(823/13), muscle L6E9, or kidney HEK293 cell line was incubated directly with C75, fatty acid oxidation was inhibited. This suggests that C75 could be transformed in the cell to its C75-CoA derivative, inhibiting CPT I activity and consequently fatty acid oxidation. In vivo, a single intraperitoneal injection of C75 in mice produced short-term inhibition of CPT I activity in mitochondria from the liver, soleus, and pancreas, indicating that C75 could be transformed to its C75-CoA derivative in these tissues. Finally, in silico molecular docking studies showed that C75-CoA occupies the same pocket in CPT I as palmitoyl-CoA, suggesting an inhibiting mechanism based on mutual exclusion. Overall, our results describe a novel role for C75 in CPT I activity, highlighting the inhibitory effect of its C75-CoA derivative.
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PMID:Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation. 1658 69

In the present work, we induced obesity in rats with high-energy-starch diet and studied exocrine pancreas response. The zymogen granule (ZG) or purified plasma membrane (PM) from the exocrine pancreas was used for the isolation of the detergent-resistant membranes (DRMs). Based on high content of cholesterol, GM1, the bile salt dependent lipase (BSDL), and GP2 enrichment, the low-density fractions were defined as lipid rafts. Additionally, the rafts vesicles were determined by immunogold labeling with anti BSDL. By combining MALDI-TOF/MS and nano-LC ESI Q-TOF MS/MS proteomic identification we have selected 33 proteins from the lipid rafts which were classified into at least four functional families. Our data suggest that the acinar PM from the diet-induced obesity rats may be organized into lipid rafts, and characterization of rafts proteome can contribute to improve our understanding of food digestion under obesity.
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PMID:Proteomic of lipid rafts in the exocrine pancreas from diet-induced obese rats. 1732 Aug 17

In this study, proteomic analysis was performed on the skin of C57BL/6J mice with type 2 diabetes and compared to nondiabetic controls. To induce obesity and subsequent diabetes, mice were placed on a high-fat diet for 16 wk. After 16 wk, both diabetic and nondiabetic control mice were sacrificed and their skin removed for analysis. Following 2-DE, proteomic profiles from the skin samples were quantified using PDQuest software. Out of more than 1000 distinct protein spots, 28 were shown to be significantly altered with 6 being decreased and 22 increased in the diabetic state compared to controls. The 28 protein spots were removed from the gels and analyzed by MALDI-TOF and MS/MS analyses. Protein identifications revealed that 17 of the 28 proteins were involved in energy metabolism (60.7% of changes observed). Collectively, none of the significantly altered proteins had been shown previously to be altered in diabetic skin. This study not only helps to identify proteins found in skin samples of obese mice with type 2 diabetes, but also shows that skin biopsies coupled with proteomic analysis may be useful as a noninvasive method for the diagnosis of hyperinsulinemia and diabetes.
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PMID:Analysis of mouse skin reveals proteins that are altered in a diet-induced diabetic state: a new method for detection of type 2 diabetes. 1739 Feb 96

A histidine-tagged recombinant N-terminal fragment of type-1 mouse liver diacylglycerol acyltransferase (DGAT; EC 2.3.1.20), MmDGAT1(1-95)His6, was expressed in Escherichia coli, and used to investigate possible acyl-CoA-binding properties. Analysis of the purified fragment by MALDI-TOF mass spectrometry revealed a polypeptide with molecular mass of about 11 kDa which was consistent with the calculated molecular mass based on the deduced amino acid sequence. Lipidex-1000 binding assays indicated that MmDGAT1(1-95)His(6) interacted with long chain fatty acyl-CoAs similar to observations on DGAT1 from oilseed rape (Brassica napus). Binding, as a function of acyl-CoA concentration, differed for palmitoyl (16:0), stearoyl (18:0), and erucoyl (cisDelta(13)22:1)-CoA. Binding of stearoyl- or erucoyl-CoA to MmDGAT1(1-95)His(6) as a function of acyl-CoA concentration, however, was sigmoid and displayed positive cooperativity suggesting that MmDGAT1 may be subject to allosteric modulation by acyl-CoAs. An intra-polypeptide segment within the N-terminal region of MmDGAT1 contained remnants of an acyl-CoA-binding signature initially identified in plant DGAT1. The acyl-CoA-binding site in mammalian DGAT1 could represent a potential target for therapeutic interventions for disorders such as type-2 diabetes and obesity.
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PMID:An N-terminal fragment of mouse DGAT1 binds different acyl-CoAs with varying affinity. 1857

Obesity is associated with significant changes in body composition and function that may alter the pharmacodynamics and pharmacokinetics of various drugs. In this study, we investigated the neuromuscular effects of cisatracurium in morbidly obese as compared to control group of normal body weight patients. In the morbidly obese group (n = 20), corrected weight was used to calculate the drug doses. In the control group (n = 20), the dose was calculated on ideal body weight (IBW). 0.15 mg/kg(-1) cisatracurium was administered as the neuromuscular blocker. Neuromuscular effects were recorded at T0 (onset time), T1 (appearance of first stimulus of TOF), T25 (25% recovery of T1) and T25-75 (time of T25 to T75, recovery time). T0 was determined as 177 +/- 23 s and 168 +/- 19 s in the morbidly obese, and control group, respectively. T25 was determined as 46 +/- 7 min and 56 +/- 8 min, in the morbidly obese and control group, respectively (p < 0.05). T25-75 was determined as 11 +/- 5 min and 14 +/- 6 min in the morbidly obese and control group, respectively (p < 0.05). Intubation conditions were determined as good in 13, excellent in 7 patients in the morbidly obese group, and as good in 4 and excellent in 16 patients in the control group (p < 0.05). As different neuromuscular effects of cisatracurium were detected, we conclude that ne uromuscular agents must be monitored in the morbidly obese patients.
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PMID:Neuromuscular effects of cisatracurium in morbidly obese patients. 1863 Jul 69

Skeletal muscle lipid accumulation is associated with several chronic metabolic disorders, including obesity, insulin resistance (IR) and type 2 diabetes. The aim of this study is to evaluate whether static imaging time-of-flight-secondary-ion mass spectrometry (TOF-SIMS) equipped with a Bismuth-cluster ion source can be used for studying skeletal muscle lipid accumulation associated with obesity. Mouse gastrocnemius muscle tissues in 10-week-old obese ob/ob (n = 8) and lean wild-type C57/BL6 (n = 6) mice were analyzed by TOF-SIMS. Our results showed that signal intensities of fatty acids (FAs) and diacylglycerols (DAGs) were significantly increased in skeletal muscle of the obese ob/ob mice as compared to the lean wild-type mice. These differences were revealed through a global analytical approach, principal component analysis (PCA) of TOF-SIMS spectra, and ion-specific TOF-SIMS images. Region-of-interest (ROI) analysis showed that FA signal intensities within the muscle cell were significantly increased in ob/ob mice. Moreover, analysis of the ratio between different FA peaks revealed changes in monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs), which is in agreement with previous reports on obesity. These changes in FA composition were also reflected in the ratio of different DAGs or phosphatidylcholines (PCs) that contain different FA residues. Imaging TOF-SIMS together with PCA of TOF-SIMS spectra is a promising tool for studying skeletal muscle lipid accumulation associated with obesity.
Obesity (Silver Spring) 2008 Dec
PMID:TOF-SIMS analysis of lipid accumulation in the skeletal muscle of ob/ob mice. 1883 14

It is well recognized that capsaicin increases thermogenesis through enhancement of catecholamine secretion from the adrenal medulla. In the present study of the antiobesity effect of capsaicin, rats (5-week old) received capsaicin (10 mg/kg) along with a high-fat diet (HFD). In comparison with saline-treated rats, body weight of those in the capsaicin-treated group decreased by 8%. We performed differential proteomic analysis using two-dimensional electrophoresis (2-DE) combined with MALDI-TOF mass spectrometry to elucidate the molecular action of capsaicin on the antiobesity effect in epididymal white adipose tissue (WAT). Protein mapping of WAT homogenates using 2-DE revealed significant alterations to a number of proteins: 10 spots were significantly up-regulated and 10 spots were remarkably down-regulated in HFD fed rats treated with capsaicin. Among them, significant down-regulation of heat shock protein 27 (Hsp27) and Steap3 protein, as well as up-regulation of olfactory receptor (Olr1434) in obese WAT was reported for the first time in association with obesity. Most of the identified proteins are associated with lipid metabolism and redox regulation, in which levels of vimentin, peroxiredoxin, and NAD(P)H:quinone oxidoreductase 1 (NQO1) were significantly reduced (>2-fold), whereas aldo-keto reductase, flavoprotein increased with capsaicin treatment. These data demonstrate that thermogenesis and lipid metabolism related proteins were markedly altered upon capsaicin treatment in WAT, suggesting that capsaicin may be a useful phytochemical for attenuation of obesity.
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PMID:Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. 2035 64

Obesity is currently epidemic in many countries worldwide and is strongly related to diabetes and cardiovascular disease. This study investigated the differences in metabolomic profiling between overweight/obese and normal-weight men. Overweight/obese (n=30) and age-matched, normal-weight men (n=30) were included. Anthropometric parameters, conventional metabolites, and biomarkers were measured. Metabolomic profiling was analyzed with UPLC-Q-TOF MS. Overweight/obese men showed higher levels of HOMA-IR, triglycerides, total cholesterol, and LDL-cholesterol, and lower levels of HDL-cholesterol and adiponectin than lean men. Overweight/obese men showed higher proportion of stearic acid and lower proportion of oleic acid in serum phospholipids. Additionally, overweight/obese individuals showed higher fat intake and lower ratio of polyunsaturated fatty acids to saturated fatty acids. We identified three lyso-phosphatidylcholine (lysoPC) as potential plasma markers and confirmed eight known metabolites for overweight/obesity men. Especially, overweight/obese subjects showed higher levels of lysoPC C14:0 and lysoPC C18:0 and lower levels of lysoPC C18:1 than lean subjects. Results confirmed abnormal metabolism of two branched-chain amino acids, two aromatic amino acids, and fatty acid synthesis and oxidation in overweight/obese men. Additionally, the amount of dietary saturated fat may influence the proportion of saturated fatty acids in serum phospholipids and the degree of saturation of the constituent acyl group of plasma lysoPC.
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PMID:Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). 2056 May 78


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