UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
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Excessive secretion of adrenal hormones, such as glucocorticoid and mineralocorticoid, leads to metabolic syndrome, including insulin resistance, obesity, and hypertension. These metabolic abnormalities are ameliorated by adrenalectomy (ADX). To identify pituitary mediators for ADX-induced physiological alterations, such as weight loss and hypotension, we investigated the effect of ADX on the pituitary transcriptome using serial analysis of gene expression (SAGE). SAGE method is based on isolation of short sequence tags, which usually correspond to unique mRNA species. The SAGE libraries were constructed from pituitary gland of intact (n = 51) and ADX (n = 12) mice. Thirty-one transcripts were differentially expressed between intact and ADX. Three transcripts encoding for proopiomelanocortin and three other transcripts involved in regulation of hormone secretion (neuromedin B, proprotein convertase subtilisin/kexin type 2, and IA-2) were induced by ADX. In addition, ADX increased the expression levels of genes encoding for cation extracellular matrix (matrix gamma-carboxyglutamate protein) and transport (solute carrier family 22 member 17). Conversely, ADX downregulated two transcripts involved in mitochondrial oxidative phosphorylation (nicotinamide adenine dinucleotide (NADH) dehydrogenase 3 and cytochrome c oxidase 3). Moreover, ADX significantly modulated the expression levels of one gene with uncharacterized function and 20 novel transcripts. This study reveals alterations of pituitary gene expressions that may be associated with ADX-induced physiological changes including weight loss.
Obesity (Silver Spring) 2009 Jan
PMID:Regulation of pituitary gene expression by adrenalectomy. 1910 26

The metabolic syndrome is often described as a group of risk factors associated with diabetes. These risk factors include, but are not limited to, such conditions as insulin resistance, obesity, high blood pressure, and oxidant stress. Here, we report on a tool that may provide some clarity on the relationship between some of these associated risk factors, especially oxidant stress and hypertension. Specifically, we describe the ability to simultaneously monitor nicotinamide dinucleotide phosphate (NADPH), reduced glutathione (GSH), and shear-induced adenosine triphosphate (ATP) release from erythrocytes using luminescence detection on a microfabricated device. The measurements are performed by delivering erythrocyte lysate (for the NADPH and GSH measurements, two analytes indicative of oxidative stress) or whole red blood cells (RBCs) (for the determination of ATP release from the cells) to an array of wells that contain the necessary reagents to generate a luminescence emission that is proportional to analyte concentration. A fluorescence macrostereomicroscope enables whole-chip imaging of the resultant emission. The concentrations of each NADPH and GSH contained within a 0.7% erythrocyte solution were determined to be 31.06 +/- 4.12 and 22.55 +/- 2.47 microM, respectively, and the average ATP released from a nonlysed 7% erythrocyte solution was determined to be 0.54 +/- 0.04 microM. Collectively, the device represents a precursor to subsequent merging of microfluidics and microtiter-plate technology for high-throughput assessment of metabolite profiles in the diabetic erythrocyte.
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PMID:Personalized metabolic assessment of erythrocytes using microfluidic delivery to an array of luminescent wells. 1930 7

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.
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PMID:5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity. 1945 97

Visfatin is highly expressed in adipose tissue (mainly by the stromal cells), but it is also ubiquitously present in most tissues. Visfatin, which plays a role in nicotinamide adenine dinucleotide (NAD) biosynthesis, has been implicated in inflammatory states. Controversial results exist about the expression, circulating levels and the role of visfatin in atherosclerosis-related diseases. Most studies showed increased levels of visfatin in diabetes mellitus, obesity, hypertension, renal and cardiovascular disease. However, other studies reported lower levels of visfatin in these diseases. The discrepancies in clinical studies may be attributed to the multifactorial regulation of visfatin. There is evidence that visfatin expression and circulating levels are influenced by fat area and distribution, inflammatory state, renal function, iron metabolism, hormones as well as several other factors. Furthermore, discrepancies and lack of correlation between commercially available visfatin assays have been reported. More research is needed to better understand the factors that control its synthesis/release and to evaluate the role of visfatin in atherosclerosis-related disease. Large studies with homogeneous populations will probably be needed to answer these questions. Whether visfatin will eventually become a therapeutic target remains to be established.
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PMID:Visfatin/PBEF and atherosclerosis-related diseases. 1948 30

The aim of the work described here was to improve our understanding of beta-cell function (BCF) and beta-cell mass (BCM) and their relationship in vivo using the minipig as a model for some of the aspects of human type 2 diabetes (T2DM). More specifically, the aim was to evaluate the following questions: How is BCF, especially high frequency pulsatile insulin secretion, affected by a primary reduction in BCM or by primary obesity or a combination of the two in the minipig? Can evaluation of BCF in vivo be used as a surrogate measure to predict BCM in minipigs over a range of BCM and body weight? We first developed a minipig model of reduced BCM and mild diabetes using administration of a combination of streptozotocin (STZ) and nicotinamide (NIA) as a tool to study effects of a primary reduction of BCM on BCF. The model was characterized using a mixed-meal oral glucose tolerance test and intravenous stimulation with glucose and arginine as well as by histology of the pancreas after euthanasia. It was shown that stable, moderate diabetes can be induced and that the model is characterized by fasting and postprandial hyperglycemia, reduced insulin secretion and reduced BCM. Several defects in insulin secretion are well documented in human T2DM; however, the role in the pathogenesis and the possible clinical relevance of high frequency (rapid) pulsatile insulin secretion is still debated. We therefore investigated this phenomenon in normal minipigs and found easily detectable pulses in peripheral vein plasma samples that were shown to be correlated with pulses found in portal vein plasma. Furthermore, the rapid kinetics of insulin in the minipig strongly facilitates pulse detection. These characteristics make the minipig particularly suitable for studying the occurrence of disturbed pulsatility in relation to T2DM. Disturbances of rapid pulsatile insulin secretion have been reported to be a very early event in the development of T2DM and include disorderliness of pulses and reduced ability to entrain pulses with glucose. However, the role of reduced BCM and/or obesity in the development of these defects in humans is unknown. Therefore, the investigations were extended to include lean NIA/STZ minipigs where it was shown that a primary reduction of BCM leads to reduced insulin pulse mass but does not change periodicity of the pulses or the ability of glucose to entrain pulses. In contrast, obesity was found to be associated with reduced pulsatile insulin secretion and improved orderliness of glucose entrained pulses in the minipig. Furthermore obesity was associated with pancreatic lipid accumulation and increased beta-cell volume, although BCM relative to body weight was not changed. Finally, a combination of obesity and reduced BCM resulted in severely disturbed insulin secretion and severe morphological changes. Thus, results from NIA/STZ minipigs suggest that not all of the defects of rapid pulsatile insulin secretion seen in human T2DM can be explained by a primary reduction of BCM mass or up to 2 weeks of mild hyperglycemia. Furthermore, based on the results from obese minipigs, obesity in itself induces small defects in rapid pulsatile insulin secretion and the combination of obesity and reduced BCM leads to further deterioration of BCF. Another major characteristic of human diabetes is thought to be reduction of BCM and the ability to follow this parameter over time would greatly improve our understanding of disease progression and allow evaluation of pharmacological methods to increase BCM. BCM cannot, at present, be measured in vivo in humans. We therefore set out to further validate data from smaller studies in lean non-human primates and minipigs showing a correlation between measures of BCF in vivo and BCM. In a large study in lean minipigs with a range of BCM, we found that a strong stimulation of insulin secretion with a combination of glucose and arginine resulted in the best correlation to BCM, as determined using stereology. A similar relationship was also shown in a group of both lean and obese animals, thereby supporting the application of similar methods to estimate BCM in humans over a range of body weights. Since changes in rapid pulsatile insulin secretion are detectable early in the development of diabetes and in obesity, we hypothesized that this parameter could also be highly correlated to BCM as it has been shown in smaller studies in lean minipigs. However, rapid pulsatile insulin secretion did not show a better correlation to BCM than combined stimulation with glucose and arginine, and thus analysis of pulses does not provide a better surrogate marker for BCM in the minipig. To evaluate the weaker correlation of glucose stimulation compared to combined glucose and arginine stimulation in vivo with BCM, we further investigated BCF in lean, beta-cell reduced minipigs by studying BCF in vitro after isolation and perfusion of their pancreases to investigate the ability of the remaining beta-cells to compensate for the loss of BCM by increasing insulin secretion per BCM. The perfused pancreas was chosen in order to allow direct measurement of the insulin secretion without the effects of peripheral tissues. During the perfusion, it was shown that the remaining beta-cells were indeed able to compensate for the loss of BCM to a large extent in response to stimulation with glucose and glucagon-like peptide-1 but not in response to arginine. This shows that the type of stimulus applied is important for the ability to compensate for reduced BCM from the remaining population of beta-cells, and further supports the use of combined stimulation with glucose and arginine for estimation of BCM in vivo. In conclusion, an animal model of reduced BCM and mild diabetes has been developed and characterized. The model has been used to evaluate effects of a primary reduction of BCM, showing a reduced rapid insulin pulse mass but normal periodicity and entrainability of the pulses, whereas obesity was associated with reduced rapid pulsatile insulin secretion. Thus, based on these data, the disturbed rapid pulsatile insulin secretion seen in T2DM humans may not directly be explained by the reduced BCM in diabetes, whereas obesity may be related to the reduced pulsatility. Furthermore, the model has been used to establish a correlation between extensive stimulation of insulin secretion in vivo and BCM obtained by stereology in both lean and obese animals. The ability to estimate BCM based on in vivo experiments in the minipig would allow longitudinal studies on changes in this parameter over time in the intact animal and support application of similar methods in humans. Such methods could be useful for the diagnosis and the measurement of the effectiveness of treatment of diabetes in humans in the future.
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PMID:Beta-cell function and mass in type 2 diabetes. 1972 71

SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1alpha and NFkappaB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD(+) metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and "nutraceutical" formulations containing resveratrol are already widely available.
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PMID:Biochemical effects of SIRT1 activators. 1989 59

Green tea catechins, especially (-)-epigallocatechin-3-gallate (EGCG), are known to regulate obesity and fat accumulation. We performed a kinetic analysis in a cell-free system to determine the mode of inhibition of glycerol-3-phosphate dehydrogenase (GPDH; EC 1.1.1.8) by EGCG. GPDH catalyzes the beta-nicotinamide adenine dinucleotide (NADH)-dependent reduction of dihydroxyacetone phosphate (DHAP) to yield glycerol-3-phosphate, which serves as one of the major precursors of triacylglycerols. We found that EGCG dose-dependently inhibited GPDH activity at a concentration of approximately 20 muM for 50 % inhibition. The IC (50) values of other green tea catechins, such as (-)-epicatechin, (-)-epicatechin-3-gallate, and (-)-epigallocatechin, were all above 100 microM. This suggests a catechin type-dependent effect. Based on double-reciprocal plots of the kinetic data, EGCG was a noncompetitive inhibitor of the GPDH substrates, NADH and DHAP, with respective inhibition constants (Ki) of 18 and 31 microM. Results of this study possibly support previous studies that EGCG mediates fat content.
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PMID:Green tea catechins: inhibitors of glycerol-3-phosphate dehydrogenase. 1993 54

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.
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PMID:Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives. 2020 51

Fat tissue produces a variety of secreted proteins with important roles in metabolism. Isolated and newly identified adipocytokine - visfatin is highly enriched in the visceral fat and it's expression level in plasma increases during the development of obesity. Visfatin exerts insulin - mimetic effects and lowers plasma glucose level throughout binding and activating the insulin receptor in animal model. However studies in humans' subjects reported conflicting results in regard to its relation with adiposity, insulin resistance, dyslipidemia, suggesting that the role of this protein in the development of obesity and insulin resistance is unclear. Visfatin - the cytokine-like protein pre-B cell colony - enhancing factor 1 was also identified as cytosolic nicotinamide phosphoribosyltransferase. This enzyme is involved in nicotinamide adenine dinucleotide (NAD) biosynthesis, related to the glucose and lipid metabolism in humans. Further study of visfatin's physiological may lead to new insights into glucose homeostasis an and or new therapies not only for metabolic disorders but also for disturbance of the immune system.
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PMID:[The role of visfatin in the pathophysiology of human]. 2022 17

Obesity is frequently associated with endothelial dysfunction. We hypothesized that high-fat feeding dysregulates the balance between endothelial derived nitric oxide and superoxide formation. Furthermore, we examined whether caloric restriction could reverse the detrimental vascular effects related to obesity. Male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Caloric restriction reversed high-fat diet-induced endothelial dysfunction. At day 150, impaired vasodilatory responses to ACh in obese mice without caloric restriction were markedly improved by preincubation with the tetrahydrobiopterin (BH(4)) precursor sepiapterin and L-arginine, a substrate for endothelial nitric oxide synthase (eNOS). Additionally, inhibition of vascular arginase by L-norvaline partially, and superoxide scavenging by Tiron completely, restored endothelial cell function. Obese mice showed increased vascular superoxide production, which was diminished by endothelial denudation, pretreated of the vascular rings with apocynin (an inhibitor of reduced nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), oxypurinol (an inhibitor of xanthine oxidase), N(G)-nitro-L-arginine methyl ester (LNAME; an inhibitor of eNOS), or by adding the BH(4) precursor sepiapterin. Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis.
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PMID:Caloric restriction reverses high-fat diet-induced endothelial dysfunction and vascular superoxide production in C57Bl/6 mice. 2051 54

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