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

Morphological changes of pancreatic B cells were investigated in ventromedial hypothalamic (VMH)-lesioned obese rats. An increase in body weight, a decrease in body length, and a marked increase in fat-pad were observed in VMH-lesioned obese rats. The volume density of pancreatic islets and that of B cells in VMH-lesioned obese rats were more increased than those in sham-operated control rats. The B cells of VMH-lesioned obese rats often showed a slight reaction for aldehyde fuchsin or anti-pig insulin serum. By the electron microscopy, the degranulated B cells were found to contain well developed Golgi apparatus and rough endoplasmic reticulum. These observations indicate increased activities of synthesis and release of insulin. We concluded that VMH-lesioned obesity was caused by accelerated lipogenesis with hypersecretion of insulin.
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PMID:[Morphological changes of pancreatic B cells in ventromedial hypothalamic (VMH)-lesioned obese rats]. 268 May 30

Pathomorphological and biochemical investigations on liver and blood serum laying hens affected by the liver obesity syndrome were carried out. It was established that the mortality due to the liver obesity syndrome varies within the range of 3.1 and 3.7% for the entire period of exploitation. A rise in mortality is observed in case fodder mixtures with higher peroxide and aldehyde number are prepared. Besides the typical changes in the liver, the pathologo-anatomical investigation established varying in its expression duodenitis of rupture of the liver and hemorrhage. In hens suffering from advanced liver obesity an increased content of total protein in the blood serum was observed. The relative and absolute content of prealbumens and albumens was also higher, while the content of globulins was relatively lower. The content of beta-lipoproteins was raised and total lipids in the blood serum were considerably increased. The investigation on total lipids and lipid fractions in the liver established a correlation between the extent of obesity and the content of total lipids. A trend toward increasing the total and particularly the esterificated holesterin was evident in affected birds. The chemical investigation of various lots of fodder mixtures established often cases of rancid fats, which was manifested by high values of the peroxide and aldehyde number. The aminoacid composition of fodder also varied too much. It is assumed that besides the genetic control of liver obesity rancid fats and insufficient content of essential amino acids in the fodder mixtures also lead to an increased mortality percentage in the affected birds.
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PMID:[Fatty liver syndrome in laying hens]. 741 36

Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the hydrolytic removal of the phosphoryl group from phosphotyrosyl (pY) proteins. PTP inhibitors provide potential treatment of human diseases/conditions such as diabetes and obesity as well as useful tools for studying the function of PTPs in signaling pathways. In this work, we have shown that certain aryl-substituted aldehydes act as reversible, slow-binding inhibitors of modest potency against PTP1B, SHP-1, and a dual-specificity phosphatase, VHR. Attachment of the tripeptide Gly-Glu-Glu to the para position of cinnamaldehyde resulted in an inhibitor (Cinn-GEE) of substantially increased potency against all three enzymes (e.g., K(I) = 5.4 microM against PTP1B). The mechanism of inhibition was investigated using Cinn-GEE specifically labeled with (13)C at the aldehyde carbon and (1)H-(13)C heteronuclear single-quantum coherence spectroscopy. While Cinn-GEE alone showed a single cross-peak at delta 9.64 ((1)H) and delta 201 ((13)C), the PTP1B/Cinn-GEE complex showed three distinct cross-peaks at delta 7.6-7.8 ((1)H) and 130-137 ((13)C). Mutation of the catalytic cysteine (Cys-215 in PTP1B) into alanine had no effect on the cross-peaks, whereas mutation of a conserved active-site arginine (Arg-221 in PTP1B) to alanine abolished all three cross-peaks. Similar experiments with Cinn-GEE that had been labeled with (13)C at the benzylic position revealed a change in the hybridization state (from sp(2) to sp(3)) for the benzylic carbon as a result of binding to PTP1B. These results rule out the possibility of a free aldehyde, aldehyde hydrate, or hemithioacetal as the enzyme-bound inhibitor form. Instead, the data are consistent with the formation of an enamine between the aldehyde group of the inhibitor and the guanidine group of Arg-221 in the PTP1B active site. These aldehydes may provide a general core structure that can be further developed into highly potent and specific PTP inhibitors.
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PMID:Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases. 1218 56

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
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PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.
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PMID:Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. 1567 Jun 60

Hepatocellular cancer accounts for almost half a million cancer deaths a year, with an escalating incidence in the Western world. Alcohol has long been recognized as a major risk factor for cancer of the liver and of other organs including oropharynx, larynx, esophagus, and possibly the breast and colon. There is compelling epidemiologic data confirming the increased risk of cancer associated with alcohol consumption, which is supported by animal experiments. Cancer of the liver associated with alcohol usually occurs in the setting of cirrhosis. Alcohol may act as a cocarcinogen, and has strong synergistic effects with other carcinogens including hepatitis B and C, aflatoxin, vinyl chloride, obesity, and diabetes mellitus. Acetaldehyde, the main metabolite of alcohol, causes hepatocellular injury, and is an important factor in causing increased oxidant stress, which damages DNA. Alcohol affects nutrition and vitamin metabolism, causing abnormalities of DNA methylation. Abnormalities of DNA methylation, a key pathway of epigenetic gene control, lead to cancer. Other nutritional and metabolic effects, for example on vitamin A metabolism, also play a key role in hepatocarcinogenesis. Alcohol enhances the effects of environmental carcinogens directly and by contributing to nutritional deficiency and impairing immunological tumor surveillance. This review summarizes the epidemiologic evidence for the role of alcohol in hepatocellular cancer, and discusses the mechanisms involved in the promotion of cancer.
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PMID:Alcohol in hepatocellular cancer. 1576 34

Mammalian isoforms of acetyl-CoA carboxylase (ACC-1 and ACC-2) play important roles in synthesis, elongation, and oxidation of long-chain fatty acids, and the possible significance of ACC in the development of obesity has led to interest in the development of inhibitors. Here, we demonstrate that pyridoxal phosphate (PLP) is a linear and reversible inhibitor of ACC-1 and ACC-2. ACC from rat liver and white adipose tissue (largely ACC-1) exhibited an IC50 of approximately 200 microm, whereas ACC-2 from heart or skeletal muscle exhibited an IC50 exceeding 500 microm. ACC from rat liver was equally sensitive to PLP following extensive purification by avidin affinity chromatography. When added before citrate, PLP inhibited ACC with a Ki of approximately 100 microm, reducing maximal activity >90% and increasing the Ka for citrate approximately 5-fold but having little effect on substrate Km values. Pre-treatment with citrate increased the apparent Ki for ACC inhibition by PLP by approximately 4-fold. Inhibition of ACC was reversed by removal of PLP, either by washing or by reaction with hydroxylamine or amino-oxyacetate. ACC was irreversibly inhibited and radiolabeled, to a stoichiometry of approximately 0.4 mol[H]/mol subunit, in the presence of PLP plus [3H]borohydride. Studies with structurally related compounds demonstrated that the reactive aldehyde and negatively charged substituents of PLP contribute importantly to ACC inhibition. The studies reported here suggest a rationale to develop ACC inhibitors that are not structurally related to the substrates or products of the reaction and an approach to probe the citrate-binding site of the enzyme.
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PMID:Inhibition of acetyl-CoA carboxylase isoforms by pyridoxal phosphate. 1624 79

alpha2-HS glycoprotein (AHSG), also known as fetuin-A, inhibits insulin receptor autophosphorylation and tyrosine kinase activity in vitro and in vivo. Earlier we have shown that fetuin-null (KO) mice demonstrate improved insulin sensitivity and resistance to diet-induced obesity. Since aging is associated with insulin resistance and impaired glucose handling, we tested the hypothesis that fetuin-null (KO) mice are resilient to changes in insulin sensitivity associated with aging. Aged (80-week-old) fetuin-null mice were leaner and demonstrated significantly lower body weights compared to age- and sex-matched wild-type (WT) littermates. Leanness in aged fetuin KO mice was accompanied by a significant increase in dark-onset energy expenditure, without marked alteration of respiratory quotient. In comparison to WT mice, fetuin KO mice demonstrated a lower fasting insulin resistance index, and significantly lower blood glucose and insulin levels, following a 4h fast. Interestingly, despite significantly decreased insulin levels during a glucose tolerance test, aged fetuin-null mice demonstrated a similar glucose excursion as WT mice, indicative of improved insulin sensitivity. Analysis of aldehyde-fuchsin stained pancreas from aged fetuin KO mice indicated no difference in islet beta-cell size or number. An insulin tolerance test confirmed the increased insulin sensitivity of aged fetuin KO mice. Further, compared to WT mice, aged fetuin-null mice demonstrated increased skeletal muscle and liver IR autophosphorylation and TK activity. Taken together, this study suggests that the absence of fetuin may contribute to the improvement of insulin sensitivity associated with aging.
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PMID:Fetuin-null mice are protected against obesity and insulin resistance associated with aging. 1701 19

Obesity is a state of mild inflammation correlated with increased oxidative stress. In general, pro-oxidative conditions lead to production of reactive aldehydes such as trans-4-hydroxy-2-nonenal (4-HNE) and trans-4-oxo-2-nonenal implicated in the development of a variety of metabolic diseases. To investigate protein modification by 4-HNE as a consequence of obesity and its potential relationship to the development of insulin resistance, proteomics technologies were utilized to identify aldehyde-modified proteins in adipose tissue. Adipose proteins from lean insulin-sensitive and obese insulin-resistant C57Bl/6J mice were incubated with biotin hydrazide and detected using horseradish peroxidase-conjugated streptavidin. High carbohydrate, high fat feeding of mice resulted in a approximately 2-3-fold increase in total adipose protein carbonylation. Consistent with an increase in oxidative stress in obesity, the abundance of glutathione S-transferase A4 (GSTA4), a key enzyme responsible for metabolizing 4-HNE, was decreased approximately 3-4-fold in adipose tissue of obese mice. To identify specific carbonylated proteins, biotin hydrazide-modified adipose proteins from obese mice were captured using avidin-Sepharose affinity chromatography, proteolytically digested, and subjected to LC-ESI MS/MS. Interestingly enzymes involved in cellular stress response, lipotoxicity, and insulin signaling such as glutathione S-transferase M1, peroxiredoxin 1, glutathione peroxidase 1, eukaryotic elongation factor 1alpha-1 (eEF1alpha1), and filamin A were identified. The adipocyte fatty acid-binding protein, a protein implicated in the regulation of insulin resistance, was found to be carbonylated in vivo with 4-HNE. In vitro modification of adipocyte fatty acid-binding protein with 4-HNE was mapped to Cys-117, occurred equivalently using either the R or S enantiomer of 4-HNE, and reduced the affinity of the protein for fatty acids approximately 10-fold. These results indicate that obesity is accompanied by an increase in the carbonylation of a number of adipose-regulatory proteins that may serve as a mechanistic link between increased oxidative stress and the development of insulin resistance.
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PMID:Carbonylation of adipose proteins in obesity and insulin resistance: identification of adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal. 1720 80

2-(3-Chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine (3) is a potent and selective 5-HT(2C) agonist that exhibits dose-dependent inhibition of food intake and reduction in body weight in rats, making it an attractive candidate for treatment of obesity. However, examination of the genotoxicity potential of 3 in the Salmonella Ames assay using tester strains TA98, TA100, TA1535, and TA1537 revealed a metabolism (rat S9/NADPH)- and dose-dependent increase of reverse mutations in strains TA100 and TA1537. The increase in reverse mutations was attenuated upon coincubation with methoxylamine and glutathione. The irreversible and concentration-dependent incorporation of radioactivity in calf thymus DNA after incubations with [14C]3 in the presence of rat S9/NADPH suggested that 3 was bioactivated to a reactive intermediate that covalently bound DNA. In vitro metabolism studies on 3 with rat S9/NADPH in the presence of methoxylamine and cyanide led to the detection of amine and cyano conjugates of 3. The mass spectrum of the amine conjugate was consistent with condensation of amine with an aldehyde metabolite derived from hydroxylation of the secondary piperazine nitrogen-alpha-carbon bond. The mass spectrum of the cyano conjugate suggested a bioactivation pathway involving N-hydroxylation of the secondary piperazine nitrogen followed by two-electron oxidation to generate an electrophilic nitrone, which reacted with cyanide. The 3-chlorobenzyl motif in 3 was also bioactivated via initial aromatic ring hydroxylation followed by elimination to a quinone-methide species that reacted with glutathione or with the secondary piperazine ring nitrogen in 3 and its monohydroxylated metabolite(s). The metabolism studies described herein provide a mechanistic basis for the mutagenicity of 3.
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PMID:Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: role of metabolic activation. 1734 39


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