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)

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.
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PMID:Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. 250 Oct 61

The regulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression was studied during the onset of obesity in the genetically obese (fa/fa) rat by determination of GAPDH activity and hybridizable mRNA amounts in adipose tissue and liver from suckling and weanling rats. GADPH activity remained low throughout the suckling period, and a burst of activity occurred after weaning in both lean and obese pups. As early as 7 days of age, adipose tissue from pre-obese rats displayed a significant increase in enzyme activity, whereas no difference could be detected in the liver. In both suckling (16 days of age) and weanling (30 days of age) obese rats a proportionate increase in GAPDH activity and mRNA amounts was observed in adipose tissue, but not in liver. It is concluded that the obese genotype influences GAPDH gene expression at a pretranslational level and in a tissue-specific manner. This phenomenon could partly contribute to the hyperactive fat accretion in the obese rat, since glycolysis is the major metabolic pathway for lipogenic substrates in adipose tissue.
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PMID:Adipose-tissue-specific increase in glyceraldehyde-3-phosphate dehydrogenase activity and mRNA amounts in suckling pre-obese Zucker rats. Effect of weaning. 317 70

This chapter focuses on the biochemical mechanisms that mediate glucose-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summarize evidence supporting the idea that glucose metabolism is required for GSIS and that the GLUT-2 facilitated glucose transporter and the glucose phosphorylating enzyme glucokinase play important roles in measuring changes in extracellular glucose concentration. The idea that glucose metabolism is linked to insulin secretion through a sequence of events involving changes in ATP:ADP ratio, inhibition of ATP-sensitive K+ channels, and activation of voltage-gated Ca2+ channels is critically reviewed, and the relative importance of ATP generated from glycolytic versus mitochondrial metabolism is evaluated. We also present the growing concept that an important signal for insulin secretion may reside at the linkage between glucose and lipid metabolism, specifically the generation of the regulatory molecule malonyl CoA that promotes fatty acid esterification and inhibits oxidation. Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term exposure of islets to high levels of fatty acids results in beta-cell dysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insulin-dependent diabetes mellitus (NIDDM).
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PMID:Metabolic coupling factors in pancreatic beta-cell signal transduction. 757 98

Activation of the endogenous protein kinase Cs in human kidney fibroblast (293) cells was found in the present study to inhibit the subsequent ability of insulin to stimulate the tyrosine phosphorylation of an expressed insulin receptor substrate-1. This inhibition was also observed in an in vitro phosphorylation reaction if the insulin receptor and its substrate were both isolated from cells in which the protein kinase C had been activated. To test whether serine phosphorylation of the insulin receptor substrate-1 was contributing to this process, serine 612 of this molecule was changed to an alanine. The insulin-stimulated tyrosine phosphorylation and the associated phosphatidylinositol 3-kinase activity of the expressed mutant were found to be comparable to those of the expressed wild-type substrate. However, unlike the wild-type protein, activation of protein kinase C did not inhibit the insulin-stimulated tyrosine phosphorylation of the S612A mutant nor its subsequent association with phosphatidylinositol 3-kinase. Tryptic peptide mapping of in vivo labeled IRS-1 and the S612A mutant revealed that PMA stimulates the phosphorylation of a peptide from wild-type IRS-1 that is absent from the tryptic peptide maps of the S612A mutant. Moreover, a synthetic peptide containing this phosphoserine and its nearby tyrosine was found to be phosphorylated by the insulin receptor to a much lower extent than the same peptide without the phosphoserine. Activation of protein kinase C was found to stimulate by 10-fold the ability of a cytosolic kinase to phosphorylate this synthetic peptide as well as the intact insulin receptor substrate-1. Finally, cytosolic extracts from the livers of ob/ob mice showed an 8-fold increase in a kinase activity capable of phosphorylating this synthetic peptide, compared to extracts of livers from lean litter mates. These results indicate that activation of protein kinase C stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell, posing a potential mechanism for insulin resistance in some models of obesity.
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PMID:Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. 933 53

A greater understanding of the factors causing the enhanced release of leptin by adipocytes in obesity is needed. Experiments were designed to determine the effects of actinomycin D on leptin release by isolated rat adipocytes during primary culture for 24 hr. In adipocytes from fed hypothyroid rats, the initial rate of leptin release over the first 6 hr was not maintained over the next 18 hr. The decline in leptin release by adipocytes in primary culture between 6 and 24 hr was reduced markedly by either dexamethasone or actinomycin D. Both actinomycin D and dexamethasone also reduced the loss of leptin mRNA seen over the 24-hr incubation. Maximal effects on leptin release and leptin mRNA accumulation required only 0.1 microM of actinomycin D, a concentration that had no significant effect on the 18S RNA content of adipocytes at the end of a 24-hr incubation. In contrast to the reduced loss of leptin mRNA seen at 24 hr, the loss of glyceraldehyde-3-phosphate dehydrogenase messenger ribonucleic acid (GAPDH mRNA) was enhanced in the presence of 0.1 microM of actinomycin D. The effects of dexamethasone could be differentiated from those of actinomycin D by the finding that cycloheximide blocked the reduced loss of leptin mRNA due to dexamethasone while having no effect on that due to actinomycin D. These results point to a unique regulation of leptin release and leptin mRNA levels by actinomycin D.
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PMID:Stimulation of leptin release by actinomycin D in rat adipocytes. 971 87

Insulin resistance, as is found in skeletal muscle of individuals with obesity and NIDDM, appears to involve a reduced capacity of the hormone to stimulate glucose uptake and/or phosphorylation. The glucose phosphorylation step, as catalyzed by hexokinase II, has been described as rate limiting for glucose disposal in muscle, but overexpression of this enzyme under control of a muscle-specific promoter in transgenic mice has had limited metabolic impact. In the current study, we investigated in a cultured muscle model whether expression of glucokinase, which in contrast to hexokinase II is not inhibited by glucose-6-phosphate (G-6-P), would have a pronounced metabolic impact. We used a recombinant adenovirus containing the cDNA-encoding rat liver glucokinase (AdCMV-GKL) to increase the glucose phosphorylating activity in cultured human muscle cells by fourfold. G-6-P levels increased in AdCMV-GKL-treated cells in a glucose concentration-dependent manner over the range of 1-30 mmol/l, whereas the much smaller increases in G-6-P in control cells were maximal at glucose concentrations <5 mmol/l. Further, cells expressing glucokinase accumulated 17 times more 2-deoxyglucose-6-phosphate than control cells. In AdCMV-GKL-treated cells, the time-dependent rise in G-6-P correlated with an increase in the activity ratio of glycogen synthase. AdCMV-GKL-treated cells also exhibited a 2.5- to 3-fold increase in glycogen content and a four- to fivefold increase in glycolytic flux, proportional to the increase in glucose phosphorylating capacity. All of these observations were made in the absence of insulin. Thus we concluded that expression of glucokinase in cultured human muscle cells results in proportional increases in insulin-independent glucose disposal, and that muscle glucose storage and utilization becomes controlled in a glucose concentration-dependent manner in AdCMV-GKL-treated cells. These results encourage testing whether delivery of glucokinase to muscle in vivo has an impact on glycemic control, which could be a method for circumventing the failure of insulin to stimulate glucose uptake and/or phosphorylation in muscle normally in insulin-resistant subjects.
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PMID:Expression of glucokinase in cultured human muscle cells confers insulin-independent and glucose concentration-dependent increases in glucose disposal and storage. 972 26

Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. NIDDM can be defined as a disease caused by defective transduction of insulin signals and IR as a complex phenotype manifesting itself, emphasized by individual and environmental factors, in the cellular systems of signal transduction. IRS is a syndrome characterized by NIDDM, hypertension, visceral obesity, CHD: the X syndrome. Up to day the described mutations of the insulin-receptor gene are rare (e.g. the leprechaunism): genetic IR. Obesity is the principal cause of IR by receptorial and post-receptorial defects: metabolic IR. The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. IR is a pattern of essential hypertension. Hypertension, dyslipidemia and abnormality of glucose metabolism are linked by IR. The so called high erythrocyte Na(+)-Li+ counter-transport is a new biochemical marker for IR and hypertension. These drugs can reduce IR: metformin, sulphonilureas, fibrats, dexfenfluramine, troglitazone, doxazosin, ACE-inhibitors.
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PMID:[Insulin resistance. Receptor and post-receptor abnormalities]. 984 54

In mitochondria, ATP synthesis is coupled to oxygen consumption by the proton electrochemical gradient established across the mitochondrial inner membrane in a process termed oxidative phosphorylation. It has long been known from stoichiometric studies that ATP synthesis is not perfectly coupled to oxygen consumption. The major inefficiency in the system is leakage of protons across the mitochondrial inner membrane driven by the proton electrochemical gradient. The kinetics of the proton leak can be determined indirectly, by measuring the oxygen consumption of mitochondria under non-phosphorylating conditions (plus oligomycin) as a function of the proton electrochemical gradient. This experimental system provides a convenient means to investigate inner membrane permeability to protons and the effect of factors that may effect that permeability. In this paper we review some results from our laboratory of indirect measurement of mitochondrial proton leak and how it has been applied to investigate the effect of aging, obesity and thyroid status on proton leak. The results show that (i) proton leak in isolated liver mitochondria is not significantly different in a comparison of young and old rats, in contrast (ii) there is an apparent increase in proton leak in in situ mitochondria in hepatocytes from old rats when compared to those from young rats, (iii) proton leak in neuronal mitochondria in situ in synaptosomes is not significantly different in young and old rats, (iv) proton leak is greater in isolated liver mitochondria from ob/ob mice compared to lean controls, (v) acute leptin (OB protein) administration restores the increased leak rate in isolated liver mitochondria from ob/ob mice to that of lean controls, (vi) administration of thyroid hormone (T3) increases proton leak in rat muscle mitochondria, and (vii) proton leak in muscle mitochondria is insensitive to the presence of GDP. It is proposed that the experimental system described here for measuring proton leak, is an ideal functional assay for determining whether the novel uncoupling proteins increase inner membrane permeability to protons.
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PMID:Indirect measurement of mitochondrial proton leak and its application. 1045 15

Skeletal muscle has a prime role in glucose homeostasis. We have previously demonstrated that adenovirus-mediated glucokinase (GK) gene transfer to skeletal muscle of Wistar rats enhances muscle glucose uptake and whole body glucose disposal under conditions of hyperglycemia and hyperinsulinemia. In this study, we have tested whether GK gene transfer to the muscle of the Zucker Diabetic Fatty rat (ZDF), a genetic model of obesity and type 2 diabetes, could improve glycemic control and prevent the onset of hyperglycemia in obese males. We show that GK delivery results in a doubling of total gastrocnemius muscle glucose phosphorylating activity 9 weeks after gene transfer. GK-treated rats exhibited slightly reduced weight and normal insulin-sensitive glucose uptake, as assessed during an insulin tolerance test, whereas age-matched rats treated with a control virus were clearly insulin resistant. The improved glucose uptake in GK-expressing rats was associated with higher gastrocnemius lactate content, whereas glycogen and triacylglyceride (TAG) levels were unmodified. Remarkably, GK-treated rats showed increased expression of both hexokinase II (HKII) and GLUT4, in accordance with a glucose-dependent regulation of these proteins. Thus, our data show that delivery of GK, despite improving insulin-sensitive glucose disposal in muscle, is not sufficient to prevent or delay the appearance of elevated glucose and insulin levels associated with severe obesity in male ZDF animals.
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PMID:Glucokinase gene transfer to skeletal muscle of diabetic Zucker fatty rats improves insulin-sensitive glucose uptake. 1178 83

AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor that regulates glucose and lipid metabolism by phosphorylating key regulatory enzymes. Despite the major role of adipose tissue in regulating energy partitioning in the organism, the role of AMPK in this tissue has not been addressed. In the present study, we subjected AMPKalpha2 knockout (KO) mice to a high-fat diet to examine the effect of AMPK on adipose tissue formation. Compared with the wild type, AMPKalpha2 KO mice exhibited increased body weight and fat mass. The increase in adipose tissue mass was due to the enlargement of the preexisting adipocytes with increased lipid accumulation. However, we did not observe any changes in adipocyte marker expression, such as peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and adipocyte fatty acid-binding protein (aFABP/aP2), or total cell number. Unlike impaired glucose homeostasis observed on normal diet feeding, when fed a high-fat diet AMPKalpha2 KO mice did not show differences in glucose tolerance and insulin sensitivity compared with wild-type mice. Our results suggest that the increase in lipid storage in adipose tissue in AMPKalpha2 KO mice may have protected these mice from further impairment of glucose homeostasis that normally accompanies high-fat feeding. Our study also demonstrates that lack of AMPKalpha2 subunit may be a factor contributing to the development of obesity.
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PMID:Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. 1533 33


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