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)

The beta(3)-adrenergic receptor gene (BAR-3) allelic variant (Trp64Arg and Arg64Arg) is correlated with obesity or non-insulin-dependent diabetes mellitus. The mitochondrial NADH dehydrogenase subunit-2 gene (ND2) variant (Mt5178A) is associated with longevity or less susceptibility to adult-onset diseases. The frequencies of both the variants are high among the Japanese population. Cross-sectional analysis of these variants was conducted to determine if they correlated well with life-style-related phenotypes and nutrient intake. The body fat rate in the BAR-3 variant+ND2 variant group was higher than those rates in the BAR-3 normal+ND2 variant, BAR-3 normal+ND2 normal. The BAR-3 normal+ND2 variant group preferred much carbohydrate and less animal protein compared with other three groups. A combination of SNPs of the nuclear BAR-3 and the mitochondrial ND2 genes may affect eating behavior besides the biochemical and metabolic process of signal transduction and electron transfer system.
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PMID:Phenotypic linkage between single-nucleotide polymorphisms of beta3-adrenergic receptor gene and NADH dehydrogenase subunit-2 gene, with special reference to eating behavior. 1294 91

In mammals, thyroid hormone responsive Spot 14 (THRSP) is a small acidic protein that is predominately expressed in lipogenic tissue (i.e., liver, abdominal fat and the mammary gland). This gene has been postulated to play a role in lipogenesis, since it responds to thyroid hormone stimulation, high glucose levels and it is localized to a chromosomal region implicated in obesity. In this paper, we report the identification and characterization of duplicated polymorphic paralogs of Spot 14 in the chicken, THRSPalpha and THRSPbeta. Despite low similarity in amino acid (aa) sequence between chickens and mammals, other properties of Spot 14 (i.e., pI, subcellular localization, transcriptional control and functional domains) appear to be highly conserved. Furthermore, a synteny group of THRSP and its flanking genes [NADH dehydrogenase (NDUFC2) and glucosyltransferase (ALG8)] appears to be conserved among chickens, humans, mice and rats. Polymorphic alleles, involving a variable number of tandem repeats (VNTR), were discovered in the putative protein coding region of the duplicated chicken THRSPalpha (9 bp) and THRSPbeta (6 or 12 bp) genes. Our study shows that the THRSPalpha locus is associated with abdominal fat traits in a broilerxLeghorn resource population.
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PMID:Duplicated Spot 14 genes in the chicken: characterization and identification of polymorphisms associated with abdominal fat traits. 1514 57

Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state.
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PMID:A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. 1598 91

Since it was first realized that biological energy transduction involves oxygen and ATP, opinions about the amount of ATP made per oxygen consumed have continually evolved. The coupling efficiency is crucial because it constrains mechanistic models of the electron-transport chain and ATP synthase, and underpins the physiology and ecology of how organisms prosper in a thermodynamically hostile environment. Mechanistically, we have a good model of proton pumping by complex III of the electron-transport chain and a reasonable understanding of complex IV and the ATP synthase, but remain ignorant about complex I. Energy transduction is plastic: coupling efficiency can vary. Whether this occurs physiologically by molecular slipping in the proton pumps remains controversial. However, the membrane clearly leaks protons, decreasing the energy funnelled into ATP synthesis. Up to 20% of the basal metabolic rate may be used to drive this basal leak. In addition, UCP1 (uncoupling protein 1) is used in specialized tissues to uncouple oxidative phosphorylation, causing adaptive thermogenesis. Other UCPs can also uncouple, but are tightly regulated; they may function to decrease coupling efficiency and so attenuate mitochondrial radical production. UCPs may also integrate inputs from different fuels in pancreatic beta-cells and modulate insulin secretion. They are exciting potential targets for treatment of obesity, cachexia, aging and diabetes.
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PMID:The efficiency and plasticity of mitochondrial energy transduction. 1624 6

Liver cirrhosis is associated with malnutrition and often, after liver transplantation, with the development of obesity and the inability to gain lean body mass. We have previously shown that peripheral blood mononuclear cell (PBMNC) complex I activity could be an appropriate marker for nutritional assessment. In this context, we hypothesized that a low pretransplant PBMNC complex I activity may predict a poor nutritional status in cirrhotic patients undergoing liver transplantation. Fifteen cirrhotic patients (CP) (8 men and 7 women) were recruited and investigated before and 4 months after liver transplantation. Body weight, body composition by DEXA, anthropometric measures (triceps skinfold thickness and midarm muscle circumference), resting energy expenditure, respiratory quotient and PBMNC complex I activity were measured on both time points. Patients were divided into 2 groups depending on their pretransplant PBMNC complex I activity (low vs high complex I activity [CP(low CI) vs CP(high CI)]), using as an arbitrary cutoff value-the mean complex I activity observed in age-matched healthy controls. Before transplantation, the CP(low CI) group who showed a lower complex I activity (2.11 +/- 0.53 vs 4.54 +/- 0.98 nmol/min per milligram of protein, P < .01) was significantly younger (44 +/- 9 vs 62 +/- 8 years old, P < .01); no differences were observed for any other nutritional parameters when compared to the CP(high CI) group. After transplantation, only the CP(low CI) group demonstrated a significant increase of complex I activity (+77%, P < .01), respiratory quotient (+10.5%, P < .02), triceps skinfold thickness (+126%, P < .005), and a significant decrease of fat-free mass (-8%, P < .01). In summary, our findings indicate that a low pretransplant PBMNC complex I activity in cirrhotic patients could be a useful marker of poor nutritional status despite the lack of traditional indicators of malnutrition by predicting metabolic disturbances and an inability to regain fat-free mass after liver transplantation.
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PMID:A low pretransplant peripheral blood mononuclear cell complex I activity predicts metabolic disturbances and inability to regain fat free mass in cirrhotic patients undergoing liver transplantation. 1918 74

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.
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PMID:Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. 1961 6

Obesity and mild hyperglycemia are characteristic of early or "prediabetes." The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H(2)O(2) largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.
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PMID:Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. 1976 76

It is a desirable goal to stimulate fuel oxidation in adipocytes and shift the balance toward less fuel storage and more burning. To understand this regulatory process, respiration was measured in primary rat adipocytes, mitochondria, and fat-fed mice. Maximum O(2) consumption, in vitro, was determined with a chemical uncoupler of oxidative phosphorylation (carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)). The adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio was measured by luminescence. Mitochondria were localized by confocal microscopy with MitoTracker Green and their membrane potential (Delta psi(M)) measured using tetramethylrhodamine ethyl ester perchlorate (TMRE). The effect of N-acetylcysteine (NAC) on respiration and body composition in vivo was assessed in mice. Addition of FCCP collapsed Delta psi(M) and decreased the ATP/ADP ratio. However, we demonstrated the same rate of adipocyte O(2) consumption in the absence or presence of fuels and FCCP. Respiration was only stimulated when reactive oxygen species (ROS) were scavenged by pyruvate or NAC: other fuels or fuel combinations had little effect. Importantly, the ROS scavenging role of pyruvate was not affected by rotenone, an inhibitor of mitochondrial complex I. In addition, mice that consumed NAC exhibited increased O(2) consumption and decreased body fat in vivo. These studies suggest for the first time that adipocyte O(2) consumption may be inhibited by ROS, because pyruvate and NAC stimulated respiration. ROS inhibition of O(2) consumption may explain the difficulty to identify effective strategies to increase fat burning in adipocytes. Stimulating fuel oxidation in adipocytes by decreasing ROS may provide a novel means to shift the balance from fuel storage to fuel burning.
Obesity (Silver Spring) 2010 Aug
PMID:Respiration in adipocytes is inhibited by reactive oxygen species. 2003 77

Metformin is a widely prescribed drug for treatment of type 2 diabetes, although no cellular mechanism of action has been established. To determine whether in vivo metformin treatment alters mitochondrial function in skeletal muscle, respiratory O(2) flux and H(2)O(2) emission were measured in saponin-permeabilized myofibers from lean and obese (fa/fa) Zucker rats treated for 4 weeks with metformin. Succinate- and palmitoylcarnitine-supported respiration generated greater than twofold higher rates of H(2)O(2) emission in myofibers from untreated obese versus lean rats, indicative of an obesity-associated increased mitochondrial oxidant emitting potential. In conjunction with improved glycemic control, metformin treatment reduced H(2)O(2) emission in muscle from obese rats to rates near or below those observed in lean rats during both succinate- and palmitoylcarnitine-supported respiration. Surprisingly, metformin treatment did not affect basal or maximal rates of O(2) consumption in muscle from obese or lean rats. Ex vivo dose-response experiments revealed that metformin inhibits complex I-linked H(2)O(2) emission at a concentration approximately 2 orders of magnitude lower than that required to inhibit respiratory O(2) flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H(2)O(2) emission by blocking reverse electron flow without affecting forward electron flow or respiratory O(2) flux in skeletal muscle.
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PMID:Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. 2060 Aug 32

Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1(-/-) mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.
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PMID:Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. 2067 60


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