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

We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-l-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity.
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PMID:Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. 1735 Nov 50

Derangements in skeletal muscle fatty acid (FA) metabolism associated with insulin resistance in obesity appear to involve decreased FA oxidation and increased accumulation of lipids such as ceramides and diacylglycerol (DAG). We investigated potential lipid-related mechanisms of metformin (Met) and/or exercise for blunting the progression of hyperglycemia/hyperinsulinemia and skeletal muscle insulin resistance in female Zucker diabetic fatty rats (ZDF), a high-fat (HF) diet-induced model of diabetes. Lean and ZDF rats consumed control or HF diet (48 kcal %fat) alone or with Met (500 mg/kg), with treadmill exercise, or with both exercise and Met interventions for 8 wk. HF-fed ZDF rats developed hyperglycemia (mean: 24.4 +/- 2.1 mM), impairments in muscle insulin-stimulated glucose transport, increases in the FA transporter FAT/CD36, and increases in total ceramide and DAG content. The development of hyperglycemia was significantly attenuated with all interventions, as was skeletal muscle FAT/CD36 abundance and ceramide and DAG content. Interestingly, improvements in insulin-stimulated glucose transport and increased GLUT4 transporter expression in isolated muscle were seen only in conditions that included exercise training. Reduced FA oxidation and increased triacylglycerol synthesis in isolated muscle were observed with all ZDF rats compared with lean rats (P < 0.01) and were unaltered by therapeutic intervention. However, exercise did induce modest increases in peroxisome proliferator-activated receptor-gamma coactivator-1alpha, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase activity. Thus reduction of skeletal muscle FAT/CD36 and content of ceramide and DAG may be important mechanisms by which exercise training blunts the progression of diet-induced insulin resistance in skeletal muscle.
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PMID:Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia. 1737 1

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) gamma agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1beta, PGC-1alpha, estrogen-related receptor alpha, and PPARalpha, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria.
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PMID:Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. 1745 54

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by approximately 40% in transgenic mice expressing a muscle-specific AMPKalpha2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (gamma1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKalpha2-inactive mice. Sedentary gamma1TG mice showed a approximately 25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a approximately 65% increase in hexokinase II protein in wild-type mice but not in AMPKalpha2-inactive mice. Hexokinase II was significantly elevated in sedentary gamma1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.
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PMID:Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. 1751 99

Studies on conjugated linoleic acid ingestion and its effect on cardiac tissue are necessary for the safe utilization of this compound as supplement for weight loss. Male Wistar 24-rats were divided into four groups (n=6):(C)given standard chow, water and 0.5 ml saline, twice a week by gavage; (C-CLA)receiving standard chow, water and 0.5 ml of conjugated linoleic acid, twice a week, by gavage; (S)given standard chow, saline by gavage, and 30% sucrose in its drinking water; (S-CLA)receiving standard chow, 30% sucrose in its drinking water and conjugated linoleic acid. After 42 days of treatment S rats had obesity with increased abdominal-circumference, dyslipidemia, oxidative stress and myocardial lower citrate synthase(CS) and higher lactate dehydrogenase(LDH) activities than C. Conjugated linoleic acid had no effects on morphometric parameters in C-CLA, as compared to C, but normalized morphometric parameters comparing S-CLA with S. There was a negative correlation between abdominal adiposity and resting metabolic rate. Conjugated linoleic acid effect, enhancing fasting-VO(2)/surface area, postprandial-carbohydrate oxidation and serum lipid hydroperoxide resembled to that of the S group. Conjugated linoleic acid induced cardiac oxidative stress in both fed conditions, and triacylglycerol accumulation in S-CLA rats. Conjugated linoleic acid depressed myocardial LDH comparing C-CLA with C, and beta-hydroxyacyl-coenzyme-A dehydrogenase/CS ratio, comparing S-CLA with S. In conclusion, dietary conjugated linoleic acid supplementation for weight loss can have long-term effects on cardiac health. Conjugated linoleic acid, isomers c9, t11 and t10, c12c9,t11" and "t10,c12" were changed to "c9, t11" and "t10, c12", respectively. Please check if appropriate.--> presented undesirable pro-oxidant effect and induced metabolic changes in cardiac tissue. Nevertheless, despite its effect on abdominal adiposity in sucrose-rich diet condition, conjugated linoleic acid may be disadvantageous because it can lead to oxidative stress and dyslipidemic profile.
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PMID:Conjugated linoleic acid and cardiac health: oxidative stress and energetic metabolism in standard and sucrose-rich diets. 1805 9

The effects of weight loss on skeletal muscle lactate transporter [monocarboxylate transporter (MCT)] expression in obese subjects were investigated to better understand how lactate transporter metabolism is regulated in insulin-resistant states. Ten obese subjects underwent non-macronutrient-specific energy restriction for 15 wk. Anthropometric measurements and a needle biopsy of the vastus lateralis muscle before and after the weight loss program were performed. Enzymatic activity, fiber type distribution, and skeletal muscle MCT protein expression were measured. Muscle from nonobese control subjects was used for comparison of MCT levels. The program induced a weight loss of 9.2 +/- 1.6 kg. Compared with controls, muscle from obese subjects showed a strong tendency (P = 0.06) for elevated MCT4 expression (+69%) before the weight loss program. MCT4 expression decreased (-7%) following weight loss to reach levels that were not statistically different from control levels. There were no differences in MCT1 expression between controls and obese subjects before and after weight loss. A highly predictive regression model (R2 = 0.93), including waist circumference, citrate synthase activity, and percentage of type 1 fibers, was found to explain the highly variable MCT1 response to weight loss in the obese group. Therefore, in obesity, MCT1 expression appears linked both to changes in oxidative parameters and to changes in visceral adipose tissue content. The strong tendency for elevated expression of muscle MCT4 could reflect the need to release greater amounts of muscle lactate in the obese state, a situation that would be normalized with weight loss as indicated by decreased MCT4 levels.
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PMID:Effect of weight loss on lactate transporter expression in skeletal muscle of obese subjects. 1807 61

The objective of this paper is to evaluate adaptations in hepatic mitochondrial protein mass, function and efficiency in a rat model of high-fat diet-induced obesity and insulin resistance that displays several correlates to human obesity. Adult male rats were fed a high-fat diet for 7 weeks. Mitochondrial state 3 and state 4 respiratory capacities were measured in liver homogenate and isolated mitochondria by using nicotinamide adenine dinucleotide, flavin adenine dinucleotide and lipid substrates. Mitochondrial efficiency was evaluated by measuring proton leak kinetics. Mitochondrial mass was assessed by ultrastructural observations and citrate synthase (CS) activity measurements. Mitochondrial oxidative damage and antioxidant defence were also considered by measuring lipid peroxidation, aconitase and superoxide dismutase (SOD) specific activity. Whole body metabolic characteristics were obtained by measuring 24-h oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ) and nonprotein respiratory quotient (NPRQ), using indirect calorimetry with urinary nitrogen analysis. Whole body glucose homeostasis was assessed by measuring plasma insulin and glucose levels after a glucose load. Adult rats fed a high-fat diet for 7 weeks, exhibit not only obesity, insulin resistance and hepatic steatosis, but also reduced respiratory capacity and increased oxidative stress in liver mitochondria. Our present results indicate that alterations in the mitochondrial compartment induced by a high-fat diet are associated with the development of insulin resistance and ectopic fat storage in the liver. Our results thus fit in with the emerging idea that mitochondrial dysfunction can led to the development of metabolic diseases, such as obesity, type 2 diabetes mellitus and nonalcoholic steatohepatitis.
Obesity (Silver Spring) 2008 May
PMID:Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. 1827 91

Reduced skeletal muscle mitochondrial content and fatty acid oxidation are associated with obesity and insulin resistance. Although the exact mechanisms remain elusive, this may result from impaired mitochondrial biogenesis or reductions in the mitochondrial reticulum network. Therefore, the purpose of this study was to determine whether the protein contents of various transcription factors, including PGC-1alpha and PGC-1beta and proteins associated with mitochondrial fusion events, were reduced in skeletal muscle of nine obese (BMI = 37.6 +/- 2.2 kg/m(-2)) compared with nine age-matched lean (BMI = 23.3 +/- 0.7 kg/m(-2)) women. The protein contents of PGC-1alpha, PGC-1beta, PPARalpha, and tFAM were not reduced with obesity. In contrast, PPARgamma was increased (+22%, P < 0.05) with obesity, and there was a trend toward an increase (+31%, P = 0.13) in PPARdelta/beta. In lean individuals, PGC-1alpha protein correlated with citrate synthase (CS; r = 0.67) and rates of palmitate oxidation (r = 0.87), whereas PGC-1beta correlated with PPARgamma (r = 0.90), PPARdelta/beta (r = 0.63), and cytochrome c oxidase IV (COX-IV; r = 0.63). In obese individuals, the relationship between PGC-1alpha and CS was maintained (r = 0.65); however, the associations between PGC-1alpha and palmitate oxidation (r = -0.38) and PGC-1beta with PPARgamma (r = 0.14), PPARdelta/beta (r = 0.21), and COX-IV (r = 0.01) were lost. In addition, mitofusin-1 (MFN-1), MFN-2, and dynamin-related protein-1 (DRP-1) total protein contents were not altered with obesity (P > 0.05). These data suggest that altered regulation, and not reductions in the protein contents of transcription factors, is associated with insulin resistance. Also, it does not appear that alterations in the proteins associated with mitochondrial network formation and degradation can account for the observed decrease in mitochondrial content.
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PMID:PGC-1alpha's relationship with skeletal muscle palmitate oxidation is not present with obesity despite maintained PGC-1alpha and PGC-1beta protein. 1834 11

Intramuscular triacylglycerol (IMTG) accumulation in obesity has been attributed to increased fatty acid transport and/or to alterations in mitochondrial fatty acid oxidation. Alternatively, an imbalance in these two processes may channel fatty acids into storage. Therefore, in red and white muscles of lean and obese Zucker rats, we examined whether the increase in IMTG accumulation was attributable to an increased rate of fatty acid transport rather than alterations in subsarcolemmal (SS) or intermyofibrillar (IMF) mitochondrial fatty acid oxidation. In obese animals selected parameters were upregulated, including palmitate transport (red: +100%; white: +51%), plasmalemmal FAT/CD36 (red: +116%; white: +115%; not plasmalemmal FABPpm, FATP1, or FATP4), IMTG concentrations (red: approximately 2-fold; white: approximately 4-fold), and mitochondrial content (red +30%). Selected mitochondrial parameters were also greater in obese animals, namely, palmitate oxidation (SS red: +91%; SS white: +26%; not IMF mitochondria), FAT/CD36 (SS: +65%; IMF: +65%), citrate synthase (SS: +19%), and beta-hydroxyacyl-CoA dehydrogenase activities (SS: +20%); carnitine palmitoyltransferase-I activity did not differ. A comparison of lean and obese rat muscles revealed that the rate of change in IMTG concentration was eightfold greater than that of fatty acid oxidation (SS mitochondria), when both parameters were expressed relative to fatty transport. Thus fatty acid transport, esterification, and oxidation (SS mitochondria) are upregulated in muscles of obese Zucker rats, with these effects being most pronounced in red muscle. The additional fatty acid taken up is channeled primarily to esterification, suggesting that upregulation in fatty acid transport as opposed to altered fatty acid oxidation is the major determinant of intramuscular lipid accumulation.
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PMID:In obese rat muscle transport of palmitate is increased and is channeled to triacylglycerol storage despite an increase in mitochondrial palmitate oxidation. 1914 81

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using (2)H(2)O, [U-(13)C(3)]propionate, and [3,4-(13)C(2)]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had approximately 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.
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PMID:The impact of obesity, sex, and diet on hepatic glucose production in cats. 1919 46


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