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

Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, db/db, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110alpha) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110alpha catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.
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PMID:Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice. 1823 69

Peroxisome proliferator-activated receptor (PPAR)-delta is a transcription factor that belongs to the PPAR family. PPAR-delta is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of PPAR-delta protects the heart from ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia. A highly selective PPAR-delta agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]acetic acid (GW0742), was administered for 7 days at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with GW0742 reduced serum levels of cardiac troponin-I and infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with GW0742 up-regulated gene expression involved in cardiac fatty acid oxidation, increased fat use in the heart, and reduced serum levels of free fatty acids. The enhanced cardiac expression of interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by GW0742. Treatment with GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac caspase-3 activity by 61% (both p < 0.01 versus vehicle). GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition, GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of PPAR-delta protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.
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PMID:In vivo activation of peroxisome proliferator-activated receptor-delta protects the heart from ischemia/reperfusion injury in Zucker fatty rats. 1828 12

Obesity is a known risk factor for induction of myocardial infarction, but, paradoxically, may also confer a protective effect against subsequent remodeling leading to heart failure. In this study, we investigated the effect of leptin, the product of the obese (ob) gene, on cardiomyocyte apoptosis, a well-characterized component of cardiac remodeling after myocardial infarction. Exposing H9c2 cells to H(2)O(2) decreased cell viability, and this was attenuated by pretreating cells with leptin for 1 h, but not 24 h. Leptin also attenuated the ability of H(2)O(2) to increase phosphatidylserine exposure and annexin V binding. Further investigation of underlying mechanisms of leptin's protective effect demonstrated that the H(2)O(2)-induced decrease in mitochondrial membrane potential (Psi) leading to cytochrome c release was attenuated by leptin pretreatment, and this was associated with reduced translocation of the pro-apoptotic Bax protein to the mitochondrial membrane. Finally, leptin prevented H(2)O(2)-induced increases in caspase-3 cleavage and activity, although again 24 h leptin pretreatment did not confer significant protection. In summary, we have demonstrated that acute leptin pretreatment mediates anti-apoptotic effects in H9c2 rat cardiomyocytes, which may be of significance in clarifying the direct impact of leptin on the heart.
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PMID:Leptin protects H9c2 rat cardiomyocytes from H2O2-induced apoptosis. 1847 63

Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.
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PMID:12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. 1878 Jul 76

Beta-cell apoptosis induced by adipokines may result in beta-cell dysfunction in type 2 diabetes. Resistin, an adipokine-linked obesity with type 2 diabetes, impairs glucose-stimulated insulin secretion (GSIS) in beta-cells. Presently, the effects of resistin on rat insulinoma cells RINm5F were examined. Treatment of RINm5F with resistin induced cell damage. Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) protected resistin-mediated cytotoxicity in RINm5F. Incubation with resistin up-regulated caspase-3 activity and induced the formation of a DNA ladder. TIMP-1 attenuated these effects. The molecular mechanism of TIMP-1 inhibition of resistin-mediated cytotoxicity appeared to involve Akt phosphorylation and activation of IkB-alpha phosphorylation. Resistin treatment suppressed Akt phosphorylation and activated IkB-alpha phosphorylation, which could be attenuated by TIMP-1. We conclude that resistin can induce beta-cell apoptosis and that resistin-related beta-cell apoptosis can be prevented by TIMP-1.
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PMID:Resistin induces rat insulinoma cell RINm5F apoptosis. 1883 35

We tested whether rat liver preservation performed by machine perfusion (MP) at 20 degrees C can enhance the functional integrity of steatotic livers versus simple cold storage. We also compared MP at 20 degrees C with hypothermic MP at 8 degrees C, and 4 degrees C. Obese and lean male Zucker rats were used as liver donors. MP was performed for 6 hours with a glucose and N-acetylcysteine-supplemented Krebs-Henseleit solution. Both MP and cold storage preserved livers were reperfused with Krebs-Henseleit solution (2 hours at 37 degrees C). MP at 4 degrees C and 8 degrees C reduced the fatty liver necrosis compared with cold storage but we further protected the organs using MP at 20 degrees C. Necrosis did not differ in livers from lean animals submitted to the different procedures; the enzymes released in steatotic livers preserved by MP at 20 degrees C were similar to those showed in nonsteatotic organs. The adenosine triphosphate/adenosine diphosphate ratio and bile production were higher and the oxidative stress and biliary enzymes were lower in steatotic livers preserved by MP at 20 degrees C as compared with cold storage. In livers from lean rats, the adenosine triphosphate/adenosine diphosphate ratio appears better conserved by MP at 20 degrees C as compared with cold storage. In steatotic livers preserved by cold storage, a 2-fold increase in tumor necrosis factor-alpha levels and caspase-3 activity was observed as compared with organs preserved by MP at 20 degrees C. These data are substantiated by better morphology, higher glycogen content, and lower reactive oxygen species production by sinusoidal cells in steatotic liver submitted to MP at 20 degrees C versus cold storage. MP at 20 degrees C improves cell survival and leads to a marked improvement in hepatic preservation of steatotic livers as compared with cold storage.
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PMID:Subnormothermic machine perfusion protects steatotic livers against preservation injury: a potential for donor pool increase? 1910 50

Cardiomyocyte apoptosis is a critical process in the pathogenesis of ischemic and diabetic cardiomyopathy, but the mechanisms are not fully understood. Thioredoxin-interacting protein (TXNIP) has recently been shown to have deleterious effects in the cardiovascular system and we therefore investigated whether it may also play a role in diabetes-associated cardiomyocyte apoptosis. In fact, TXNIP expression was increased in H9C2 cardiomyocytes incubated at high glucose, and cardiac expression of TXNIP and cleaved caspase-3 were also elevated in vivo in streptozotocin- and obesity-induced diabetic mice. Together, these findings not only suggest that TXNIP is involved in diabetic cardiomyopathy but also that it may represent a novel therapeutic target. Surprisingly, testing putative TXNIP modulators revealed that calcium channel blockers reduce cardiomyocyte TXNIP transcription and protein levels in a dose-dependent manner. Oral administration of verapamil for 3 wk also reduced cardiac TXNIP expression in mice even in the face of severe diabetes, and these reduced TXNIP levels were associated with decreased apoptosis. To determine whether lack of TXNIP can mimic the verapamil-induced decrease in apoptosis, we used TXNIP-deficient HcB-19 mice, harboring a natural nonsense mutation in the TXNIP gene. Interestingly, we found significantly reduced cleaved caspase-3 levels in HcB-19 hearts, suggesting that TXNIP plays a critical role in cardiac apoptosis and that the verapamil effects were mediated by TXNIP reduction. Thus our results suggest that TXNIP reduction is a powerful target to enhance cardiomyocyte survival and that agents such as calcium channel blockers may be useful in trying to achieve this goal and prevent diabetic cardiomyopathy.
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PMID:Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein. 1925 88

We examined the effect of type 2 diabetes on stroke-induced Alzheimer's disease-like pathological and behavioral changes in rats. Rats were treated for 2 months with high fat diet (HFD) followed by streptozotocin (STZ) injection to induce type 2 diabetes (HFD-STZ model). Middle cerebral artery occlusion (MCAO) was used to induce cerebral focal ischemia. Animals were divided into four groups: Sham-NPD, Sham-HFD-STZ, MCAO-NPD and MCAO-HFD-STZ. The results showed that HFD-STZ treatment induced obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia and insulin resistance, characteristics of type 2 diabetes. The performance of rats in the Morris water maze test was impaired in MCAO-NPD and Sham-HFD-STZ rats, indicating cognitive deficits. Hippocampal caspase-3+ and beta amyloid (Abeta+) cell numbers, as well as beta-site amyloid precursor protein-cleaving enzyme (BACE1) levels and activity, increased in both groups. Moreover, HFD-STZ treatment exacerbated stroke-induced cognitive deficits, additively increased MCAO-induced activation of caspase-3, and increased levels of BACE1, C99 and Abeta. However, the level of insulin decreased in MCAO-HFD-STZ rats. These results suggested that type 2 diabetes deteriorated stroke-induced brain damage and cognitive impairment, which might be associated with increased Abeta generation and cytotoxicity. We concluded that type 2 diabetes exacerbated poststroke dementia possibly due to brain injury and synergistic generation of Abeta via activation of BACE1.
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PMID:Exacerbation of poststroke dementia by type 2 diabetes is associated with synergistic increases of beta-secretase activation and beta-amyloid generation in rat brains. 1937 2

Salicornia herbacea has been used as a folk medicine for disorders such as constipation, obesity, diabetes, and cancer. Recent studies have shown that S. herbacea has antioxidative, anti-inflammatory, immunomodulatory, antihyperglycemic, and antihyperlipidemic activities. In the present work, we investigated the protective effects of the chlorogenic acid derivative, 3-caffeoyl, 4-dihydrocaffeoyl quinic acid (CDCQ), which was isolated from S. herbacea, against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in Hepa1c1c7 cells. Pretreatment of Hepa1c1c7 cells with CDCQ significantly reduced t-BHP-induced generation of ROS, caspase-3 activation, and subsequent cell death. Also, CDCQ up-regulated heme oxygenase-1 (HO-1) expression, which conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, CDCQ-induced nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2), which is upstream of CDCQ-induced HO-1 expression, and PI3K/Akt activation, a pathway that is involved in induced Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of CDCQ against t-BHP-induced hepatotoxicity may be due, at least in part, to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the PI3K/Akt-Nrf2 signaling pathways.
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PMID:Protective mechanisms of 3-caffeoyl, 4-dihydrocaffeoyl quinic acid from Salicornia herbacea against tert-butyl hydroperoxide-induced oxidative damage. 1964 27

Cardiomyocyte apoptosis is a component of cardiac remodeling that can contribute to heart failure in obesity. A role for leptin in mediating this process has been suggested and the objective of this work was to investigate the effect of leptin on apoptosis and associated mechanisms in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic myocardial ischemia/reperfusion. Qualitative immunofluorescent and quantitative laser scanning cytometry approaches demonstrated that exposure of cells to HR increased DNA fragmentation (TUNEL staining) which was attenuated by leptin (6 nM, 1 h) pretreatment. We also found increased annexin-V binding and caspase-3 activity in cells exposed to HR, both of which were attenuated by leptin pretreatment. Leptin reduced HR-induced translocation of the pro-apoptotic protein Bax to the mitochondrial membrane, which provides a mechanism to explain its protective effect. Consequently, leptin attenuated the HR-induced decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria. Leptin treatment increased the phosphorylation of p38 MAPK and AMPK and respective inhibitors of these kinases, SB203580 and Compound C, prevented the ability of leptin to decrease HR-induced caspase-3 activity. In conclusion, we establish mechanisms via which leptin exerts anti-apoptotic effects that may be of significance in understanding the development of heart failure in obesity.
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PMID:Leptin attenuates hypoxia/reoxygenation-induced activation of the intrinsic pathway of apoptosis in rat H9c2 cells. 1965 55


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