Dissociation of obesity, hypercholesterolemia and diabetes from atherosclerosis in ob/ob mice

Yen, Terence T.; Allan, J. A.; Pearson, D; Schinitsky, M R

doi:10.1007/bf01945927

Cited by 25 publications

(18 citation statements)

References 4 publications

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“…17 Furthermore, a direct influence of leptin on vascular health is supported by the ob/ob mouse, which lacks leptin and consequently becomes hyperphagic and grossly obese but is nevertheless resistant to atherosclerosis. 21,22 Atherosclerosis risk in heterozygotes is intermediate between ob/ob homozygotes and control animals, which suggests a dose-response relation between leptin levels and the atherosclerotic process. 22 Obese humans have increased leptin production per unit of fat mass 13 and consequently disproportionately elevated leptin concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Influence of Leptin on Arterial Distensibility

et al. 2002

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Background-The mechanisms by which obesity increases the risk of atherosclerotic cardiovascular disease (CVD) are poorly understood. In experimental models, leptin, a hormone produced by adipose tissue, has been shown adversely to affect vascular health. Therefore, we tested the hypothesis that high leptin concentrations are associated with lower arterial distensibility, an index of circulatory function relevant to the atherosclerotic process. Methods and Results-Noninvasive, high-resolution, vascular ultrasound was used to measure brachial artery distensibility in 294 healthy adolescents (aged 13 to 16 years) who had a broad range of body mass indexes. Fat mass was measured by bioelectric impedance analysis; fasting serum leptin concentration by radioimmunoassay; and lipid profile, fasting insulin, glucose, and C-reactive protein concentrations by standard laboratory techniques. Higher leptin concentrations were associated with impaired arterial distensibility (regression coefficient, Ϫ1.3% change in arterial distension per 10% increase in leptin; 95% CI, Ϫ1.9% to Ϫ0.8%; PϽ0.001). This association was independent of fat mass, blood pressure, and C-reactive protein, fasting insulin, or LDL cholesterol concentrations. Conclusions-Elevation in leptin was associated with impaired vascular function, independent of the metabolic and inflammatory disturbances associated with obesity. Our observations are consistent with data from experimental models and suggest that high leptin concentration is an important mechanism for the adverse influence of body fatness on CVD.

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Section: Discussionmentioning

confidence: 99%

“…These mice are resistant to atherosclerosis despite being grossly obese. 21,22 Alternatively, obesity could influence vascular function by an effect on inflammation. C-reactive protein (CRP) is elevated in obese individuals and associated with a greater risk of CVD.…”

Section: See P 1904mentioning

confidence: 99%

Influence of Leptin on Arterial Distensibility

et al. 2002

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“…ob/ob mice are genetically obese and develop type 2 diabetes. 13,14 They also have hyperlipidemia and develop fatty livers spontaneously. 15 Our previous studies showed that the intestinal flora of ob/ob mice produce excessive EtOH 16 and that ob/ob fatty liver disease can be improved by insulin-sensitizing agents, such as metformin, 17 that inhibit hepatic TNF-␣ activity.…”

Section: A Lthough Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Li¹

2003

Hepatology

836

582

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Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor ␣ (TNF-␣). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-␣ improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-␣ activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet ؉ VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-␣ messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNFregulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor B (NF-B), the target of IKK␤, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid ␤-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions. (HEPATOLOGY 2003;37:343-350.)

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“…In vitro proatherogenic effects of leptin include endothelial cell activation, migration, and proliferation (5,6); smooth muscle cell proliferation, migration, and calcification (7,8); platelet agregation (9); activation of monocytes (10); and modulation of the immune response (11,12). In vivo, leptin receptors are expressed in vascular cells and atherosclerotic lesions (13), and leptin signaling promotes atherosclerosis in mice models (14,15).…”

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confidence: 99%

Signaling Pathways Involved in Human Vascular Smooth Muscle Cell Proliferation and Matrix Metalloproteinase-2 Expression Induced by Leptin

et al. 2005

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Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-B (NF-B) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-B. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKCdependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-B pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes. Diabetes

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Dissociation of obesity, hypercholesterolemia and diabetes from atherosclerosis in ob/ob mice

Cited by 25 publications

References 4 publications

Influence of Leptin on Arterial Distensibility

Influence of Leptin on Arterial Distensibility

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Signaling Pathways Involved in Human Vascular Smooth Muscle Cell Proliferation and Matrix Metalloproteinase-2 Expression Induced by Leptin

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