Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Jan Silhavy
PROVIDER: E-MTAB-2406 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
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Project description:Inflammation, oxidative and dicarbonyl stress play important roles in the pathophysiology of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver, however, its “pleiotropic“ effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP). In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL6 while levels of human CRP remained unchanged and metformin also significantly reduced oxidative stress (levels of conjugated dienes and TBARS) in the liver while no significant effects were observed in SHR control rats. In addition, in the presence of high human CRP, metformin reduced methylglyoxal levels in left ventricles but not in kidneys. Finally, metformin treatment reduced adipose tissue lipolysis. Possible molecular mechanisms of metformin action studied by gene expression profiling in the liver revealed deregulated genes from inflammatory, insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP metformin protects against inflammation, oxidative and dicarbonyl stress in the heart and ameliorates insulin resistance and dyslipidemia.
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