Diacerhein attenuates the inflammatory response and improves survival in a model of severe sepsis.

INTRODUCTION: Hyperglycemia and insulin resistance have been associated with a worse outcome in sepsis. Although tight glycemic control through insulin therapy has been shown to reduce morbidity and mortality rates, the effect of intensive insulin therapy in patients with severe sepsis is controversial because of the increased risk of serious adverse events related to hypoglycemia. Recently, knowledge about diacerhein, an anthraquinone drug with powerful antiinflammatory properties, revealed that this drug improves insulin sensitivity, mediated by the reversal of chronic subclinical inflammation. The aim of the present study was to evaluate whether the antiinflammatory effects of diacerhein after onset of sepsis-induced glycemic alterations is beneficial and whether the survival rate is prolonged in this situation. METHODS: Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Blood glucose and inflammatory cytokine levels were assessed 24 hours after CLP. The effect of diacerhein on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle, and adipose tissue. RESULTS: Here we demonstrated that diacerhein treatment improves survival during peritoneal-induced sepsis and inhibits sepsis-induced insulin resistance by improving insulin signaling via increased insulin-receptor substrate-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. Diacerhein also decreases the activation of endoplasmic reticulum stress signaling that involves upregulation of proinflammatory pathways, such as the I kappa B kinase and c-Jun NH2-terminal kinase, which blunts insulin-induced insulin signaling in liver, muscle, and adipose tissue. Additionally, our data show that this drug promoted downregulation of proinflammatory signaling cascades that culminate in transcription of immunomodulatory factors such interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. CONCLUSIONS: This study demonstrated that diacerhein treatment increases survival and attenuates the inflammatory response with a significant effect on insulin sensitivity. On the basis of efficacy and safety profile, diacerhein represents a novel antiinflammatory therapy for management of insulin resistance in sepsis and a potential approach for future clinical trials.

Topiramate treatment improves hypothalamic insulin and leptin signaling and action and reduces obesity in mice.

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator α and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity.