and studies in mice with leptin deficiency suggested that the cardiac hyper trophy table 5 developing in states of chronic hyperleptinemia Inhibitors,Modulators,Libraries may result from the inability to transduce anti hypertrophic andor cardioprotective effects of the adipokine. While the effects of leptin on cell shortening and intracel lular Ca2 transients were found to be abrogated in cardio myocytes isolated from HFD fed obese rats, others reported a preserved signal transduction in response to lep tin in hyperleptinemic obese mice or rats. Thus, the role of the adipokine in mediating cardiac hyper trophy, in particular in the presence of elevated systemic leptin levels, and the possible existence of a cardiac leptin resistance in obesity remains unclear.

Inhibitors,Modulators,Libraries The leptin receptor belongs to the family of cyto kine type I receptors known to signal via activation of Janus kinase 2 and signal transducer and activator of transcription 3. Analysis of cardiomyocytes ex vivo revealed that leptin promotes hypertrophy via acti vation of p38 and p4244 MAP kinases as well as protein kinase B. On the other hand, it is unknown whether STAT3 activation downstream of LepR is required to transmit the cardiac effects of leptin and whether it may be involved in mediating protective signals, as previously reported in mice with cardiomyocyte specific STAT3 deletion. In this study, we examined the cardiac phenotype of diet induced and genetically obese hyperleptinemic mice, developing with age or after continuous B adrenergic stimulation.

Moreover, we determined the importance of leptin Inhibitors,Modulators,Libraries mediated STAT3 activation for the development of cardiac hypertrophy in obesity by analyzing mice with targeted mutation of the STAT3 binding site within LepR. Methods Animals C57Bl6J leptin receptor deficient dbdb mice and C57Bl6J wildtype controls were obtained from Harlan Winkelmann, Germany. Mice heterozygous mutant for the LepRS1138 allele were obtained from Pro fessor Martin Myers and bred at the animal facility of the University of Goettingen, Germany, to generate homozygous mutant obese LepRS1138 mice. Age and gender matched WT and heterozygous littermates were used as controls. To Inhibitors,Modulators,Libraries induce obesity, 3 months old mice were switched to high fat diet for 4 months, while controls were maintained on normal rodent chow. The composition of both diets is shown in Additional file 1 Table S1.

To examine the cardiac response to hypertrophic stimuli other than leptin, osmotic minipumps Inhibitors,Modulators,Libraries were filled with isoprenaline hydrochloride and implanted for 14 days under the dorsal skinfold of 2 months old, 2% isoflurane http://www.selleckchem.com/products/AG-014699.html anesthetized mice. At the time of tissue harvest, mice were weighed followed by intraperitoneal anesthesia with a mixture of 2% xylazine and 10% ketamine hydrochloride, and blood was drawn by cardiac punc ture. Hearts were rapidly excised, the atria removed and ventricles immediately processed for protein isolation or cryoembedding, respectively.