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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SiCMetabol (Signaling Cascades in Metabolic Diseases)

Teaser

Summary

According to the World Health Organization (WHO) over 2.1 billion people are obese or overweight worldwide. Obesity is a major factor predisposing for development of type 2 diabetes and other associated diseases. Up to date bariatric surgery represents the most effective treatment for obesity. However, this surgical intervention causes number of postoperative complications, leads to malabsorption of the crucial nutrients and is irreversible. Recently, strategies to increase energy dissipation by adipose tissue have gained a lot of attention as a potential target for treatment of obesity. However, to develop drugs selectively promoting energy expenditure by adipocytes we need to understand complex signaling networks regulating diverse functions of these cells. Our research concentrates on identification of canonical and unconventional signaling modules regulating energy expenditure of adipocytes and other functions of these cells. For this purpose, we utilize targeted and high-throughput approaches, combining different biological methods (including mouse genetics, cell biology and biochemistry as well as omics approaches).

Work performed

Recently we discovered that genetic ablation of Protein Kinase D1 (PKD1) in adipocytes promotes energy dissipation and attenuates the course of obesity and diabetes in mice (M. LÃ¶ffler, EMBO J., Nov. 2018). Moreover, we showed that deletion of closely related kinase Protein kinase D2 (PKD2) in mice results in similar phenotype. Finally, deletion of third PKD isoform, PKD3, in hepatocytes promotes insulin sensitivity.

Final results

Our results indicate that PKD isoforms might represent an attractive target for treatment of obesity and diabetes. Therefore, in future we will test chemical substances, which have a potential to inhibit PKDs activity for treatment of obesity and diabetes. PKD isoforms belong to classical group of proteins mediating signaling in the different cell types, namely kinases. However, we postulate that abundance of kinases is regulated by multiple degradation pathways in the cell, especially by the components of ubiquitin-proteasome pathway. Therefore, in future we will investigate the impact of ubiquitin-proteasome pathway on adipocytes function, whole organism metabolism as well as development of metabolic diseases.