Decoding kinase-mediated signaling networks promoting lipolysis in health and disease

• Applicant: Privatdozent Grzegorz Sumara, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Biochemistry ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245619385

Adaption to changes in nutrient availability is pivotal for survival of living organisms. Specific responses to fasting and feeding in different organs are regulated by a complex array of hormonal cues. Deregulation of nutrient sensing leads to development of metabolic diseases including type 2 diabetes (T2D).Adipose tissue and liver are central to the adaptation to food deprivation as they can store large quantities of nutrients and release them when needed. Adipose tissue responds to shortage of nutrients by inducing lipolysis – a process leading to mobilization and release of free fatty acids (FFAs) and glycerol through catabolism of stored triglycerides. Liver catabolizes stored polysaccharides and induces gluconeogenesis (de novo glucose production) from glycerol and other substrates upon nutrient deprivation. Hepatic sugar absorption and utilization decreases, while beta-oxidation of adipose tissue-derived FFAs and production of ketone bodies is induced.Importantly, uncontrolled activation of the fasting response in these organs largely independent of changes in food supply contributes to chronic hyperglycemia and hyperlipidemia, hallmarks of T2D that constitutes a major world-wide health concern.As a postdoc, I discovered gut-derived serotonin (GDS) as a fundamentally new hormone implicated in regulation of the fasting response in mice. I showed that GDS promotes lipolysis in adipose tissue and gluconeogenesis in liver while it blocks hepatic glucose uptake. Strikingly, inhibition of GDS synthesis was sufficient to ameliorate hyperglycemia and hyperlipidemia in diabetic mice. However, molecular mechanisms mediating GDS action on adipose tissue and liver are unknown. In the future, one important task of my laboratory will thus be the understanding of these mechanisms using a combination of targeted and unbiased approaches.Additionally, I have previously implicated Protein kinase D1 (PKD1) in development of diabetes and maintaining of pancreatic β cells function. My preliminary observations supported by the work of others indicate that PKD1 might be also implicated in regulation of liver and adipose tissue metabolism. Having access to conditional liver and adipose-specific PKD1 knockout mice we will focus on the function of this kinase in hepatic and adipose metabolism in the context of hormonal signaling and more broadly in fasting and feeding response.In an attempt to more globally assess the role of hormonally regulated signaling cascades in liver metabolism, we will utilize unbiased screening approach, to identify new kinases regulating gluconeogenesis, glucose uptake and FFAs beta-oxidation in this organ.I believe that the comprehensive design of the proposed project will lead to the identification of new molecules affecting important processes in response to changes in nutrient availability in liver and adipose tissue, which will hopefully result in the development of more precise pharmacological strategies to treat T2D.

• DFG Programme: Independent Junior Research Groups