"Dipeptidyl peptidase-4 (DPP-4) is an exoprotease that cleaves N-terminal dipeptides from several substrates such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GLP), impairing the function of the incretin system, which is of key importance for glucose homeostasis. Indeed, DPP4 inhibitors are currently in clinical use for type 2 diabetes. The host group has described for the first time that DPP4 is secreted by adipose and strongly correlates with adipocyte volume and parameters of the metabolic syndrome and is decreased to the lean level after weight reduction in humans. Moreover, novel data obtained in the host group suggest that DPP4 may impair insulin sensitivity in an auto- and paracrine manner. Thus, DPP4 arises as a novel adipokine potentially linking obesity to the metabolic syndrome. Since there is a growing interest in anti-diabetic therapies based on DPP4 inhibition, a deeper understanding of the role of adipose DPP4 on the onset and progression of insulin resistance is needed. This project aims to explore the impact of adipose DPP4 deletion in diet- induced obesity (ADDIO). For this purpose the host group is generating an adipose-specific DPP4 knockout mouse to prove a causal role
of this protein in the development of the metabolic syndrome. Our global aim will be pursued following a 3 step strategy: Firstly, we will assess the impact of adipose DPP4 genetic deletion by characterizing the metabolic phenotype of adipose-specific DPP4 knockout mice.
We will next determine the impact of genetic deletion of adipose DPP4 on the development of diet-induced impaired glucose tolerance and insulin resistance. Finally, we will explore the mechanism responsible for the potential protective/delaying effect of adipose DPP4 genetic deletion on impaired glucose tolerance and insulin resistance in obesity."
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