Diabesity - novel molecular targets for obesity and type 2 diabetes
 
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Professor Jens Brüning
Institute of Genetics
University of Cologne
Joseph-Stelzmann-Str. 9
50931, Cologne
Germany
Phone: +49 221 4784070
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Professor Jens Brüning
Workpackage 8 leader
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Research

Aim
The group works on different projects aiming to characterize signaling pathways responsible for the regulation of energy and glucose homeostasis.  The experimental approach focuses on the generation and characterization of mouse models with targeted disruption of genes in the leptin, insulin and cytokine signaling pathways.  Particularly, the experiments are based on the establishment of conditional mutants with cell type-specific and/or timely controlled disruption of signaling molecules.

Central regulation of energy homeostasis
Energy homeostasis of the mammalian organism is tightly controlled through a balance of energy intake and energy expenditure.  Over the last ten years a variety of signals has been identified regulating both food intake and energy expenditure in mammals.  These include the adipocyte-derived hormone leptin, which signals through leptin receptors expressed in hypothalamic neurons to inhibit food intake and to stimulate energy expenditure.  Likewise, the pancreas-derived hormone insulin has been shown to acutely inhibit food intake through the activation of neuronal insulin receptors.  Moreover, a variety of interleukin-type signals such as interleukin-6 and ciliary neurotrophic factor have been demonstrated to regulate either food intake or metabolic rate.

However, it is unclear which particular neuronal population mediates the effects of these signals.  Moreover, the intracellular signaling cascade responsible for the regulation of energy intake and expenditure has not fully been elucidated and lastly the interaction of these different types of signals remains largely unclear.  Therefore, we are generating mice with conditional inactivation of genes in theses signaling pathways in defined neuronal populations.

Insulin resistance in inflammation and athlerosclerosis
Apart from the classical insulin target tissues such as skeletal muscle, liver and adipose tissue, insulin receptors are widely expressed throughout the mammalian organism.  Insulin and IGF-1 receptors are also expressed in lymphocytes and their expression is regulated through lymphocyte development.  Moreover, macrophages express both types of receptors and it has been shown that insulin stimulates the uptake of glycosylated end products in these cells.  Since clinically type 2 diabetes and insulin resistance are closely linked to the development of atherosclerosis and there is growing evidence for a role of inflammatory processes in the development of atherosclerosis, another focus of our work is to study the role of insulin signaling in lymphocytes and macrophages.

 

Diabesity: Novel molecular targets for obesity and type 2 diabetes
   
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