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RESEARCH TOPIC 1: Environmental Metabolic Diseases – Discovery and Validation of Novel CNS Targets

Leader: Mathias Treier
Workpackages (WP): 1-6
Main objectives:
The main objective of research topic 1 is the identification of novel CNS targets and circuits relevant to the control of systems metabolism, obesity and T2D. Therefore main research efforts within topic 1 are directed towards dissecting the role of the hypothalamus complemented by quantitative metabolic expression and epigenetic profiling of peripheral target organs in combination with complex in silico human data analysis.

RESEARCH TOPIC 2: Integrating central and peripheral processes

Leader: Matthias Blüher
Workpackages (WP): 7-10
Background:
Obesity and comorbid disorders such as type 2 diabetes or steatohepatitis are increasing health problems, and the multifactorial nature of these metabolic diseases has been studied in detail. Although symptoms and conditions vary greatly, many metabolic diseases share one common mechanistic underpinning: dysfunctional communication between peripheral organs and metabolic centers in the CNS. A network of homeostatic and hedonic centers in the CNS tightly controls systemic energy and glucose metabolism.
Main objectives:
The common main objective of all projects within research topic 2 is to unravel molecular mechanisms contributing to impaired cross-talk between peripheral organs and the CNS in obesity and metabolic diseases. More specifically, we aim to:
  • elucidate how CNS-derived signals regulate lipid homeostasis in the liver, and control energy expenditure via induction of thermogenic adipocyte differentiation in depots of white adipose tissue
  • identify altered neural circuits in obese humans using fMRI and novel obesity-induced signals from murine and human adipose tissue regulating brain neurocircuits
  •  characterize the impact of intestinal stem cell recruitment and turnover on metabolism investigate the effects of central insulin on insulin sensitivity in liver and skeletal muscle.

RESEARCH TOPIC 3: Impaired CNS control of metabolism and therapeutic intervention

Leaders: Magdalena Götz & Matthias Tschöp
Workpackages (WP): 11-19
Main objectives:
The main objective of research topic 3 is the discovery of novel therapeutic strategies for the treatment of obesity and diabetes, based on the visualization and dissection of relevant recently emerging (patho-)physiological processes in the CNS. These key processes include for example
a) pathological hypothalamic meta-inflammation
b) cellular edifferentiation versus re-differentiation of cells involved in CNS control of systemic metabolism or
c) novel molecular machinery responsible for hypothalamic hormone and nutrient sensing resistance.

RESEARCH TOPIC 4: Next generation CNS Imaging for metabolic disease

Leader: Jon Shah
Workpackages (WP): 20�������������������������25
Main objectives:
This research topic was designed to move the alliance beyond the current state of the art in a number of very important ways. Comprehensive metabolic imaging is simply not feasible at 3T, the typical clinical field strength. Further, hybrid MR-PET imaging enables the simultaneous measurement of, say, 18F-FDG with PET together with structural / functional / metabolic MRI. The methodology has moved away from standard imaging on clinical 3T systems and standalone PET machine and has focused on UHF-MRI and hybrid MR-PET at 3T. Thus, this research topic has provided a platform for advanced imaging within the alliance enabling a comprehensive metabolic exam of patients to be performed. Structural brain MRI has been used to investigate myelin water using relaxographic techniques at high field and white-matter changes at a microscopic level have also been investigated at 7T. Glutamate has an important role in brain metabolism, and is furthermore the main excitatory neurotransmitter in the brain, whereas GABA is the principle inhibitory neurotransmitter. Both of these substances are detectable with proton MRS. From the methodological standpoint both the MEGA-PRESS and the MEGA-sLASER techniques for generating GABA-edited signals have been implemented and deployed.