Glycosphingolipids and the central regulation of metabolism Sugar analogues as research tools

This thesis describes different studies using sugar analogues to investigate the impact of glycosphingolipid metabolism, in different brain structures involved in the development of α-synucleinopathies and the control of energy homeostasis. Part I comprises several novel approaches to visualize and manipulate different lysosomal and non-lysosomal glycosidases using activity-based probes (cyclophellitol-epoxide type ABPs) capable of selectively labeling active glucocerebrosidase (GBA) or active GBA and glucocerebrosidase 2 together (cyclophellitol-aziridine type ABPs). Special attention is dedicated to the visualization of active GBA and Galactosylceramidase in the brain, in view of their major role in the development of Gaucher disease and Krabbe disease, respectively. Part 2 investigates the use of sugar analogues as beneficial pharmacological agents for the treatment of obesity and type 2 diabetes. These studies focus on the pleotropic effects of N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) in lean and obese rodents on energy metabolism, with an emphasis on the brain mechanisms involved. Evidence is presented for an endocrine-brain axis mediating the satiety and metabolic effects of AMP-DNM with a major role for the Glucagon-like peptide-1 pathway and taste receptors in the gut. In conclusion, sugar analogues can be useful tools for fundamental research and are meaningful candidate drugs to be applied in the clinic to diagnose lysosomal storage diseases or to treat metabolic syndrome. The major role for the brain in mediating the potent effects of the distinct sugar analogues, indicates that future research should be aimed specifically at brain/periphery interventions to modulate different metabolic needs involved in neuropathy and the control of energy metabolism.