Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/122704

In Collections

This item can be found in the following collections:

Chao, D.H.M.; Wang, Y.N.; Foppen, E.; Ottenhoff, R.; Roomen, C. van; Parlevliet, E.T.; ... ; Yi, C.X. (2019)

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1

Article / Letter to editor
Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT...Show moreObesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.Show less
All authors
Chao, D.H.M.; Wang, Y.N.; Foppen, E.; Ottenhoff, R.; Roomen, C. van; Parlevliet, E.T.; Eijk, M. van; Verhoek, M.; Boot, R.; Marques, A.R.; Scheij, S.; Mirzaian, M.; Kooijman, S.; Jansen, K.; Wang, D.W.; Mergen, C.; Seeley, R.J.; Tschop, M.H.; Overkleeft, H.; Rensen, P.C.N.; Kalsbeek, A.; Aerts, J.M.F.G.; Yi, C.X.
Date
2019-12-01
Journal
Diabetes
Volume
68
Issue
12
Pages
2223 - 2234
DOI
doi:10.2337/db19-0049