TY - JOUR
T1 - The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1
AU - Herrera Moro Chao, Daniela
AU - Wang, Yanan
AU - Foppen, Ewout
AU - Ottenhoff, Roelof
AU - van Roomen, Cindy
AU - Parlevliet, Edwin T.
AU - van Eijk, Marco
AU - Verhoek, Marri
AU - Boot, Rolf
AU - Marques, Andre R.
AU - Scheij, Saskia
AU - Mirzaian, Mina
AU - Kooijman, Sander
AU - Jansen, Kirstin
AU - Wang, Dawei
AU - Mergen, Clarita
AU - Seeley, Randy J.
AU - Tschöp, Matthias H.
AU - Overkleeft, Herman
AU - Rensen, Patrick C. N.
AU - Kalsbeek, Andries
AU - Aerts, Johannes M. F. G.
AU - Yi, Chun-Xia
PY - 2019
Y1 - 2019
N2 - 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 through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.
AB - 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 through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85075813215&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31578192
U2 - https://doi.org/10.2337/db19-0049
DO - https://doi.org/10.2337/db19-0049
M3 - Article
C2 - 31578192
SN - 0012-1797
VL - 68
SP - 2223
EP - 2234
JO - Diabetes
JF - Diabetes
IS - 12
ER -