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

Daniela Herrera Moro Chao, Yanan Wang, Ewout Foppen, Roelof Ottenhoff, Cindy van Roomen, Edwin T Parlevliet, Marco van Eijk, Marri Verhoek, Rolf Boot, Andre R Marques, Saskia Scheij, Mina Mirzaian, Sander Kooijman, Kirstin Jansen, Dawei Wang, Clarita Mergen, Randy J Seeley, Matthias H Tschöp, Herman Overkleeft, Patrick C N RensenAndries Kalsbeek, Johannes M F G Aerts, Chun-Xia Yi

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Abstract

Obesity is taking worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar 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.

Original languageEnglish
Pages (from-to)2223-2234
JournalDiabetes
Volume68
DOIs
Publication statusPublished - 2019

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