The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1
- 2 October 2019
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 68 (12), 2223-2234
- https://doi.org/10.2337/db19-0049
Abstract
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.Keywords
Funding Information
- European Research Council Advanced Grant CHEMSPHINGO
- Dutch Heart Foundation (2009T038)
- Netherlands Cardiovascular Research Initiative (CVON2017-20)
- ZonMW-VENI (91617027)
- AMC
- Dutch Diabetes Research Foundation (91617027)
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