Impaired brain glucose metabolism in glucagon-like peptide-1 receptor knockout mice

Background: Quantitative mapping of the brain's metabolism is a critical tool in studying and diagnosing many conditions, from obesity to neurodegenerative diseases. In particular, noninvasive approaches are urgently required. Recently, there have been promising drug development approaches for the treatment of disorders related to glucose metabolism in the brain and, therefore, against obesity-associated diseases. One of the most important drug targets to emerge has been the Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R). GLP and GLP-1R play an important role in regulating blood sugar and maintaining energy homeostasis. However, the macroscopic effects on brain metabolism and function due to the presence of GLP-1R are unclear.

Methods: To explore the physiological role of GLP-1R in mouse brain glucose metabolism, and its relationship to brain function, we used three methods. We used deuterium magnetic resonance spectroscopy (DMRS) to provide quantitative information about metabolic flux, fluorodeoxyglucose positron emission tomography (FDG-PET) to measure brain glucose metabolism, and resting state-functional MRI (rs-fMRI) to measure brain functional connectivity. We used these methods in both mice with complete GLP-1R knockout (GLP-1R KO) and wild-type C57BL/6N (WT) mice.

Results: The metabolic rate of GLP-1R KO mice was significantly slower than that of WT mice (p = 0.0345, WT mice 0.02335 ± 0.057 mM/min, GLP-1R KO mice 0.01998 ± 0.07 mM/min). Quantification of the mean [¹⁸F]FDG signal in the whole brain also showed significantly reduced glucose uptake in GLP-1R KO mice versus control mice (p = 0.0314). Observing rs-fMRI, the functional brain connectivity in GLP-1R KO mice was significantly lower than that in the WT group (p = 0.0032 for gFCD, p = 0.0002 for whole-brain correlation, p < 0.0001 for ALFF).

Conclusions: GLP-1R KO mice exhibit impaired brain glucose metabolism to high doses of exogenous glucose, and they also have reduced functional connectivity. This suggests that the GLP-1R KO mouse model may serve as a model for correlated metabolic and functional connectivity loss.