Abstract
Neuronal loss alongside altered energy metabolism, are key features of Huntington’s disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 µg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD.
Highlights
Huntington’s disease (HD) is an autosomal dominant polyglutamine expansion disease[1], associated with neuronal loss[2]
As a catabolic state is present in human HD35,36 and HD mouse models[32], this suggests that normalization of energy metabolism might be beneficial
The R6/2 mouse model is the most widely used model of HD32, replicating many features seen in human patients, including weight loss due to increased energy metabolism[37]
Summary
Huntington’s disease (HD) is an autosomal dominant polyglutamine expansion disease[1], associated with neuronal loss[2]. A dysfunctional central energy metabolism is thought to promote neurodegenerative processes in HD10. This is in line with growing evidence demonstrating that many neurodegenerative disorders are metabolic diseases, mediated by impairments in brain energy metabolism, including insulin responsiveness and glucose utilization (reviewed in[11,12]). Peripheral and central energy metabolism are affected by gut peptide hormones, such as glucagon-like peptide-1 (GLP-1) and ghrelin (reviewed in[13]). GLP-1 mimetics (such as exendin-4 and liraglutide) have been shown to exert neuroprotective effects, being beneficial in Parkinson’s disease (PD)[16], Huntington’s disease (HD)[17] and Alzheimer’s disease (AD)[18] mouse models, and in clinical studies involving PD and AD patients[19]. We hypothesize that peripheral injection of liraglutide, together with the orexigenic peptide hormone ghrelin, would maintain body weight and protect against brain/cognitive dysfunction in HD
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