Background Huntington’s disease (HD) is a polyglutamine expansion disease associated with striatal and cortical neuronal loss, and with type 2 diabetes (T2D) features. Thus, an efficient anti-T2D drug – liraglutide - may protect against HD. But, as cachexia may occur in HD and liraglutide is also anorectic, a peripheral (co-) administration of liraglutide with the orexigenic ghrelin may protect against brain/cognitive dysfunction in HD.
Aims We studied the role of subcutaneous (sc) (co-)injection of liraglutide plus ghrelin in brain metabolic markers and motor/cognitive dysfunction in HD.
Methods Brain cortices from 12 week-old R6/2 and WT mice sc-treated with liraglutide and/or ghrelin (2 weeks) were used to measure cAMP, insulin, glucose, cholesterol, free-fatty acids (FFA), triglycerides and caspase-3 activity. Motor/exploratory activity was given by open-field test.
Results Liraglutide alone or plus ghrelin rescued body weight loss, lowered fat mass and peripheral T2D features in HD mice.
Brains from saline-treated R6/2 mice had higher cAMP and insulin, and lower glucose levels, suggesting either a brain insulin/GLP-1 resistance and/or a local stimulation of glucose metabolism (e.g. towards triglyceride synthesis). They may be also using FFA as alternative fuels (via degradation by Krebs cycle or β-oxidation) and cholesterol to maintain lipid rafts within brain. Though brain caspase-3 was slightly inhibited, exploratory activity was lower in R6/2 mice.
Liraglutide alone increased whereas together with ghrelin decreased brain cAMP levels in R6/2 mice. Liraglutide alone or plus ghrelin lowered their brain insulin levels, suggesting a recovery from insulin resistance. Liraglutide alone slightly increased R6/2 mouse brain glucose and lowered triglycerides and FFA, whereas liraglutide plus ghrelin slightly lowered their brain glucose, triglycerides, FFA and cholesterol levels. This suggested a liraglutide induction of glucose (energy) metabolism, protecting R6/2 mice from caspase-3 activation and restoring their exploratory behaviour. When added with ghrelin, liraglutide’s beneficial effects were not potentiated.
Conclusions Liraglutide plus ghrelin had anti-T2D effects in HD. Liraglutide alone rescued brain insulin resistance, caspase-related apoptosis and motor impairment.
This work was supported by European funds from FEDER, through the Programa Operacional Factores de Competitividade – COMPETE 2020; by a Seed Fund from European Huntington’s Disease Network; by Portuguese funds from FCT – Fundação para a Ciência e a Tecnologia (PTDC/SAU-TOX/117481/2010); and by European Social Fund: Fellowship SFRH/BPD/84473/2012 to A. I. Duarte).
- Liraglutide and ghrelin