Liraglutide (Victoza®) is a once-daily glucagon-like peptide-1 (GLP-1) mimetic currently prescribed as a therapy for type-2 diabetes(Reference Knudsen1). Liraglutide mimics all of the glucoregulatory, insulin-releasing and extra-pancreatic actions of GLP-1, especially the glucose-dependent stimulation of insulin secretion(Reference Lovshin and Drucker2). Recent studies have shown that Liraglutide crosses the blood-brain-barrier when administered peripherally(Reference McClean, Gault and Harriott3) and GLP-1R deficient mice exhibit impaired memory and learning(Reference Abbas, Faivre and Holscher4). Therefore, the present study examined the effects of daily treatment with Liraglutide on the cognitive function in an animal model of diet-induced obesity which exhibits compromised cognitive performance.
Young Swiss TO mice (6–8 weeks old; n 10 per group) maintained on high-fat diet (45% fat, 20% protein and 35% carbohydrate) for 20 weeks received twice-daily injections of Liraglutide (200 μg/kg bw; sc) or saline vehicle over 28 d. An additional group of mice on standard diet (10% fat, 30% protein, 60% carbohydrate) received twice-daily saline injections. Energy intake, bodyweight and plasma glucose and insulin concentrations were monitored at regular intervals. Glucose tolerance, open field assessment, object recognition testing and electrophysiological long-term potentiation (LTP) were performed at the termination of the study.
Treatment with Liraglutide significantly reduced bodyweight (1.1-fold; P<0.05) and energy intake (1.5-fold; P<0.01), while improving non-fasting glucose (50–230% reduction; P<0.01 to P<0.001), insulin (30–50% increase; P<0.05 to P<0.01) and normalising glucose tolerance (40–50% improvement; P<0.05) compared to high fat controls. During the object recognition trial, mice on high-fat diet demonstrated a significant decrease in recognition index (RI), whereas mice treated with Liraglutide exhibited a significant increase in RI (1.4-fold; P<0.05) indicative of enhanced memory and learning ability. Interestingly, the RI for Liraglutide-treated mice was broadly similar to that observed for healthy age-matched normal mice, highlighting a reversal in the cognitive decline following Liraglutide treatment in this model. In vivo hippocampal LTP was completely abolished following high-fat diet. However, daily treatment with Liraglutide ameliorated (P<0.001 to P<0.0001) the detrimental effects of high-fat diet on LTP formation and maintenance.
In conclusion, this study demonstrates that prolonged GLP-1R activation with Liraglutide exhibits beneficial effects on the cognitive function and hippocampal synaptic plasticity in a mouse model of high-fat diet-induced obesity. Given the increasing awareness of a negative impact of obesity-diabetes on brain function, possible protective effects of GLP-1 mimetics on cognitive parameters need to be assessed in the rising numbers of obese type-2 diabetes patients taking incretin therapeutics.
