Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice.
OBJECTIVE
Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic (ob/ob) mice.


RESULTS
Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2 consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feeding bouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide.


CONCLUSIONS
Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival.
Diabetes Research Group, The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
W D
WD
Porter
P R
PR
Flatt
C
C
Hölscher
V A
VA
Gault
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects; D059305:Diet, High-Fat; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000069450:Liraglutide; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects; D015398:Signal Transduction; D020813:Receptor, trkB
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; C499317:Ascl1 protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB