title: Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.
abstract: The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3β. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Pathak
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pathak
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Lynch
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
authors.forename: N
authors.initials: N
authors.lastname: Irwin
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK. Electronic address: va.gault@ulster.ac.uk.
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D000089622:Doublecortin Domain Proteins; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D002149:Energy Intake / Q000187:drug effects; D005768:Gastrointestinal Hormones / Q000494:pharmacology*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C000607531:(Ser2)Oxm(Lys38-gamma-Glu-PAL); D001786:Blood Glucose; D000089622:Doublecortin Domain Proteins; D005768:Gastrointestinal Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides
keywords: Cognition; Glucagon-like peptide-1; Hippocampus; Oxyntomodulin; Oxyntomodulin analogues