title: Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice.
abstract: OBJECTIVE
  Both leptin and insulin sensitivity have been linked with pathophysiological processes involving the central nervous system in general, and the hippocampus in particular, but the role of leptin in hippocampal neurogenesis has not yet been elucidated. Also, no previous studies have evaluated whether amylin or the endogenous insulin sensitiser adiponectin interact with leptin to alter hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells or investigated the role of leptin, amylin or adiponectin signalling in mouse HN cells.
  
  
  METHODS
  Hippocampal neurogenesis and leptin, amylin and adiponectin signalling were studied in vitro using mouse H19-7 HN cell lines.
  
  
  RESULTS
  Amylin decreased cell proliferation in a dose-dependent manner. This effect was diminished by leptin administration and was dependent on signal transducer and activator of transcription 3 (STAT3)/AMP-activated protein kinase (AMPK)/extracellular signal-regulated kinase (ERK). Adiponectin effects were null. We also observed, using immunocytochemical analysis, that amylin decreased activation of microtubule-associated protein 2, a specific neurite outgrowth marker, and synapsin, a specific synaptogenesis marker. By contrast, both effects were attenuated by co-administration of leptin. Finally, we observed that these effects were blocked by pre-treatment with AG490, a STAT3 inhibitor, and STAT3 small interfering RNA administration.
  
  
  CONCLUSIONS
  Our data suggest that amylin in pharmacological concentrations may have a neurotoxic effect whereas leptin in physiological and pharmacological concentrations has a protective effect counteracting amylin-decreased hippocampal neurogenesis via STAT3/AMPK/ERK signalling in mouse H19-7 HN cell lines. Overall, our data support a novel role for leptin and amylin in the processes of mouse hippocampal neurogenesis and provide new insights into the mechanisms of neurogenic regulation.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA.
authors.forename: H-S
authors.initials: HS
authors.lastname: Moon
authors.forename: F
authors.initials: F
authors.lastname: Dincer
authors.forename: C S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases