Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons.
Insulin plays a key role in the maintenance of nutrient homeostasis through central regulation of neuropeptides. Neuropeptide Y (NPY) and agouti-related peptide (AgRP) are vital orexigenic peptides that are regulated by insulin, although the processes utilized are unknown. Using a hypothalamic, clonal cell line, mHypoE-46, which endogenously expresses NPY, AgRP and the insulin receptor, we studied the mechanisms involved in the regulation of the NPY/AgRP neuron by insulin. We determined that insulin has direct actions on the neurons and acts to repress NPY/AgRP gene expression through a MAPK MEK/ERK-dependent pathway. Transient transfection analysis determined that human NPY and AgRP 5' flanking gene regions were not regulated by insulin in the mouse cell line, while sequence comparison analysis indicated only a 50% sequence similarity between human and mouse NPY and AgRP 5' flanking regions. These experiments indicate that insulin acts directly on specific hypothalamic neurons to regulate neuropeptide transcription.
Mayer
Christopher M
CM
Department of Physiology, University of Toronto, Toronto, ON, Canada.
Belsham
Denise D
DD
D024506:5' Flanking Region / Q000235:genetics; D054369:Agouti-Related Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007031:Hypothalamus / Q000166:cytology*; D007328:Insulin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
D054369:Agouti-Related Protein; D002070:Butadienes; D007328:Insulin; D009478:Neuropeptide Y; D009570:Nitriles; C113580:U 0126; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases