Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin.
The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.
Cai
Fang
F
Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Gyulkhandanyan
Armen V
AV
Wheeler
Michael B
MB
Belsham
Denise D
DD
D055372:AMP-Activated Protein Kinases; D045744:Cell Line, Tumor; D002999:Clone Cells; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology*; D008858:Microscopy, Phase-Contrast; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
D007328:Insulin; D020738:Leptin; D009097:Multienzyme Complexes; D015221:Potassium Channels; D011333:Pro-Opiomelanocortin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose