Increased uncoupling protein (UCP) activity in Drosophila insulin-producing neurons attenuates insulin signaling and extends lifespan.
To understand the role of mitochondrial uncoupling protein (UCP) in regulating insulin signaling and glucose homeostasis, we created transgenicDrosophila lines with targeted UCP expression in insulin producing cells (IPCs). Increased UCP activity in IPCs results in decreased steady state Ca(2+) levels in IPCs as well as decreased PI3K activity and increased FoxO nuclear localization in periphery. This reduced systemic insulin signaling is accompanied by a mild hyperglycemia and extended life span. To test the hypothesis that ATP-sensitive potassium (K(ATP)) channels may link changes in metabolic activity (e.g., glucose mediated ATP production or UCP-mediated ATP reduction) with insulin secretion, we characterized the effects of glucose and a specific K(ATP) channel blocker, glibenclamide on membrane potential in adult IPCs. Exposure to glucose depolarizes membrane potential of IPCs and this effect is mimicked with glibenclamide, suggesting that K(ATP) channels contribute to the mechanism whereby IPCs sense changes in circulating sugar. Further, as demonstrated in mammalian beta-pancreatic cells, high glucose initiates a robust Ca(2+) influx in adult IPCs. The presence of functional K(ATP) channels in adult IPCs is further substantiated by in situ hybridization detecting the transcript for the sulfonylurea receptor (Sur) subunit of the K(ATP) channel in those cells. Quantitative expression analysis demon-strates a reduction in transcripts for both Sur and the inward rectifying potassium channel (Kir) subunits when IPCs are partially ablated. In summary, we have demonstrated a role for UCP in adult Drosophila IPCs in influencing systemic insulin signaling and longevity by a mechanism that may involve K(ATP) channels.
Fridell
Yih-Woei C
YW
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA. woei.fridell@uconn.edu
Hoh
Melissa
M
Kréneisz
Orsolya
O
Hosier
Suzanne
S
Chang
Chengyi
C
Scantling
Dane
D
Mulkey
Daniel K
DK
Helfand
Stephen L
SL
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005905:Glyburide / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D008136:Longevity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D015398:Signal Transduction; D064233:Sulfonylurea Receptors; D000071256:Uncoupling Protein 1
D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D007473:Ion Channels; D054086:KATP Channels; D024101:Mitochondrial Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000071256:Uncoupling Protein 1; C577513:sulfonylurea receptor, Drosophila; D019869:Phosphatidylinositol 3-Kinases; D005905:Glyburide; D002118:Calcium