Priority Research Paper Volume 1, Issue 8 pp 699—713
Increased uncoupling protein (UCP) activity in Drosophila insulin-producing neurons attenuates insulin signaling and extends lifespan
- 1 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA
- 2 Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA
- 3 Current address: Department of Allied Health Sciences, University of Connecticut, Storrs, CT 06269, USA
received: June 18, 2009 ; accepted: July 19, 2009 ; published: July 21, 2009 ;https://doi.org/10.18632/aging.100067
How to Cite
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 Ca2+ 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 (KATP) 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 KATP 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 KATP channels contribute to the mechanism whereby IPCs sense changes in circulating sugar. Further, as demonstrated in mammalian β-pancreatic cells, high glucose initiates a robust Ca2+ influx in adult IPCs. The presence of functional KATP channels in adult IPCs is further substantiated by in situ hybridization detecting the transcript for the sulfonylurea receptor (Sur) subunit of the KATP 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 KATP channels.