Oleate induces KATP channel-dependent hyperpolarisation in mouse hypothalamic glucose-excited neurones without altering cellular energy charge

Selma Dadak, Craig Beall, Julia M. Vlachaki Walker, Marc P. M. Soutar, Rory J. McCrimmon, Michael L. J. Ashford (Lead / Corresponding author)

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7 Citations (Scopus)
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Abstract

The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurones) and mouse arcuate nucleus (ARC) neurones. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate and glucose sensing properties of mouse hypothalamic neurones. Oleate or lowered glucose concentration caused hyperpolarisation and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K+ channels (KATP). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of KATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarised a subpopulation of ARC GE neurones by KATP activation. Additionally, in a separate small population of ARC neurones, oleate application or lowered glucose concentration caused membrane depolarisation. In conclusion, oleate induces KATP-dependent hyperpolarisation and inhibition of firing of a subgroup of GE hypothalamic neurones without altering cellular energy charge.
Original languageEnglish
Pages (from-to)29-42
Number of pages14
JournalNeuroscience
Volume346
Early online date9 Jan 2017
DOIs
Publication statusPublished - 27 Mar 2017

Keywords

  • Glucose sensing
  • KATP
  • Oleate
  • Hypothalamus
  • Mitochondria
  • Fatty acid oxidation

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