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) neurons) and mouse arcuate nucleus (
ARC) neurons. 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 neurons.
Oleate or lowered
glucose concentration caused hyperpolarization 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 hyperpolarized a subpopulation of
ARC GE neurons by KATP activation. Additionally, in a separate small population of
ARC neurons,
oleate application or lowered
glucose concentration caused membrane depolarization. In conclusion,
oleate induces KATP-dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge.