Leptin is an
adipokine produced by the adipose tissue regulating
body weight through its appetite-suppressing effect and, as such, exerts a relevant action on the adipo-adrenal axis.
Leptin has a dual action on adrenal mouse chromaffin cells both at rest and during stimulation. At rest, the
adipokine inhibits the spontaneous firing of most cells by enhancing the probability of
BK channel opening through the
phosphoinositide 3-kinase signalling cascade. This inhibitory effect is absent in db(-) /db(-) mice deprived of Ob receptors. During sustained stimulation,
leptin preserves cell excitability by generating well-adapted action potential (AP) trains of lower frequency and broader width and increases
catecholamine secretion by increasing the size of the ready-releasable pool and the rate of vesicle release. In conclusion,
leptin dampens AP firing at rest but preserves AP firing and enhances
catecholamine release during sustained stimulation, highlighting the importance of the adipo-adrenal axis in the
leptin-mediated increase of sympathetic tone and
catecholamine release.
ABSTRACT:
Leptin is an
adipokine produced by the adipose tissue regulating
body weight through its appetite-suppressing effect. Besides being expressed in the hypothalamus and hippocampus,
leptin receptors (ObRs) are also present in chromaffin cells of the adrenal medulla. In the present study, we report the effect of
leptin on mouse chromaffin cell (MCC) functionality, focusing on cell excitability and
catecholamine secretion. Acute application of
leptin (1 nm) on spontaneously firing MCCs caused a slowly developing membrane hyperpolarization followed by complete blockade of action potential (AP) firing. This inhibitory effect at rest was abolished by the
BK channel blocker
paxilline (1 μm), suggesting the involvement of BK
potassium channels. Single-channel recordings in 'perforated microvesicles' confirmed that
leptin increased
BK channel open probability without altering its unitary conductance.
BK channel up-regulation was associated with the
phosphoinositide 3-kinase (PI3K) signalling cascade because the PI3K specific inhibitor
wortmannin (100 nm) fully prevented BK current increase. We also tested the effect of
leptin on evoked AP firing and Ca(2+) -driven exocytosis. Although
leptin preserves well-adapted AP trains of lower frequency, APs are broader and depolarization-evoked exocytosis is increased as a result of the larger size of the ready-releasable pool and higher frequency of vesicle release. The kinetics and quantal size of single secretory events remained unaltered.
Leptin had no effect on firing and secretion in db(-) /db(-) mice lacking the ObR gene, confirming its specificity. In conclusion,
leptin exhibits a dual action on MCC activity. It dampens AP firing at rest but preserves AP firing and increases
catecholamine secretion during sustained stimulation, highlighting the importance of the adipo-adrenal axis in the
leptin-mediated increase of sympathetic tone and
catecholamine release.