A voltage-dependent depolarization induced by low external glucose in neurons of the nucleus of the tractus solitarius: interaction with KATP channels.

KEY POINTS: Neurons from the brainstem nucleus of the tractus solitarius (NTS) participate in the counter-regulatory mechanisms in response to hypoglycaemia. ATP-sensitive potassium (KATP ) channels are expressed in NTS neurons, and are partially open at rest in normoglycaemic 5 mM glucose. In normoglycaemic conditions, most NTS neurons depolarize in response to low external glucose (0.5 mM), via a voltage-dependent mechanism. Conversely, most NTS neurons incubated in hyperglycaemic 10 mM glucose do not respond to low glucose due to a more positive resting membrane potential caused by the closure of KATP channels following increased intracellular metabolic ATP. Our findings show that in hyperglycaemic conditions, NTS neurons failed to sense rapid changes in external glucose, which could be related to hypoglycaemia-associated autonomic failure. ABSTRACT: The nucleus of the tractus solitarius (NTS) is an integrative centre for autonomic counter-regulatory responses to hypoglycaemia. KATP channels link the metabolic status of the neuron to its excitability. Here we investigated the influence of KATP channels on the membrane potential of NTS neurons in normo- and hyperglycaemic external glucose concentrations, and after switching to a hypoglycaemic concentration, using in vitro electrophysiological recordings in brainstem slices. We found that in normoglycaemic (5 mM) glucose, tolbutamide, a KATP channel antagonist, depolarized the membrane of most neurons, and this effect was observed in more hyperpolarized neurons. All neurons hyperpolarized after pharmacological activation of KATP channels. Most NTS neurons depolarized in the presence of low glucose (0.5 mM), and this effect was only seen in hyperpolarized neurons. The effect of glucose was caused by a cationic current with a reversal potential around -50 mV. In the presence of hyperglycaemic glucose (10 mM), neurons were more depolarized, and fewer neurons responded to KATP blockage. Application of 0.5 mM glucose solution to these neurons depolarized the membrane only in more hyperpolarized neurons. We conclude that NTS neurons present with KATP channels open at rest in normoglycaemic conditions, and their membrane potential is affected by extracellular glucose. Moreover, NTS neurons depolarize the membrane in response to the application of a low glucose solution, but this effect is occluded by membrane depolarization triggered by KATP blockage. Our data suggest a homeostatic regulation of the membrane potential by external glucose, and a possible mechanism related to the hypoglycaemia-associated autonomic failure.

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension.

Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.