High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner.

Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.

Astrocyte Gliotransmission in the Regulation of Systemic Metabolism.

Normal brain function highly relies on the appropriate functioning of astrocytes. These glial cells are strategically situated between blood vessels and neurons, provide significant substrate support to neuronal demand, and are sensitive to neuronal activity and energy-related molecules. Astrocytes respond to many metabolic conditions and regulate a wide array of physiological processes, including cerebral vascular remodeling, glucose sensing, feeding, and circadian rhythms for the control of systemic metabolism and behavior-related responses. This regulation ultimately elicits counterregulatory mechanisms in order to couple whole-body energy availability with brain function. Therefore, understanding the role of astrocyte crosstalk with neighboring cells via the release of molecules, e.g., gliotransmitters, into the parenchyma in response to metabolic and neuronal cues is of fundamental relevance to elucidate the distinct roles of these glial cells in the neuroendocrine control of metabolism. Here, we review the mechanisms underlying astrocyte-released gliotransmitters that have been reported to be crucial for maintaining homeostatic regulation of systemic metabolism.

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.

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.

Mechanism of Action of Novel Glibenclamide Derivatives on Potassium and Calcium Channels for Insulin Secretion.

Glibenclamide is widely used and remains a cornerstone and an effective antihyperglycemic drug. After the casual discovery of its hypoglycemic potential, this compound was introduced for diabetes treatment. However, the long-term side effects reveal that glibenclamide should be replaced by new molecules able to maintain the health of ß-cells, protecting them from hyperstimulation/hyperexcitability, hyperinsulinemia, functional failure and cell death. The aim of this review was to highlight the main mechanism of action of glibenclamide and the influence of its derivatives, such as acylhydrazones, sulfonamides and sulfonylthioureas on ß-cells potassium and calcium channels for insulin secretion as well as the contribution of these new compounds to restore glucose homeostasis. Furthermore, the role of glibenclamide-based novel structures that promise less excitability of ß-cell in a long-term treatment with effectiveness and safety for diabetes therapy was discussed.

Differential expression of genes encoding proteins of the HGF/MET system in insulinomas.

BACKGROUND: Insulinomas are the most common functional pancreatic neuroendocrine tumors, whereas histopathological features do not predict their biological behaviour. In an attempt to better understand the molecular processes involved in the tumorigenesis of islet beta cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two inhibitors of HGF activator and of matriptase). METHODS: Quantitative real-time reverse transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes in 24 sporadic insulinomas: 15 grade 1 (G1), six grade 2 (G2) and three hepatic metastases. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. RESULTS: Overexpression of MET was observed in the three hepatic metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. A positive correlation was observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. CONCLUSION: The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoral progression and metastatization in insulinomas.