Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Gruber T

PROVIDER: S-EPMC8183500 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Gruber Tim T Pan Chenchen C Contreras Raian E RE Wiedemann Tobias T Morgan Donald A DA Skowronski Alicja A AA Lefort Sandrine S De Bernardis Murat Cahuê C Le Thuc Ophelia O Legutko Beata B Ruiz-Ojeda Francisco J FJ Fuente-Fernández María de la M García-Villalón Angel Luis AL González-Hedström Daniel D Huber Melanie M Szigeti-Buck Klara K Müller Timo D TD Ussar Siegfried S Pfluger Paul P Woods Steve C SC Ertürk Ali A LeDuc Charles A CA Rahmouni Kamal K Granado Miriam M Horvath Tamas L TL Tschöp Matthias H MH García-Cáceres Cristina C

Cell metabolism 20210504 6

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 m ...[more]

PMID: 33951475

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Project description:PurposeMaternal obesity has emerged as an important risk factor for the development of metabolic disorders in the offspring. The hypothalamus as the center of energy homeostasis regulation is known to function based on complex neuronal networks that evolve during fetal and early postnatal development and maintain their plasticity into adulthood. Development of hypothalamic feeding networks and their functional plasticity can be modulated by various metabolic cues, especially in early stages of development. Here, we aimed at determining the underlying molecular mechanisms that contribute to disturbed hypothalamic network formation in offspring of obese mouse dams.MethodsFemale mice were fed either a control diet (CO) or a high-fat diet (HFD) after weaning until mating and during pregnancy and gestation. Male offspring was sacrificed at postnatal day (P) 21. The hypothalamus was subjected to gene array analysis, quantitative PCR and western blot analysis.ResultsP21 HFD offspring displayed increased body weight, circulating insulin levels, and strongly increased activation of the hypothalamic insulin signaling cascade with a concomitant increase in ionized calcium binding adapter molecule 1 (IBA1) expression. At the same time, the global gene expression profile in CO and HFD offspring differed significantly. More specifically, manifest influences on several key pathways of hypothalamic neurogenesis, axogenesis, and regulation of synaptic transmission and plasticity were detectable. Target gene expression analysis revealed significantly decreased mRNA expression of several neurotrophic factors and co-factors and their receptors, accompanied by decreased activation of their respective intracellular signal transduction.ConclusionTaken together, these results suggest a potential role for disturbed neurotrophin signaling and thus impaired neurogenesis, axogenesis, and synaptic plasticity in the pathogenesis of the offspring's hypothalamic feeding network dysfunction due to maternal obesity.

Dataset Information

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

Publications

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

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