Endothelial Notch signaling controls insulin transport in muscle

Hasan, Sana S.; Jabs, Markus; Taylor, Jacqueline; Wiedmann, Lena; Leibing, Thomas; Nordström, Viola; Federico, Giuseppina; Roma, Letícia Prates; Carlein, Christopher; Wolff, Gretchen; Ekim-Üstünel, Bilgen; Brune, Maik; Moll, Iris; Tetzlaff, Fabian; Gröne, Hermann Josef; Fleming, Thomas; Géraud, Cyrill; Herzig, Stephan; Nawroth, Peter P.; Fischer, Andreas

doi:10.15252/emmm.201809271

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…Mediated by nitric oxide, insulin increases the protein expression and secretion of VEGF ( Doronzo et al, 2004 ). Hasan et al (2020) demonstrated that obesity leads to higher activation of Notch signaling in ECs. This results in decreased insulin sensitivity and lower glucose uptake in the muscles.…”

Section: Metabolic Disorders Related To Obesity and Cardiovascular Comentioning

confidence: 99%

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Herold

Kalucka

2021

Front. Physiol.

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Obesity is a worldwide health problem, and as its prevalence increases, so does the burden of obesity-associated co-morbidities like type 2 diabetes or cardiovascular diseases (CVDs). Adipose tissue (AT) is an endocrine organ embedded in a dense vascular network. AT regulates the production of hormones, angiogenic factors, and cytokines. During the development of obesity, AT expands through the increase in fat cell size (hypertrophy) and/or fat cell number (hyperplasia). The plasticity and expansion of AT is related to its angiogenic capacities. Angiogenesis is a tightly orchestrated process, which involves endothelial cell (EC) proliferation, migration, invasion, and new tube formation. The expansion of AT is accelerated by hypoxia, inflammation, and structural remodeling of blood vessels. The paracrine signaling regulates the functional link between ECs and adipocytes. Adipocytes can secrete both pro-angiogenic molecules, e.g., tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), or vascular endothelial growth factor (VEGF), and anti-angiogenic factors, e.g., serpins. If the pro-angiogenic molecules dominate, the angiogenesis is dysregulated and the endothelium becomes dysfunctional. However, if anti-angiogenic molecules are overexpressed relative to the angiogenic regulators, the angiogenesis is repressed, and AT becomes hypoxic. Furthermore, in the presence of chronic nutritional excess, endothelium loses its primary function and contributes to the inflammation and fibrosis of AT, which increases the risk for CVDs. This review discusses the current understanding of ECs function in AT, the cross-talk between adipose and ECs, and how obesity can lead to its dysfunction. Understanding the interplay of angiogenesis with AT can be an approach to therapy obesity and obesity-related diseases such as CVDs.

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Section: Metabolic Disorders Related To Obesity and Cardiovascular Comentioning

confidence: 99%

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Herold

Kalucka

2021

Front. Physiol.

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“…A recent study showed that Notch signaling in EC was involved in regulating insulin transport across the endothelium to muscle cells. Inhibition of Notch signaling affected caveolae formation in EC and improved insulin sensitivity, glucose tolerance, and glucose uptake in muscle in a high-fat diet model [ 25 ]. In contrast to EC, internalized insulin is degraded in VSMC, and directional transport of intact insulin is not observed.…”

Section: Structure and Signaling Of Insulin Receptors In Ec And Vsmcmentioning

confidence: 99%

Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes

et al. 2021

Molecular Metabolism

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Background Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. Scope of review In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. Major conclusions Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes.

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“…A number of transport mechanisms have been proposed and are disrupted in the obese insulin-resistant state, including fluid-phase, clathrin vesicle and caveolae-mediated transport (83-86) (Figure 2). The molecular mechanisms are discussed in greater detail elsewhere (8,9), however, a role for endothelial Notch signalling in regulating caveolae-mediated transcytosis of insulin has recently been described (83). Sustained Notch signalling was associated with reduced insulin transcytosis as a consequence of reduced caveolae-related gene expression.…”

Section: Trans-endothelial Transport Of Glucosementioning

confidence: 99%

“…Sustained Notch signalling was associated with reduced insulin transcytosis as a consequence of reduced caveolae-related gene expression. Importantly, mice with HFD-induced insulin resistance displayed elevated endothelial Notch activity, that when inhibited, led to a restoration in caveolae-mediated insulin transport and improved glucose tolerance (83).…”

Section: Trans-endothelial Transport Of Glucosementioning

confidence: 99%

Trans-endothelial trafficking of metabolic substrates and its importance in cardio-metabolic disease

Faulkner

2021

Biochemical Society Transactions

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The endothelium acts as a gatekeeper, controlling the movement of biomolecules between the circulation and underlying tissues. Although conditions of metabolic stress are traditionally considered as causes of endothelial dysfunction, a principal driver of cardiovascular disease, accumulating evidence suggests that endothelial cells are also active players in maintaining local metabolic homeostasis, in part, through regulating the supply of metabolic substrates, including lipids and glucose, to energy-demanding organs. Therefore, endothelial dysfunction, in terms of altered trans-endothelial trafficking of these substrates, may in fact be an early contributor towards the establishment of metabolic dysfunction and subsequent cardiovascular disease. Understanding the molecular mechanisms that underpin substrate trafficking through the endothelium represents an important area within the vascular and metabolism fields that may offer an opportunity for identifying novel therapeutic targets. This mini-review summarises the emerging mechanisms regulating the trafficking of lipids and glucose through the endothelial barrier and how this may impact on the development of cardio-metabolic disease.

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Endothelial Notch signaling controls insulin transport in muscle

Cited by 22 publications

References 39 publications

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes

Trans-endothelial trafficking of metabolic substrates and its importance in cardio-metabolic disease

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