The role of insulin receptor signaling in the brain

Plum, Leona; Schubert, Markus; Brüning, Jens C.

doi:10.1016/j.tem.2005.01.008

Cited by 523 publications

(391 citation statements)

References 80 publications

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“…By contrast, brain-specific insulin receptor knockout mice exhibit hyperphagia and obesity (46). Insulin signaling also controls peripheral glucose metabolism and insulin sensitivity by regulating hepatic glucose production (17). Although the exact nature of insulin resistance in the CNS is not clear, our finding of insulin signal impairment in cholesterol-depleted neuron-derived cells suggests another mechanism by which insulin deficiency in the CNS can augment the effect of diabetes on brain dysfunction.…”

Section: Discussionmentioning

confidence: 80%

“…Although neurons were once regarded as insulinindependent tissues, it is now clear that the brain is an insulinresponsive tissue and that neurons express insulin receptors and many components of their downstream signaling pathways (13,14). Studies using intracerebroventricular injection of insulin and techniques to knock down or knock out insulin signaling proteins have shown that insulin action in the CNS plays an important role in energy homeostasis (15), learning and memory (16), and peripheral glucose metabolism (17). Insulin also has a neurotrophic function (18,19), and insulin signaling in the brain has been shown to be altered in Alzheimer disease (20,21).…”

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confidence: 99%

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Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Fukui¹,

Ferris²,

Kahn

2015

Journal of Biological Chemistry

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Background: Cholesterol synthesis is decreased in the brain in diabetes. Results: Cholesterol depletion in neuron-derived cells results in impaired insulin/IGF-1 and neurotrophin signaling and altered apoptosis. Conclusion: Reduction of cellular cholesterol in diabetes causes defects in signal transduction and function in neuron-derived cells. Significance: Reduced brain cholesterol could contribute to the higher prevalence of cognitive dysfunction and Alzheimer disease in diabetes.

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Fukui¹,

Ferris²,

Kahn

2015

Journal of Biological Chemistry

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“…Efficient signaling by leptin and insulin is essential for the maintenance of body energy homeostasis, with disruptions in these processes strongly associated with diabetes and obesity (1,2) and, at least for insulin, neurodegenerative disorders such as Alzheimer disease (3,4). In recent years there has been a significant increase in understanding the intracellular signaling processes associated with the actions of insulin on a wide variety of cell types (5).…”

mentioning

confidence: 99%

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Ning

Miller

Laidlaw

et al. 2009

Journal of Biological Chemistry

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Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic ␤-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptinmediated F-actin depolymerization and consequent ATP-sensitive K ؉ channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones.Efficient signaling by leptin and insulin is essential for the maintenance of body energy homeostasis, with disruptions in these processes strongly associated with diabetes and obesity (1, 2) and, at least for insulin, neurodegenerative disorders such as Alzheimer disease (3, 4). In recent years there has been a significant increase in understanding the intracellular signaling processes associated with the actions of insulin on a wide variety of cell types (5). However, our knowledge of leptin signaling is less advanced, with most studies indicating that leptin and insulin share many signaling intermediates in common, often leading to similar cellular outcomes (6, 7). In particular, signaling through the STAT (signal transducers and activators of transcription), mitogen-activated protein kinase, and PI3K 3 pathways have been reported extensively in numerous cell types for both leptin and insulin (5, 8).Nevertheless, leptin and insulin can cause differing and sometimes opposing cellular outputs, even on the same cell type. This is demonstrated in hypothalamic neurons, where electrophysiological or imaging studies show differential outcomes for leptin and insulin action (9 -11). Thus, although superficially leptin may utilize the same signaling pathways as insulin, the exact nature of the leptin-induced signaling intermediates and their interplay with one another and with individual effectors is still relatively unknown. Recently, it was demonstrated that although leptin, lik...

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“…Indeed, recent studies have demonstrated that insulin regulates several processes in the brain, including food intake, energy homeostasis, reproductive endocrinology, synaptic plasticity and neuronal survival [132][133][134][135] . Moreover, systemic infusion of insulin in healthy humans promotes learning and memory 136 .…”

Section: Insulin In the Brainmentioning

confidence: 99%

Efficient non-viral transfection of adult neural stem/progenitor cells, without affecting viability, proliferation or differentiation

2005

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Stroke is one of the leading causes of chronic disability and death in the Western world. Today, no treatment can repair the cellular loss associated with an ischemic lesion. However, the discovery and dynamic regulation of neural stem/progenitor cells in the adult mammalian brain has resulted in exciting possibilities for future therapeutic interventions. Endogenous or grafted neural stem/progenitor cells are activated following an ischemic insult. These cells undergo directed migration towards infarcted areas, and differentiate in response to the insult. Unfortunately, the results of this regenerative effort are limited compared to the amount of tissue loss. This could be due to low survival of the recruited cells, but could also be explained by insufficient activation or dysfunctional lineage selection. Whether the lineage selection of neural stem/progenitor cells is altered following a lesion in the brain, what signals that are responsible for their activation or whether these cells can participate in post-lesion regeneration, astrogliosis or neuroprotection have yet to become clear. A greater understanding of these processes is necessary for finding ways to improve the endogenous regenerative capacity. We found that reactive astrocytes, a prominent part of the post-ischemic environment, induced astroglial differentiation of adult neural stem/progenitor cells in vitro. Moreover, astrocytes derived from these cells were shown to participate in glial scar formation in vitro. After studying gene expression in the peri-infarct region following focal ischemia, the expression of several genes was induced. We chose to focus our attention on one of these genes and its product, thyrotropin-releasing hormone (TRH). Immunoreactivity for TRH was found in several areas in both lesioned and intact brain regions, including in microglia present in the areas surrounding the lesion. Furthermore, TRH receptors were expressed on cultured neural stem/progenitor cells and TRH potently induced the proliferation of these cells. TRH is an interesting target for stroke treatment, but it also has many central effects in the brain and systemic administration may prove problematic. An interesting protocol for local delivery of TRH would be by grafting stem/progenitor cells, genetically engineered to secrete the peptide. In order to create a foundation for neuroprotective gene therapy, we developed efficient methods for non-viral transfection of neural stem/progenitor cells. Since neural stem/progenitor cells migrate towards the ischemic area we wanted to investigate whether these cells secreted factors that could protect neurons against excitotoxicity, the main inducer of cell death following a stroke. Mass spectrometric analysis of factors secreted from cultured neural stem/progenitor cells led to the identification of a novel neuroprotective peptide, which we termed pentinin. This peptide potently reduced excitotoxicity in both mature and immature neurons in an ex vivo hippocampal slice model. The results presented in this the...

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The role of insulin receptor signaling in the brain

Cited by 523 publications

References 80 publications

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Efficient non-viral transfection of adult neural stem/progenitor cells, without affecting viability, proliferation or differentiation

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