Signaling by insulin-like growth factor 1 in brain

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Abstract

The homologous insulin and insulin-like growth factor (IGF) receptors are both expressed in the brain, in overlapping but distinct neuroanatomical patterns. In contrast to insulin, IGF1 is also highly expressed within the brain and is essential for normal brain development. IGF1 promotes projection neuron growth, dendritic arborization and synaptogenesis. IGF1 acts in an autocrine and/or paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3K)/Akt, also known as protein kinase B (PKB)/glycogen synthase kinase 3β (GSK3β) pathways similar to insulin signaling in peripheral tissues. IGF1 promotes neuronal survival during normal brain development mainly in hippocampal and olfactory systems that depend on postnatal neurogenesis. IGF1's anabolic and neuroprotective roles may be coordinated by inhibition of GSK3β. The identification of GSK3β as a major target of brain IGF1 signaling provides a unifying pathway for IGF1's well-established anabolic and anti-apoptotic functions, with IGF1-induced inhibition of GSK3β triggering multifaceted anabolic and neuroprotective effects.

Section snippets

Insulin and IGF1

Insulin and insulin-like growth factor (IGF) 1 are genetically related polypeptides that have similar tertiary structures and substantial amino acid identity. Insulin is synthesized predominantly in pancreatic beta cells from which its release is regulated by nutrient stimuli. IGF1 is made in great abundance by the liver where its synthesis is stimulated by pituitary growth hormone (GH). IGF1 is also synthesized locally in many tissues, including the brain, where GH does not regulate its

Insulin and IGF1 receptors

Like the cognate peptides, the insulin and IGF1 receptors (Fig. 1) demonstrate close structural homology and sequence identity (LeRoith, 1996). Insulin and IGF1 bind their cognate receptors with highest affinity, but cross-reactivity occurs at higher hormone concentrations. The insulin and IGF1 receptors are receptor tyrosine kinases (RTK) that, after ligand binding induced autophosphorylation, associate with insulin receptor substrate (IRS) adapter proteins. These IRS proteins bind to tyrosine

Sources of brain insulin and IGF1

Circulating insulin and IGF1 may influence hypothalamic neurons by interacting with receptors localized in the median eminence and circumventricular structures outside the blood–brain barrier. Both insulin and IGF1 receptors are expressed on brain capillaries, but IGF1 crosses the blood–brain barrier with significantly greater efficiency than insulin (Reinhardt and Bondy, 1994). After intra-carotid infusion of radiolabeled ligands, 3–4-fold more IGF1 is detected within isocortical parenchyma,

Regulation of brain IGF system expression

While it has been known for many years that IGF1 production in the liver and in some peripheral tissues is regulated by GH, there is virtually no understanding of factors regulating brain IGF1 expression. Nor is there any information on the regulation of brain IGF1 receptor or IGFBP expression. Because the insulin/IGF system is generally responsive to nutritional status Calikoglu et al., 2001, Thissen et al., 1994, we investigated the effects of modest caloric restriction and alteration of

Conclusions

Brain glucose utilization is usually viewed as a barometer of neural activity, but neurons also require glucose to support growth, repair and remodeling processes. We have reviewed evidence that IGF1 promotes brain anabolic activity resulting in increased neuronal survival, process growth and synaptogenesis during early postnatal development. It appears that IGF1 promotes neuronal growth and dendritogenesis by ‘insulin-like’ anabolic effects on glucose utilization and protein synthesis,

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