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The many faces of insulin-like peptide signalling in the brain

Nature Reviews Neuroscience volume 13, pages 225–239 (2012)Cite this article

Subjects

Key Points

  • Insulin-like peptides (ILPs), which comprise insulin, insulin-like growth factor 1 (IGF1) and IGF2, influence overall brain development by affecting proliferation, survival and differentiation of brain cells and by having modulatory roles in the refinement of brain circuitries.

  • Peripheral ILPs enter the brain through the blood–cerebrospinal fluid barrier and blood–brain barrier in a tonic fashion (dependent on circulating levels) and in a phasic manner according to local brain activity.

  • The adult brain is a major target of ILPs; here, they act as modulators of synaptic plasticity to orchestrate and control energy allocation.

  • We propose that central and peripheral ILPs cooperate as a functional network in brain physiology and disease.

Abstract

Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis — they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation.

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Figure 1: Distribution of insulin and insulin-like growth factor receptors in the brain.
Figure 2: Signalling pathways.
Figure 3: Peripheral ILPs enter the brain.
Figure 4: Spatial compartmentalization of ILPs in the brain.
Figure 5: IGF1 in brain development.
Figure 6: Modulation of synaptic plasticity by ILPs.

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Acknowledgements

We acknowledge past members of the laboratory for their important contributions to work cited in this Review. We apologize to authors whose work is not included owing to space limitations.

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  1. Cajal Institute, CSIC and Ciberned, Avenida Doctor Arce, 37, Madrid, 28002, Spain

    Ana M. Fernandez & Ignacio Torres-Alemán

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Ignacio Torres-Alemán owns shares in spin-off companies involved in developing drugs for neurodegenerative diseases. Ana M. Fernandez declares no competing financial interests.

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Glossary

Transcytosis

Regulated endocytosis and transport of molecules from one side of the cell to the other for their eventual release.

Neurovascular coupling

A process by which brain activity is coupled to blood flow to assure proper nutrient and oxygen supply.

Tanycytes

Ependymal cells located in the floor of the third ventricle that have processes extending deep into the hypothalamus.

Insulin receptor substrates

(IRSs). A family of large docking proteins for tyrosine kinase receptors, including insulin and IGF1 receptors, with multiple protein–protein interacting sites and complex post-transductional regulatory mechanisms, such as phosphorylation, dephosphorylation and ubiquitylation.

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Fernandez, A., Torres-Alemán, I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci 13, 225–239 (2012). https://doi.org/10.1038/nrn3209

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