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Brain insulin signalling in metabolic homeostasis and disease

Abstract

Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.

Key points

  • Insulin crosses the blood–brain barrier via a saturable transport to bind to insulin receptors widely expressed throughout the brain; insulin signalling in the brain regulates systemic nutrient partitioning in animal models and humans.

  • Brain insulin action controls appetite, adipose tissue lipolysis, hepatic triglyceride secretion and branched-chain amino acid metabolism, protecting the organism from ectopic lipid accumulation and lipotoxicity.

  • The role of brain insulin in suppressing hepatic glucose production remains controversial.

  • Overnutrition rapidly induces brain insulin resistance even before peripheral insulin signalling is impaired, implicating brain insulin resistance as a key culprit of metabolic disease and diabetes.

  • Tools to assess brain insulin action in humans are limited and involve MRI techniques, PET, magnetoencephalography and electroencephalography.

  • Pharmacological interventions to improve brain insulin signalling have therapeutic potential for metabolic disease, diabetes and non-alcoholic fatty liver disease; augmenting brain insulin signalling might be particularly beneficial in preventing lipotoxicity with a low risk of hypoglycaemia.

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Fig. 1: Brain insulin signalling cascade.
Fig. 2: Physiological functions of brain insulin action.
Fig. 3: Brain insulin resistance and its metabolic sequelae.
Fig. 4: An evolutionary advantage for brain insulin resistance?

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Acknowledgements

The authors acknowledge the support of the Austrian Science Fund (FWF) grant KLI782 to T.S. and Manpei Suzuki Diabetes Foundation to K.S. and the NIH grants DK074873, DK083568 and DK082724 to C.B.

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T.S. and C.B. researched data for the article, contributed to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission. K.S. researched data for the article, contributed to discussion of the content and wrote the article.

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Correspondence to Thomas Scherer or Christoph Buettner.

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Scherer, T., Sakamoto, K. & Buettner, C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 17, 468–483 (2021). https://doi.org/10.1038/s41574-021-00498-x

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