Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function

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Peptide hormones, initially identified in the periphery and best known for regulation of food intake and appetite, have increasingly been shown to regulate brain functions not only within the hypothalamus but elsewhere. The hippocampus, in particular, expresses receptors for many hormones. Both insulin and ghrelin are now known to enhance hippocampal memory processes; in addition, insulin acts to increase local hippocampal metabolism and regulate synaptic plasticity, while administration of ghrelin has been shown to promote dendritic spine synaptic formation and to increase anxiety. While insulin's effects appear to be specifically within the hippocampus, ghrelin may act at a range of sites within the limbic system.

Section snippets

Insulin

Interest in insulin as a potential modulator of hippocampal function was prompted by the finding that in contrast to the majority of brain regions, the hippocampus expresses both insulin receptors and the insulin-regulated glucose transporter GluT4 (as well as the recently discovered GluTX). Subsequently, changes in hippocampal insulin receptor expression were reported following spatial memory training [6] which depend on both hippocampal subregion and length of time allowed for memory

Ghrelin

Similarly to insulin, interest in ghrelin as a potential regulator of hippocampal function arose in the wake of the identification of receptors for ghrelin (growth hormone secretagogue receptors; GHSR) within the hippocampus, combined with the finding that ghrelin is expressed in the brain. Studies of ghrelin's effects on the brain have thus far been confined to animal models.

Insulin and ghrelin

Potential interactions, within the brain, between the two peptidergic systems have been little studied. However, the two systems do interact: either systemic or central increases in insulin lead to a reduction in circulating ghrelin [42, 43], while insulin may mediate some of the effects of ghrelin on appetite and food intake [44]. The reverse is not true, as ghrelin does not appear to regulate circulating insulin levels [45]; however, a recent study suggests that ghrelin may modulate insulin

Other peptides

The finding that both ghrelin and insulin act to enhance hippocampal function is in contrast to their opposing actions on food intake and within the hypothalamus; this paradox is extended with the finding that preproghrelin also produces obestatin [47], a peptide which opposes ghrelin's actions on food intake yet produces similar effects on memory and anxiety [48]. See, also, the reviews of leptin's actions elsewhere in this volume, for a further example of dissociations between diverse actions

Summary

Recent work has clearly established a role for peripherally secreted peptide hormones in modulation of hippocampal processes; it seems likely that the array of gut-derived memory modulators will expand further as novel peptides are discovered and characterized, and existing candidates tested. The traditional idea of the brain as unresponsive to circulating hormonal stimuli must be discarded, with all aspects of neuronal function, including metabolism, seemingly responsive to hormonal

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I thank Drs Robert Sherwin and Rory McCrimmon for their many valuable insights and helpful discussion. This work was supported by a grant from the NIDDK (DK077106) to ECM.

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