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Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour

Abstract

The bioactive peptides galanin, spexin and kisspeptin have a common ancestral origin and their pathophysiological roles are increasingly the subject of investigation. Evidence suggests that these bioactive peptides play a role in the regulation of metabolism, pancreatic β-cell function, energy homeostasis, mood and behaviour in several species, including zebrafish, rodents and humans. Galanin signalling suppresses insulin secretion in animal models (but not in humans), is potently obesogenic and plays putative roles governing certain evolutionary behaviours and mood modulation. Spexin decreases insulin secretion and has potent anorectic, analgesic, anxiolytic and antidepressive-like effects in animal models. Kisspeptin modulates glucose-stimulated insulin secretion, food intake and/or energy expenditure in animal models and humans. Furthermore, kisspeptin is implicated in the control of reproductive behaviour in animals, modulation of human sexual and emotional brain processing, and has antidepressive and fear-suppressing effects. In addition, galanin-like peptide is a further member of the galaninergic family that plays emerging key roles in metabolism and behaviour. Therapeutic interventions targeting galanin, spexin and/or kisspeptin signalling pathways could therefore contribute to the treatment of conditions ranging from obesity to mood disorders. However, many gaps and controversies exist, which must be addressed before the therapeutic potential of these bioactive peptides can be established.

Key points

  • The bioactive peptides galanin, spexin and kisspeptin have a common ancestral genetic origin and similar peptide sequences and have wide central and peripheral tissue distribution.

  • Galanin and spexin act through galanin receptors 1–3, whereas kisspeptin acts through the kisspeptin receptor.

  • These bioactive peptides control key metabolic, emotional and behavioural processes in species ranging from zebrafish to humans.

  • Although some actions are well described in animal models, controversies remain about their roles in several aspects of human physiology.

  • Further study of therapeutic agents targeting the signalling pathways of these bioactive peptides could identify a possible role for these in the management of type 2 diabetes mellitus, obesity, and behavioural and mood disorders.

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Fig. 1: Amino acid sequences for mature galanin, galanin-like peptide, spexin and kisspeptin in humans.
Fig. 2: Galanin functions in metabolism, mood and behaviour in rodents and fish.
Fig. 3: Spexin functions in metabolism, mood and behaviour.
Fig. 4: Kisspeptin functions in metabolism, mood and behaviour.

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Acknowledgements

The authors acknowledge the support of the National Institute for Health Research (NIHR), the NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre (BRC) at Imperial College Healthcare NHS Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The Section of Endocrinology and Investigative Medicine is funded by grants from the UK Medical Research Council (MRC) and NIHR. E.G.M. acknowledges the support of an MRC Clinical Research Training Fellowship (MR/T006242/1). C.I.-E. acknowledges the support of an Imperial College-BRC IPPRF Fellowship (P79696). A.A. acknowledges the support of an NIHR Clinician Scientist Award (CS-2018-18-ST2-002). A.N.C. acknowledges the support of the NHS. W.S.D. acknowledges the support of an NIHR Professorship (RP-2014-05-001).

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All authors contributed to writing the article, reviewing/editing the manuscript before submission, and made substantial contributions to discussions of the content. E.G.M. and C.I-E. researched data for the article.

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Glossary

Corticotropin releasing factor

(CRF). A neuropeptide that acts as the central driver of the hormonal stress response by activating the synthesis and release of adrenocorticotropic hormone from the anterior pituitary.

Rostral periventricular region of the third ventricle

A group of cells residing in the preoptic area of the hypothalamus, encompassing the anteroventral periventricular and the periventricular nuclei.

Circumventricular organs

These are specialized neuroepithelial midline structures that are not protected by the blood–brain barrier.

Periaqueductal grey matter

A complex nucleus that coordinates the antinociceptive, behavioural and autonomic responses to stress and injury.

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Mills, E.G., Izzi-Engbeaya, C., Abbara, A. et al. Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour. Nat Rev Endocrinol 17, 97–113 (2021). https://doi.org/10.1038/s41574-020-00438-1

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