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  • Review Article
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The intersection between ghrelin, metabolism and circadian rhythms

Nature Reviews Endocrinology volume 20, pages 228–238 (2024)Cite this article

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Abstract

Despite the growing popular interest in sleep and diet, many gaps exist in our scientific understanding of the interaction between circadian rhythms and metabolism. In this Review, we explore a promising, bidirectional role for ghrelin in mediating this interaction. Ghrelin both influences and is influenced by central and peripheral circadian systems. Specifically, we focus on how ghrelin impacts outputs of circadian rhythm, including neuronal activity, circulating growth hormone levels, locomotor activity and eating behaviour. We also consider the effects of circadian rhythms on ghrelin expression and the consequences of disrupted circadian patterns, such as shift work and jet lag, on ghrelin secretion. Our Review is aimed at both the casual reader interested in gaining more insight into the scientific context surrounding the trending topics of sleep and metabolism, as well as experienced scientists in the fields of ghrelin and circadian biology seeking inspiration and a comprehensive overview of how these fields are related.

Key points

  • Disrupted circadian and metabolic systems are a growing cause of societal health burden.

  • The ghrelin system regulates many key metabolic functions including food intake, body weight, blood glucose, food anticipatory activity, growth hormone secretion and body temperature.

  • Ghrelin and GHSR (growth hormone secretagogue receptor, which serves as the receptor for ghrelin) mRNA and protein expression are regulated by the circadian system.

  • Ghrelin affects neuronal firing, food anticipatory activity and thermoregulation in a circadian-dependent manner.

  • Given the expansion in scientific technology in the past 25 years, many more tools now exist to better understand the role of the ghrelin system in metabolism and circadian biology.

  • Future studies are needed to elucidate further the connections between the ghrelin system, metabolism and circadian systems, and to provide novel avenues for therapeutic approaches.

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Fig. 1: Major sites of expression of the hormones ghrelin and LEAP2 and their receptor, GHSR.
Fig. 2: Overview of the ghrelin system and its physiological functions.
Fig. 3: GHSR-expressing neurons in SCN of GHSR-IRES-Cre mice.
Fig. 4: Representative traces of human and rat plasma ghrelin secretion patterns.
Fig. 5: Intersections of ghrelin, metabolism and circadian rhythms.

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Acknowledgements

The authors’ works is supported through research grants from the NIH (R01 DK103884, P01DK119130 and 5T32GM008014).

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Authors and Affiliations

  1. Medical Scientist Training Program, UT Southwestern Medical Center, Dallas, TX, USA

    Soumya S. Kulkarni

  2. Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Soumya S. Kulkarni, Omprakash Singh & Jeffrey M. Zigman

  3. Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Jeffrey M. Zigman

  4. Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA

    Jeffrey M. Zigman

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  1. Soumya S. Kulkarni
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All authors researched data for the article. S.S.K. and J.M.Z. contributed to the discussion of content, wrote the article and reviewed/edited it before submission.

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Correspondence to Jeffrey M. Zigman.

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Competing interests

J.M.Z. owns stock in Medtronic, Eli Lilly and Novo Nordisk, and received research funding from Novo Nordisk for another project during the writing of this Review. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Yu Zhou and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Kulkarni, S.S., Singh, O. & Zigman, J.M. The intersection between ghrelin, metabolism and circadian rhythms. Nat Rev Endocrinol 20, 228–238 (2024). https://doi.org/10.1038/s41574-023-00927-z

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