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Maturational effect of leptin on CO2 chemosensitivity in newborn rats

Pediatric Research volume 94, pages 971–978 (2023)Cite this article

Abstract

Background

Leptin augments central CO2 chemosensitivity and stabilizes breathing in adults. Premature infants have unstable breathing and low leptin levels. Leptin receptors are on CO2 sensitive neurons in the Nucleus Tractus Solitarius (NTS) and locus coeruleus (LC). We hypothesized that exogenous leptin improves hypercapnic respiratory response in newborn rats by improving central CO2 chemosensitivity.

Methods

In rats at postnatal day (p)4 and p21, hyperoxic and hypercapnic ventilatory responses, and pSTAT and SOCS3 protein expression in the hypothalamus, NTS and LC were measured before and after treatment with exogenous leptin (6 µg/g).

Results

Exogenous leptin increased the hypercapnic response in p21 but not in p4 rats (P ≤ 0.001). At p4, leptin increased pSTAT expression only in the LC, and SOCS3 expression in the NTS and LC; while at p21 pSTAT and SOCS3 levels were higher in the hypothalamus, NTS, and LC (P ≤ 0.05).

Conclusions

We describe the developmental profile of the effect of exogenous leptin on CO2 chemosensitivity. Exogenous leptin does not augment central CO2 sensitivity during the first week of life in newborn rats. The translational implication of these findings is that low plasma leptin levels in premature infants may not be contributing to respiratory instability.

Impact

  • Exogenous leptin does not augment CO2 sensitivity during the first week of life in newborn rats, similar to the developmental period when feeding behavior is resistant to leptin.

  • Exogenous leptin increases CO2 chemosensitivity in newborn rats after the 3rd week of life and upregulates the expression of pSTAT and SOC3 in the hypothalamus, NTS and LC.

  • Low plasma leptin levels in premature infants are unlikely contributors to respiratory instability via decreased CO2 sensitivity in premature infants. Thus, it is highly unlikely that exogenous leptin would alter this response.

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Fig. 1: Representative ventilatory tracing of rats using whole-body plethysmography in postnatal days 4 and 21.
Fig. 2: Effect of leptin on the hyperoxic ventilatory response of rats at postnatal days 4 and 21.
Fig. 3: Effect of leptin on respiratory variability.
Fig. 4: Leptin increases the hypercapnic ventilatory response (HCVR) at postnatal day 21, but not at postnatal day 4.
Fig. 5: Effect of leptin on pSTAT3 and SOCS3 protein expression in the brain.

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Data availability

All data generated and analyzed have been included in this article and Supplementary materials.

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Acknowledgements

Dr. Gauda would like to thank Dr. Seva Polotsky for the use of the whole-body plethysmograph in his laboratory and Ariel Mason for performing the pilot experiment that was done at Johns Hopkins in 2016, and Ms. Sonia Dos Santos for proof-reading the final draft.

Funding

Supported by the Women’s Auxiliary Chair in Neonatology at The Hospital for Sick Children.

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Liran Tamir-Hostovsky, Julijana Ivanovska, Rachana Patel, Huanhuan Wang, Nikola Ivanovski, Jaques Belik & Estelle B. Gauda

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Liran Tamir-Hostovsky

  3. Translational Program, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Julijana Ivanovska, Nikola Ivanovski, Jaques Belik & Estelle B. Gauda

  4. Cellular and Molecular Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Eleana Parajón

  5. Division of General and Thoracic Surgery, Developmental and Stem Cell Biology Program, Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    George Biouss & Agostino Pierro

  6. Keenan Research Centre for Biomedical Sciences, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada

    Gaspard Montandon

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Contributions

L.T.-H.; E.B.G., J.B., G.M.: Substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. Drafting the article or revising it critically for important intellectual content and final approval of the version to be published. R.P., E.P., J.I.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. H.W., G.B., A.P., N.I.: Substantial contributions to acquisition and analysis of data.

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Correspondence to Liran Tamir-Hostovsky.

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Tamir-Hostovsky, L., Ivanovska, J., Parajón, E. et al. Maturational effect of leptin on CO2 chemosensitivity in newborn rats. Pediatr Res 94, 971–978 (2023). https://doi.org/10.1038/s41390-023-02604-3

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