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Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice

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Abstract

Background/Objectives

Alteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated.

Methods

We used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice.

Results

Postnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin.

Conclusions

Early postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.

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Fig. 1: Neonatal leptin antagonism improves body composition without affecting growth in neonatally overnourished mice.
Fig. 2: Neonatal leptin antagonism causes a shift in adipocyte size distribution in neonatally overfed mice.
Fig. 3: Neonatal leptin antagonism reverses alterations in glucose metabolism in neonatally overfed mice.
Fig. 4: Neonatal overnutrition causes central leptin resistance that can be improved with leptin antagonist.

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Acknowledgements

This work was supported by a research grant from the Inserm (grant 1172, to SGB). We thank the mouse metabolic phenotyping and cellular imaging cores of the UMS2014-US41 for accessing the metabolic cages and confocal microscope, respectively.

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Authors and Affiliations

  1. Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1,000 Days for Health, Lille, 59000, France

    Gustav Colldén, Emilie Caron & Sebastien G. Bouret

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  1. Gustav Colldén
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  2. Emilie Caron
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  3. Sebastien G. Bouret
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Contributions

GC and SGB conceived and designed the project. GC performed experiments. SGB, GC, and EC analyzed data. GC and SGB wrote the manuscript. All the authors read and approved the manuscript.

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Correspondence to Sebastien G. Bouret.

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Colldén, G., Caron, E. & Bouret, S.G. Neonatal leptin antagonism improves metabolic programming of postnatally overnourished mice. Int J Obes 46, 1138–1144 (2022). https://doi.org/10.1038/s41366-022-01093-4

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