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Exendin-4 is effective against metabolic disorders induced by intrauterine and postnatal overnutrition in rodents

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Abstract

Aims/hypothesis

Maternal obesity leads to increased adiposity, hyperlipidaemia and glucose intolerance in offspring. The analogue of glucagon-like peptide-1, exendin-4 (Ex-4), has been shown to induce weight loss in both adolescence and adulthood. We hypothesised that, in rats, daily injection of Ex-4 would reduce body fat and improve metabolic disorders in offspring from obese dams, especially those consuming a high-fat diet (HFD).

Methods

Female Sprague Dawley rats were fed chow or an HFD for 5 weeks before mating, and throughout gestation and lactation. At postnatal day 20, male pups from HFD-fed mothers were weaned onto chow or HFD and those from chow-fed mothers were fed chow. Within each dietary group, half of the pups were injected with Ex-4 (15 μg/kg/day i.p.) for 6 weeks, while the other half received saline.

Results

Maternal obesity alone or combined with postweaning HFD consumption led to increased adiposity, hyperinsulinaemia, hyperlipidaemia, inflammation and impaired regulation of hypothalamic appetite regulators by glucose in offspring, while glucose intolerance was only observed in HFD-fed rats from obese dams. Ex-4 injection significantly reduced adiposity, hyperlipidaemia and insulin resistance in HFD-fed rats from obese dams. It also restored glucose tolerance and the lipid-lowering effect of blood glucose. However, Ex-4 did not change hypothalamic appetite regulation or the response of appetite regulators to hyperglycaemia. Liver and adipose inflammatory cytokine expression was significantly reduced by Ex-4.

Conclusions/interpretation

Ex-4 reversed the detrimental impact of maternal obesity on lipid and glucose metabolism in offspring regardless of diet, supporting its potential application in reducing metabolic disorders in high-risk populations.

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Abbreviations

Arc:

Arcuate nucleus

BW:

Body weight

C-C:

Pups from lean dams fed standard rodent chow diet and injected with saline

C-C+E:

Pups from lean dams fed standard rodent chow diet and injected with exendin-4

Ex-4:

Exendin-4

GLP-1:

Glucagon-like peptide-1

H-C:

Pups from HFD-fed dams fed chow and injected with saline

H-C+E:

Pups from HFD-fed dams fed chow and injected with exendin-4

HFD:

High-fat diet

H-H:

Pups from HFD-fed dams fed HFD and injected with saline

H-H+E:

Pups from HFD-fed dams fed HFD and injected with exendin-4

IPGTT:

Intraperitoneal glucose tolerance test

mTOR:

Mammalian target of rapamycin

NPY:

Neuropeptide Y

POMC:

Proopiomelanocortin

PVN:

Paraventricular nucleus

Rp:

Retroperitoneal

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Acknowledgements

We thank S. Rajia and V. Caruso (Pharmacology, School of Medical Sciences, University of New South Wales, Australia) for assistance with tissue harvesting at the endpoint.

Funding

This work presents independent research that was supported by Research Student Support from the Faculty of Science, University of Technology, Sydney to HC, and a research grant from Diabetes Australia Research Trust to HC, DS and MJM.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

HC, DS and MJM were involved in the project design, applying for funding and data interpretation. HC, KP and DS contributed to the animal experiments, data generation and interpretation, SS and CP contributed to data generation and interpretation. HC and KP wrote the first draft of the manuscript, and all authors read and modified the manuscript and approved the final draft.

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Authors and Affiliations

  1. School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, NSW, 2007, Australia

    Hui Chen & Katherine Pegg

  2. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Hui Chen & Margaret J. Morris

  3. Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

    David Simar & Clovis Palmer

  4. Department of Medicine, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia

    Sonia Saad

  5. Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia

    Clovis Palmer

Authors
  1. Hui Chen
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  2. David Simar
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  3. Katherine Pegg
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  4. Sonia Saad
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  6. Margaret J. Morris
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Correspondence to Hui Chen or Margaret J. Morris.

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Chen, H., Simar, D., Pegg, K. et al. Exendin-4 is effective against metabolic disorders induced by intrauterine and postnatal overnutrition in rodents. Diabetologia 57, 614–622 (2014). https://doi.org/10.1007/s00125-013-3132-5

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  • DOI: https://doi.org/10.1007/s00125-013-3132-5

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