Maternal obesity impairs brain glucose metabolism and neural response to hyperglycemia in male rat offspring

Authors

  • Hui Chen,

    Corresponding author
    1. School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, NSW, Australia
    2. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
    • Address correspondence and reprint requests to Hui Chen, School of Medical and Molecular Biosciences, Faculty of Science, University of Technology, Sydney, NSW 2007, Australia. E-mail: hui.chen-1@uts.edu.au; Margaret J. Morris, Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. E-mail: m.morris@unsw.edu.au

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  • David Simar,

    1. Inflammation and Infection Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
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  • Margaret J. Morris

    1. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
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Abstract

Hypothalamic appetite regulators neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) are modulated by glucose. This study investigated how maternal obesity disturbs glucose regulation of NPY and POMC, and whether this deregulation is linked to abnormal hypothalamic glucose uptake-lactate conversion. As post-natal high-fat diet (HFD) can exaggerate the effects of maternal obesity, its additional impact was also investigated. Female Sprague Dawley rats were fed a HFD (20 kJ/g) to model maternal obesity. At weaning, male pups were fed chow or HFD. At 9 weeks, in vivo hypothalamic NPY and POMC mRNA responses to acute hyperglycemia were measured; while hypothalami were glucose challenged in vitro to assess glucose uptake-lactate release and related gene expression. Maternal obesity dampened in vivo hypothalamic NPY response to acute hyperglycemia, and lowered in vitro hypothalamic glucose uptake and lactate release. When challenged with 20 mM glucose, hypothalamic glucose transporter 1, monocarboxylate transporters, lactate dehydrogenase-b, NPY and POMC mRNA expression were down-regulated in offspring exposed to maternal obesity. Post-natal HFD consumption reduced in vitro lactate release and monocarboxylate transporter 2 mRNA, but increased POMC mRNA levels when challenged with 20 mM glucose. Overall, maternal obesity produced stronger effects than post-natal HFD consumption to impair hypothalamic glucose metabolism. However, they both disturbed NPY response to hyperglycemia, potentially leading to hyperphagia.

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Maternal obesity reduced hypothalamic glucose uptake-lactate conversion, which disturbs glucose regulation of neuropeptide Y (NPY) and potentially leads to hyperphagia. The down-regulation of hypothalamic glucose and lactate transporters and the synchronously decreased mammalian target of rapamycin (mTOR) expression in response to maternal obesity may be an underlying mechanism. Post-weaning high-fat diet (HFD) consumption also impaired hypothalamic NPY response to hyperglycemia, however less potently than maternal obesity, potentially because of its limited impact on glucose-lactate conversion and transporter expression.

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