Maternal obesity impairs hippocampal BDNF production and spatial learning performance in young mouse offspring

https://doi.org/10.1016/j.neuint.2010.05.015Get rights and content

Abstract

Maternal obesity may affect the child's long-term development and health, increasing the risk of diabetes and metabolic syndrome. In addition to the metabolic and endocrine systems, recent reports have indicated that maternal obesity also modulates neural circuit formation in the offspring. However, this not yet been fully investigated. Here, we examined the effect of diet-induced maternal obesity on hippocampal development and function in the mouse offspring. Adult female mice were fed either a normal diet (ND, 4% fat) or a high-fat diet (HFD, 32% fat) before mating and throughout pregnancy and lactation. After weaning, all offspring were fed with a normal diet. We found that HFD offspring showed increased lipid peroxidation in the hippocampus during early postnatal development. HFD offspring had less brain-derived neurotrophic factor (BDNF) in the hippocampus than ND offspring. BDNF has been shown to play crucial roles in neuronal differentiation, plasticity and hippocampus-dependent cognitive functions such as spatial learning and memory. Using retroviral labeling, we demonstrated that dendritic arborization of new hippocampal neurons was impaired in the young HFD offspring. Finally, we evaluated cognitive function in these offspring using hippocampus-dependent behavioral tasks. The Barnes maze test demonstrated that HFD offspring showed impaired acquisition of spatial learning in the young but not adult period. This study, using a mouse model, indicates that diet-induced maternal obesity impairs hippocampal BDNF production and spatial cognitive function in young offspring, possibly due to their metabolic and oxidative changes.

Section snippets

Animal maintenance and diets

Four-week-old C57BL/6J female mice were purchased from Clea Japan (Tokyo, Japan) and were kept in a humidity-controlled room with a 12-h light–dark cycle (lights on at 8:00 AM). The animals had ad libitum access to food and water. During non-breeding periods, four to five mice were housed per cage, and during breeding, one female was housed with one male. After acclimation of the animals for 1 week, mice were weight-matched and divided into two groups (n = 50 per group). Mice were fed with either

Development of maternal obesity

Age-matched female mice were fed the ND or the HFD for 6 weeks before breeding, and continued on this diet throughout gestation and lactation as reported previously (Samuelsson et al., 2008, Tozuka et al., 2009a, Kirk et al., 2009). After 6 weeks on the obesogenic diet, the female mice were heavier than controls, at which point they were mated. In our previous study, we reported that HFD-fed dams showed increased body weight and hyperlipidemia at 11 weeks of age (just before the mating)

Discussion

The typical diet in modern human society in the developed world is an energy-rich diet containing high levels of fats and sugars. Chronic consumption of this type of diet has long been associated with adverse effects on brain health and function. There is a great need to elucidate the mechanisms by which this diet can affect neurodevelopment, plasticity and cognitive function. More importantly, it has been documented that maternal diet and metabolic function can affect brain development and

Acknowledgements

We thank Masayuki Sekiguchi (NCNP), Heng Li (NCNP), Daisuke Yamada (NCNP), Hiromi Fujita (NCNP) and Takashi Namba (Nagoya University) for informative discussions and technical assistance. This work was supported in part by grants-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan; the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation; and a grant from the Japan Science and Technology Agency.

References (81)

  • H. Kim et al.

    The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups

    Int. J. Dev. Neurosci.

    (2007)
  • I. Kodomari et al.

    Maternal supply of BDNF to mouse fetal brain through the placenta

    Neurochem. Int.

    (2009)
  • I. Kodomari et al.

    Ghrelin alters postnatal endocrine secretion and behavior in mouse offspring

    Neurochem. Int.

    (2009)
  • H.H. Lee et al.

    Maternal swimming during pregnancy enhances short-term memory and neurogenesis in the hippocampus of rat pups

    Brain Dev.

    (2006)
  • N. Matsuzawa-Nagata et al.

    Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity

    Metabolism

    (2008)
  • R. Molteni et al.

    A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning

    Neuroscience

    (2002)
  • P. Parnpiansil et al.

    Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup

    Neurosci. Lett.

    (2003)
  • M.J. Schaaf et al.

    Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone

    Brain Res.

    (1998)
  • H. Scharfman et al.

    Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats

    Exp. Neurol.

    (2005)
  • C.G. Souza et al.

    Highly palatable diet consumption increases protein oxidation in rat frontal cortex and anxiety-like behavior

    Life Sci.

    (2007)
  • Y. Tozuka et al.

    Excitatory GABAergic inputs promote neuronal differentiation in adult hippocampal progenitor cells

    Neuron

    (2005)
  • Y. Tozuka et al.

    “Bio-communication” between mother and offspring: lessons from animals and new perspectives for brain science

    J. Pharmacol. Sci.

    (2009)
  • C.L. White et al.

    Effects of high fat diet on Morris maze performance, oxidative stress, and inflammation in rats: contributions of maternal diet

    Neurobiol. Dis.

    (2009)
  • G. Winocur et al.

    The effects of high fat diets and environmental influences on cognitive performance in rats

    Behav. Brain Res.

    (1999)
  • G. Winocur et al.

    Studies of the effects of high fat diets on cognitive function in a rat model

    Neurobiol. Aging

    (2005)
  • C. Zhao et al.

    Mechanisms and functional implications of adult neurogenesis

    Cell

    (2008)
  • H. Ageta et al.

    Activin in the brain modulates anxiety-related behavior and adult neurogenesis

    PLoS One

    (2008)
  • R.E. Andersen

    The spread of the childhood obesity epidemic

    CMAJ

    (2000)
  • J. Bełtowski et al.

    The effect of dietary-induced obesity on lipid peroxidation, antioxidant enzymes and total plasma antioxidant capacity

    J. Physiol. Pharmacol.

    (2000)
  • M. Bergami et al.

    Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • A. Bick-Sander et al.

    Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • D.K. Binder et al.

    Brain-derived neurotrophic factor

    Growth Factors

    (2004)
  • S. Boullu-Ciocca et al.

    Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome

    Diabetes

    (2005)
  • K.D. Bruce et al.

    Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression

    Hepatology

    (2009)
  • G.Q. Chang et al.

    Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity

    J. Neurosci.

    (2008)
  • H.M. Chao et al.

    Adrenal steroid regulation of neurotrophic factor expression in the rat hippocampus

    Endocrinology

    (1998)
  • R.H. Chapman et al.

    Failure of severe maternal stress or ACTH during pregnancy to affect emotionality of male rat offspring: implications of litter effects for prenatal studies

    Dev. Psychobiol.

    (1979)
  • H. Chen et al.

    Hypothalamic neuroendocrine circuitry is programmed by maternal obesity: interaction with postnatal nutritional environment

    PLoS One

    (2009)
  • I. Chinen et al.

    Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats

    Endocrinology

    (2007)
  • D. Dupret et al.

    Spatial relational memory requires hippocampal adult neurogenesis

    PLoS One

    (2008)
  • Cited by (209)

    View all citing articles on Scopus
    View full text