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

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Abstract

This study was undertaken to investigate the effects of prenatal and postnatal exposure to high fat diet on the brain. Female rats were divided into high fat diet (HFD) and control diet (CD) groups 4 weeks prior to breeding and throughout gestation and lactation. After weaning, male progeny were placed on a chow diet until 8 weeks old, and then segregated into HFD or CD groups. At 20 weeks old, rats were evaluated in the Morris water maze, and markers of oxidative stress and inflammation were documented in the brain. In comparison to rats fed CD, cognitive decline in HFD progeny from HFD dams manifested as a decline in retention, but not acquisition, in the water maze. HFD was also associated with significant increases in 3-nitrotyrosine, inducible nitric oxide synthase, IL-6, and glial markers Iba-1 and GFAP, with the largest increases frequently observed in HFD animals born to HFD dams. Thus, these data collectively suggest that HFD increases oxidative and inflammatory signaling in the brain, and further indicate that maternal HFD consumption might sensitize offspring to the detrimental effects of HFD.

Introduction

Obesity is clinically identified based on measurements of body mass index (Mei et al., 2002), but can be generally defined as the physiological condition in which excess body fat has accumulated to an extent that detrimentally affects overall health. This working definition is based on the dramatically enhanced risk for a myriad of diseases associated with obesity, including type 2 diabetes, cardiovascular disease, gastrointestinal and respiratory difficulties, and many types of cancer (reviewed in Haslam and James, 2005). Emerging data also show that obesity in human populations is associated with cognitive decline and enhanced vulnerability to brain injury, while experimental studies in animal models confirm a profile of heightened brain vulnerability and decreased cognitive function. For example, studies have reported deficits in learning, memory, and executive function in obese as compared to non-obese patients (Elias et al., 2003, Elias et al., 2005, Waldstein and Katzel, 2006). Other studies of young and middle-aged adults have confirmed an association of obesity with declines in executive function (Gunstad et al., 2007). Likewise, animal studies indicate that experimental obesity is associated with cognitive decline and specific decreases in dendritic spine density (Stranahan et al., 2008) and in the expression of synaptic marker proteins such as synapsin and GAP-43 (Molteni et al., 2002, Wu et al., 2004). Although the physiologic mechanisms whereby obesity adversely affects the brain are poorly understood, both experimental and human studies have shown that obesity is associated with increased oxidative stress (Mattson et al., 2003, Zhang et al., 2005, Souza et al., 2007), which is strongly implicated in cognitive decline caused by brain injury (Ansari et al., 2008a, Ansari et al., 2008b) or neurodegenerative disease (Joseph et al., 1998, Kamat et al., 2008, Sayre et al., 2008).

While it is generally accepted that obesity is associated with adverse health outcomes, studies have also shown that maternal obesity is specifically associated with a variety of pregnancy complications, including labor and delivery difficulties, fetal and neonatal death, maternal hypertension, preeclampsia, and gestational diabetes (Lu et al., 2001, Bhattacharya et al., 2007, Thompson et al., 2008). Furthermore, it is possible that maternal obesity might precipitate adverse outcomes that persist through adulthood in offspring. Indeed, evidence suggests that epigenetic events initiated during the prenatal period can result in persistent adaptations in structure, physiology and metabolism that predispose offspring towards disease and impaired physiology (Barker, 1995, Lucas, 1998). For example, animal studies have shown that maternal overnutrition and/or neonatal overfeeding predispose offspring to obesity (Levin and Govek, 1998, Plagemann et al., 1999, Shankar et al., 2008). Specifically related to neurological function, prenatal exposure to cigarette smoke, cocaine, or alcohol all impair cognitive function (Bredy et al., 2004, Singer et al., 2004, Willford et al., 2006, Toro et al., 2008). Thus, the possibility exists that maternal obesity could enhance both the propensity towards, and the neurological consequences of, obesity in adult offspring.

This study was undertaken to investigate the effects of diet-induced obesity on the brain, with additional emphasis on the contributions of maternal diet to the neurological consequences of obesity. Experimental high fat diet (HFD) consumption can induce obesity, hyperglycemia, whole-body insulin resistance, and generalized metabolic syndrome in rodents (Tschöp and Heiman, 2001, Oakes et al., 1997, Buettner et al., 2007) suggesting that HFD per se is sufficient to induce obesity and metabolic disease. To determine the effects of both maternal and progeny diet-induced obesity on brain function, breeding age female Long Evans rats were divided into 2 groups and fed either HFD or control diet (CD) from 4 weeks prior to breeding and throughout gestation and lactation. After weaning, male progeny were placed on a chow diet until 8 weeks old, at which time they were segregated into HFD or CD diet groups, and maintained on their respective diets until 20 weeks of age. Body weight and retroperitoneal fat pad weight were measured at the end of study, as was cognitive performance and levels of specific markers of oxidative stress and inflammation in the cortex.

Section snippets

Animal treatments and tissue preparation

The Institutional Animal Care and Use Committee approved all experimental protocols which were consistent with the NIH guidelines on the use of experimental animals. Rats used in this study were a subset of a larger study group designed to determine the role of maternal adiposity on fetal programming related to body weight regulation (White et al., in press). Twenty 8-week old virgin female Long Evans rats (Harlan Laboratories, Indianapolis, IN) were singly housed with a 12-hour light/dark

Effects of HFD on body weight and composition

Female rats were fed HFD or CD beginning 4 weeks before breeding and continuing throughout gestation and lactation. By 2 weeks on the diet, the HFD dams weighed significantly more than the CD rats, and this difference continued through the end of lactation (Table 1).

Male pups from HFD and CD dams were all weaned to standard labchow at 3 weeks old, maintained on this diet until 8 weeks old, at which time they were segregated into HFD and CD groups. During this period, body weights progressively

Discussion

In this manuscript, data obtained from rats born to obese HFD dams and consuming either a HFD (HFD/HFD) or CD (HFD/CD), and rats born to CD dams and consuming either CD (CD/CD) or HFD in adulthood (CD/HFD) are described. Experiments were designed to evaluate if the interaction of maternal and offspring HFD could alter cognitive function and perturb brain homeostasis in vivo. Using the Morris water maze to evaluate cognitive ability, data show that retention across days of training was impaired

Acknowledgments

The authors are grateful to Kenneth Ballard for his expert technical assistance and animal handling. This work was supported by grants from the NIH (NS46267, DA19398, and AG05119 to ABK; and DK07246, RR021945, and NS051570 to CDM). This work used PBRC Core facilities (Bioimaging and Animal Phenotyping) that are funded by the NIH (P20-RR021945 and P30-DK072476).

References (99)

  • GreenwoodC.E. et al.

    High-fat diets, insulin resistance and declining cognitive function

    Neurobiol. Aging

    (2005)
  • GunstadJ. et al.

    Elevated body mass index is associated with executive dysfunction in otherwise healthy adults

    Compr. Psychiatry

    (2007)
  • GuoF. et al.

    High-fat feeding during pregnancy and lactation affects offspring metabolism in rats

    Physiol. Behav.

    (1995)
  • HaslamD.W. et al.

    Obesity Lancet Neurol.

    (2005)
  • JanasA. et al.

    The cholinesterase inhibitor, phenserine, improves Morris water maze performance of scopolamine-treated rats

    Life Sci.

    (2005)
  • JosephJ.A. et al.

    Age-related neurodegeneration and oxidative stress: putative nutritional intervention

    Neurol. Clin.

    (1998)
  • LuG.C. et al.

    The effect of the increasing prevalence of maternal obesity on perinatal morbidity

    Am. J. Obstet. Gynecol.

    (2001)
  • LucasA.

    Programming by early nutrition: an experimental approach

    J. Nutr.

    (1998)
  • MeiZ. et al.

    Validity of body mass index compared with other body-composition screening indexes for the assessment of body fatness in children and adolescents

    Am. J. Clin. Nutr.

    (2002)
  • MielkeJ.G. et al.

    Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice

    Behav. Brain Res.

    (2006)
  • MolteniR. et al.

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

    Neuroscience

    (2002)
  • MorrisonC.

    Leptin signaling in brain: a link between nutrition and cognition?

    Biochim. Biophys. Acta

    (2009)
  • MorrisonC.D.

    Leptin resistance and the response to positive energy balance

    Physiol. Behav.

    (2008)
  • OomuraY. et al.

    Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats

    Peptides

    (2006)
  • PezzarossaA. et al.

    Effects of maternal weight variations and gestational diabetes mellitus on neonatal birth weight

    J. Diabetes Complicat.

    (1996)
  • PlagemannA. et al.

    Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats

    Brain Res.

    (1999)
  • ReynoldsA. et al.

    Oxidative stress and the pathogenesis of neurodegenerative disorders

    Int. Rev. Neurobiol.

    (2007)
  • RollsB.J. et al.

    Pregnancy and lactation in the obese rat: effects on maternal and pup weights

    Physiol. Behav.

    (1982)
  • SouzaC.G. et al.

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

    Life Sci.

    (2007)
  • SriramK. et al.

    Obesity exacerbates chemically induced neurodegeneration

    Neuroscience

    (2002)
  • TartagliaL.A. et al.

    Identification and expression cloning of a leptin receptor, OB-R

    Cell

    (1995)
  • Vega-AvelairaD. et al.

    Age-related changes in the spinal cord microglial and astrocytic response profile to nerve injury

    Brain Behav. Immun.

    (2007)
  • WangC.X. et al.

    Involvement of inflammatory cytokines in central nervous system injury

    Prog. Neurobiol.

    (2002)
  • WaynerM.J. et al.

    Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo

    Peptides

    (2004)
  • WinocurG. et al.

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

    Neurobiol. Aging

    (2005)
  • ZhangX. et al.

    High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex

    Exp. Neurol.

    (2005)
  • AhimaR.S. et al.

    Adipokines in obesity

    Front. Horm. Res.

    (2008)
  • AhmedZ. et al.

    Actin-binding proteins coronin-1a and IBA-1 are effective microglial markers for immunohistochemistry

    J. Histochem. Cytochem.

    (2007)
  • AnsariM.A. et al.

    A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI

    J. Neurotrauma.

    (2008)
  • BayolS.A. et al.

    A maternal ‘junk food’ diet in pregnancy and lactation promotes an exacerbated taste for ‘junk food’ and a greater propensity for obesity in rat offspring

    Br. J. Nutr.

    (2007)
  • Ben-HaroushA. et al.

    Maternal obesity is a major risk factor for large-for-gestational-infants in pregnancies complicated by gestational diabetes

    Arch. Gynecol. Obstet.

    (2008)
  • BhattacharyaS. et al.

    Effect of body mass index on pregnancy outcomes in nulliparous women delivering singleton babies

    BMC Public Health

    (2007)
  • Bruce-KellerA.J. et al.

    Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17beta-estradiol

    J. Neurochem.

    (2001)
  • Bruce-KellerA.J. et al.

    Obesity and vulnerability of the CNS

    Biochim. Biophys. Acta

    (2008)
  • BuettnerR. et al.

    High-fat diets: modeling the metabolic disorders of human obesity in rodents

    Obesity (Silver Spring)

    (2007)
  • ChangG.Q. 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)
  • ChenH. et al.

    Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism

    Endocrinology

    (2008)
  • ChinenI. et al.

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

    Endocrinology

    (2007)
  • DahlgrenJ. et al.

    Prenatal cytokine exposure results in obesity and gender-specific programming

    Am. J. Physiol. Endocrinol. Metab.

    (2001)
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