Abstract
Obesity-associated comorbidities such as cognitive impairment and anxiety are increasing public health burdens that have gained prevalence in children. To better understand the impact of childhood obesity on brain function, mice were fed with a high-fat diet (HFD) from weaning for 1, 3 or 6 weeks. When compared to low-fat diet (LFD)-fed mice (LFD-mice), HFD-fed mice (HFD-mice) had impaired novel object recognition (NOR) after 1 week. After 3 weeks, HFD-mice had impaired NOR and object location recognition (OLR). Additionally, these mice displayed anxiety-like behavior by measure of both the open-field and elevated zero maze (EZM) testing. At 6 weeks, HFD-mice were comparable to LFD-mice in NOR, open-field and EZM performance but they remained impaired during OLR testing. Glyburide, a second-generation sulfonylurea for the treatment of type 2 diabetes, was chosen as a countermeasure based on previous data exhibiting its potential as an anxiolytic. Interestingly, a single dose of glyburide corrected deficiencies in NOR and mitigated anxiety-like behaviors in mice fed with HFD-diet for 3-weeks. Taken together these results indicate that a HFD negatively impacts a subset of hippocampal-independent behaviors relatively rapidly, but such behaviors normalize with age. In contrast, impairment of hippocampal-sensitive memory takes longer to develop but persists. Since single-dose glyburide restores brain function in 3-week-old HFD-mice, drugs that block ATP-sensitive K+ (KATP) channels may be of clinical relevance in the treatment of obesity-associated childhood cognitive issues and psychopathologies.
Highlights
With over one billion overweight and obese individuals afflicted, world-wide overnutrition is a significant threat to human health (Kelly et al, 2008)
When high-fat diet (HFD)-mice were compared to low fat diet (LFD)-mice at 3 and 6 weeks post feeding, there was a 30% and 42% increase, respectively, in fasting blood glucose (FBG) levels
Food intake was comparable in HFD-mice and LFD-mice, but this resulted in a 37%, 28%, and 14% increase in calories ingested in HFD-mice after 1, 3 and 6 weeks of feeding, respectively
Summary
With over one billion overweight and obese individuals afflicted, world-wide overnutrition is a significant threat to human health (Kelly et al, 2008). Extension of the obese phenotype into childhood is associated with added risks including diminished cognition and executive function (Liang et al, 2014). Obese children are susceptible to certain psychological complications like attention deficit hyperactivity disorder (ADHD), impulsivity, inattention and anxiety (Daniels et al, 2005; Kalarchian and Marcus, 2012). Current work demonstrates that childhood and adolescent obesity is disadvantageous, especially as psychological illness and/or cognitive impairment persists even when consumption of a high-fat diet (HFD) is well in the past (Wang et al, 2015). Given the projected prevalence of childhood obesity in the 30 years (Ogden et al, 2014) and the magnitude of associated co-morbidities, identifying therapeutics to address this accelerating health concern is crucial
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