J Comp Neurol. 2015 Apr 1;523(5):757-68. doi: 10.1002/cne.23708.

Childhood and Adolescent Obesity and Long-Term Cognitive Consequences During Aging

Jun Wang1,2, Daniel Freire1, Lindsay Knable1, Wei Zhao1, Bing Gong,1 Paolo Mazzola1,3, Lap Ho1, Samara Levine1, and Giulio M. Pasinetti1,2

 

1Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029

2Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468

3Department of Health Sciences, University of Milano-Bicocca, and Geriatric Clinic, San Gerardo University Hospital, 20900 Monza MB, Italy

 

Abstract:

The prevalence of childhood/adolescent obesity and insulin resistance has reached an epidemic level. Obesity’s immediate clinical impacts have been extensively studied; however, current clinical evidence underscores the long-term implications. The current study explored the impacts of brief childhood/adolescent obesity and insulin resistance on cognitive function in later life. To mimic childhood/adolescent obesity and insulin resistance, we exposed 9-week-old C57BL/6J mice to a high-fat diet for 15 weeks, after which the mice exhibited diet-induced obesity and insulin resistance. We then put these mice back on a normal low-fat diet, after which the mice exhibited normal body weight and glucose tolerance. However, a spatial memory test in the forms of the Morris water maze (MWM) and contextual fear conditioning at 85 weeks of age showed that these mice had severe deficits in learning and long-term memory consolidation. Mechanistic investigations identified increased expression of histone deacetylases 5, accompanied by reduced expression of brain-derived neurotrophic factor, in the brains 61 weeks after the mice had been off the high-fat diet. Electrophysiology studies showed that hippocampal slices isolated from these mice are more susceptible to synaptic impairments compared with slices isolated from the control mice. We demonstrated that a 15-week occurrence of obesity and insulin resistance during childhood/adolescence induces irreversible epigenetic modifications in the brain that persist following restoration of normal metabolic homeostasis, leading to brain synaptic dysfunction during aging. Our study provides experimental evidence that limited early-life exposure to obesity and insulin resistance may have long-term deleterious consequences in the brain, contributing to the onset/progression of cognitive dysfunction during aging.

 

Supplement:

It is well established that chronic obesity and insulin resistance are associated with increased risk for a wide spectrum of diseases, including age-related cognitive deterioration. However, there is very little evidence on the long-term consequences of childhood/adolescent obesity. This study was designed to investigate the impacts of a brief period of obesity during childhood/adolescence on cognitive function during advanced age.

Using an experimental model of obesity and insulin resistance, we exposed the animals to a 15-week period of high fat diet, inducing an obesity/insulin resistance phenotype in mice, equivalent to 5 years until 16 years of age in humans. The animals were then reverted back to a normal diet for the rest of their lives. They exhibited normal periphery homeostasis, including normal body weight and normal glucose utilization capacity. However, cognitive tests performed when the animals reached advanced age demonstrated impairments in learning and memory formation. Mechanistic investigations suggested that brain-derived neurotrophic factor (BDNF) may play an important role in this process. BDNF is a key regulator of synaptogenesis and synaptic plasticity, which are essential to learning and memory. We further demonstrated that the reduced expression of BDNF was very likely a result of increased expression of HDAC5, a histone deacetylase whose activity can reduce BDNF chromatin accessibility, leading to reduced transcription of BDNF. Previously, we demonstrated that the level of HDAC5 is significantly increased in the brains of diabetic patients and in the brains of mice with chronic obesity and insulin resistance (1). This persistent increase of HDAC5 in the brain, albeit the lack of periphery obesity/insulin resistance phenotype, suggests that even when the periphery recovers to normal homeostasis, the epigenetic changes in the brain may persist long-term and continue to induce pathological alterations both structurally and functionally, leading to a more susceptible, less resilient cognitive machinery.

In conclusion, our study, for the first time, demonstrates that brief occurrence of obesity and insulin resistance during childhood/adolescence may induce irreversible epigenetic modifications in the brain that persist following restoration of normal metabolic homeostasis, leading to brain synaptic dysfunction in healthy adults during aging. Our study provides experimental evidence implicating that limited early life exposure to obesity and insulin resistance may have long-term deleterious consequences in the brain, contributing to the onset/progression of cognitive dysfunction during aging. A majority of the clinical studies to date have focused on the cardiometabolic morbidity, while our study provides the scientific impetus for clinical investigation of the long-term impacts of childhood/adolescent obesity on cognitive function and brain wellness during aging.

 

fig1

Fig 1. Brief exposure to diabetes during adolescence leads to long-term pathogenic consequences in the brain, which persist even after restoration of peripheral physiological homeostasis.

 

Acknowledgements

This study was supported in part by discretionary funding from the Icahn School of Medicine at Mount Sinai to Dr. Giulio Pasinetti and in part with resources and the use of facilities at the James J. Peters Veterans Affairs Medical Center, Bronx, NY. In addition, Dr. Pasinetti holds a Career Scientist Award in the Research and Development unit and is the Director of the Basic and Biomedical Research and Training Program, GRECC, James J. Peters Veterans Affairs Medical Center. We also acknowledge that the contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

 

References:

  1. Wang J, Gong B, Zhao W, Tang C, Varghese M, Nguyen T, Bi W, Bilski A, Begum S, Vempati P, et al. Epigenetic mechanisms linking diabetes and synaptic impairments. Diabetes 2013 Oct 23;63(2):645-54.

 

Pasinetti photo

Dr. Giulio M. Pasinetti

Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029

 

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