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Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys.

ABSTRACT: Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neurodegenerative disorders. In the motor cortex with increased BMI we saw the upregulation of genes involved in apoptosis, altered gene expression in metabolic pathways, and the downregulation of pERK1/2 (MAPK1), a protein involved in cellular survival. In the caudate nucleus with increased BMI we saw the upregulation of known obesity related genes (the insulin receptor (INSR) and the glucagon-like peptide-2 receptor (GLP2R)), apoptosis related genes, and altered expression of genes involved in various metabolic processes. These studies suggest that the effects of high BMI on the brain transcriptome persist regardless of two months of calorie restriction. We hypothesize that active lifestyles with low BMIs together create a brain homeostasis more conducive to brain resiliency and neuronal survival.

SUBMITTER: Mitchell AC

PROVIDER: S-EPMC3292695 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys.

Mitchell Amanda C AC Leak Rehana K RK Zigmond Michael J MJ Cameron Judy L JL Mirnics Károly K

Genomics 20111229 3

Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neuro ...[more]

PMID: 22227022

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Project description:The reinforcing effects and long-term consequences of cocaine self-administration have been associated with brain regions of the mesolimbic dopamine pathway, namely the nucleus accumbens (NAc). Studies of cocaine-induced biochemical adaptations in rodent models have advanced our knowledge; however, unbiased detailed assessments of intracellular alterations in the primate brain are scarce, yet essential, to develop a comprehensive understanding of cocaine addiction. To this end, two-dimensional difference in gel electrophoresis (2D-DIGE) was used to compare changes in cytosolic protein abundance in the NAc between rhesus monkeys self-administering cocaine and controls. Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser-desorption ionization time-of-flight time-of-flight (MALDI-TOF-TOF). In total, 1098 spots were subjected to statistical analysis with 22 spots found to be differentially abundant of which 18 proteins were positively identified by mass spectrometry. In addition, approximately 1000 protein spots were constitutively expressed of which 21 proteins were positively identified by mass spectrometry. Increased levels of proteins in the cocaine-exposed monkeys include glial fibrillary acidic protein, syntaxin-binding protein 3, protein kinase C isoform, adenylate kinase isoenzyme 5 and mitochondrial-related proteins, whereas decreased levels of proteins included beta-soluble N-ethylmaleimide-sensitive factor attachment protein and neural and non-neural enolase. Using a complimentary proteomics approach, the differential expression of phosphorylated proteins in the cytosolic fraction of these subjects was examined. Two-dimensional gel electrophoresis (2DGE) was followed by gel staining with Pro-Q Diamond phosphoprotein gel stain, enabling differentiation of approximately 150 phosphoprotein spots between the groups. Following excision and trypsin digestions, MALDI-TOF-TOF was used to confirm the identity of 15 cocaine-altered phosphoproteins. Significant increased levels were detected for gamma-aminobutyric acid type A receptor-associated protein 1, 14-3-3 gamma-protein, glutathione S-transferase and brain-type aldolase, whereas significant decreases were observed for beta-actin, Rab GDP-dissociation inhibitor, guanine deaminase, peroxiredoxin 2 isoform b and several mitochondrial proteins. Results from these studies indicate coordinated dysregulation of proteins related to cell structure, signaling, metabolism and mitochondrial function. These data extend and compliment previous studies of cocaine-induced biochemical alterations in human postmortem brain tissue, using an animal model that closely recapitulates the human condition and provide new insight into the molecular basis of the disease and potential targets for pharmacotherapeutic intervention.

Project description:Heightened stress reactivity is associated with hippocampal atrophy, age-related cognitive deficits, and increased risk for Alzheimer's disease. This temperament predisposition may aggravate age-associated brain pathology or be reflective of it. This association may be mediated through repeated activation of the stress hormone axis over time. Dietary interventions, such as calorie restriction (CR), affect stress biology and may moderate the pathogenic relationship between stress reactivity and brain in limbic and prefrontal regions.Rhesus monkeys (Macaca mulatta) aged 19-31 years consumed either a standard diet (N=18) or were maintained on 30% CR relative to baseline intake (N=26) for 13-19 years. Behavior was rated in both normative and aversive contexts. Urinary cortisol was collected. Animals underwent magnetic resonance imaging and diffusion tensor imaging (DTI) to acquire volumetric and tissue microstructure data respectively. Voxel-wise statistics regressed a global stress reactivity factor, cortisol, and their interaction on brain indices across and between dietary groups.CR significantly reduced stress reactivity during aversive contexts without affecting activity, orientation, or attention behavior. Stress reactivity was associated with less volume and tissue density in areas important for emotional regulation and the endocrine axis including prefrontal cortices, hippocampus, amygdala, and hypothalamus. CR reduced these relationships. A Cortisol by Stress Reactivity voxel-wise interaction indicated that only monkeys with high stress reactivity and high basal cortisol demonstrated lower brain volume and tissue density in prefrontal cortices, hippocampus, and amygdala.High stress reactivity predicted lower volume and microstructural tissue density in regions involved in emotional processing and modulation. A CR diet reduced stress reactivity and regional associations with neural modalities. High levels of cortisol appear to mediate some of these relationships.

Dataset Information

Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys.

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Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys.

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