Brain Glucose Uptake Research Articles

Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Strongly Predict Whole-Body Insulin Resistance in the Development of Type 2 Diabetes

We aimed to elucidate tissue-specific glucose uptake in the development of whole-body insulin resistance and type 2 diabetes (T2D). We recruited 13 T2D(D), 12 prediabetes (IFG/IGT) (P), and 10 control (C) subjects, matched for age and BMI. Integrated whole-body 18F-FDG PET and MRI was performed during a hyperinsulinemic euglycemic clamp to assess glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver correlated positively with the M-value. Muscle and adipose tissue MRglu was lower in both P and D. D had lower liver MRglu than P and C. Brain MRglu was higher in D and P and it was inversely correlated with M-values. The M-value was best predicted by a multivariate model (adjusted r2= 0.85) including muscle (Std.β-Coeff.=0.64, p<0.001), VAT (Std.β-Coeff.=0.18, p<0.05) and brain MRglu (Std.β-Coeff.=-0.33, p<0.001). In the development of T2D, brain glucose uptake is enhanced during hyperinsulinemia in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated brain MRglu were independently associated with whole-body insulin resistance. This suggests that these alterations may contribute to T2D development.Table 1.Table 1M-Value (g/kg lbm/min)MRglu Muscle (μmol/100g/min)MRglu Liver (<μmol/100g/min)MRglu VAT (μmol/100g/min)MRglu SAT (μmol/100g/min)MRgluHeart (μmol/100g/min)MRgluBrain (μmol/100g/min)Control10.82 ± 1.1415.4 ± 1.96.2 ± 0.73.4 ± 0.52 ± 0.480.5 ± 4.815.8 ± 1.4Prediabetes6.33 ± 0.96 **8.8 ± 1.2**6.6 ± 0.82.5 ± 0.4*1.8 ± 0.176.7 ± 9.418.4 ± 0.9*T2D5.12 ± 0.69 **6.7 ± 1.2**3.7 ± 0.6*¤2.1 ± 0.3*1.4 ± 0.2*79.7 ± 7.419.3 ± 1.1* M-ValueMuscleLiverVATSATHeartBrainMuscler=0.884**r=0.335*r=0.712**r=0.596**r=0.156r=-0.437**Liverr=0.403*r=0.335*r=0.462**r=0.557**r=-0.166r=-0.167VATr=0.707**r=0.712**r=0.462**r=0.683**r=0.126r=-0.259SATr=0.574**r=0.596**r=0.557**r=0.683**r=0.064r=-0.058Heartr=0.149r=0.156r=-0.166r=0.126r=0.064r=-0.007Brainr=-0.616**r=-0.437**r=-0.167r=-0.259r=-0.058r=-0.007* p<0.05, ** p<0.01 for comparisons vs. C, or ¤ p<0.for comparison vs. P. Disclosure G.J. Boersma: None. K. Heurling: None. M.J. Pereira: None. E. Johansson: None. M. Lubberink: None. P. Katsogiannos: None. S. Skrtic: Employee; Self; AstraZeneca. J. Kullberg: Stock/Shareholder; Self; Antaros Medical. Board Member; Self; Antaros Medical. Employee; Self; Antaros Medical. H. Ahlström: Stock/Shareholder; Self; Antaros Medical AB. J.W. Eriksson: Employee; Spouse/Partner; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp.. Research Support; Self; Bristol-Myers Squibb Company.

Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease.

In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Evaluation of drug effects on cerebral blood flow and glucose uptake in un-anesthetized and un-stimulated rats: application of free-moving apparatus enabling to keep rats free during PET/SPECT tracer injection and uptake.

ObjectivesThe purpose of this study is the development of novel fluorine-18-fluorodeoxyglucose (18F-FDG)-PET and 99mTc-hexamethylpropylene amine oxime (HMPAO) SPECT methods with free-moving apparatus on conscious rats to investigate brain activity without the effects of anesthesia and tactual stimulation. We also assessed the sensitivity of the experimental system by an intervention study using fluoxetine as a reference drug.Materials and methodsA catheter was inserted into the femoral vein and connected to a free-moving cannula system. After fluoxetine administration, the rats were given an injection of 18F-FDG or 99mTc-HMPAO via the intravenous cannula and released into a free-moving cage. After the tracer was trapped in the brain, the rats were anesthetized and scanned with PET or SPECT scanners. Then a volume of interest analysis and statistical parametric mapping were performed.ResultsWe could inject the tracer without touching the rats, while keeping them conscious until the tracers were distributed and trapped in the brain using the developed system. The effects of fluoxetine on glucose uptake and cerebral blood flow were perceptively detected by volume of interest and statistical parametric mapping analysis.ConclusionWe successfully developed free-moving 18F-FDG-PET and 99mTc-HMPAO-SPECT imaging systems and detected detailed glucose uptake and cerebral blood flow changes in the conscious rat brain with fluoxetine administration. This system is expected to be useful to assess brain activity without the effects of anesthesia and tactual stimulation to evaluate drug effect or animal brain function.

Metabolism and Redox Signaling in Brain Aging

A decrease in energy metabolism is associated with brain aging, which was assessed in terms of a coordinated metabolic triad encompassed by mitochondria, insulin signaling (IIS), and JNT ((c-Jun N-terminal kinase) signaling. Impairment of these coordinated responses leads to the cognitive decline that occurs with aging and neurodegenerative disorders. The complexity of the antagonism and cross-talk between IIS- and JNT (signaling and how they converge on mitochondrial function underscores the significance of an insulin resistance state. The hypometabolic state inherent in brain aging, a mouse model of Alzheimer's disease, and high-fat diet-induced obesity was accompanied by decreased brain glucose uptake, an imbalance between IIS- and JNT (signaling, decreased rate of glycolysis and flux of metabolites to the TCA cycle, and diminished synaptic plasticity. These effects are not cell specific, for astrocytes developed an age-dependent energy phenotype (increased mitochondrial oxidative metabolism and biogenesis) and augmented responses to inflammatory cytokines. In most of the models described above, the hypometabolic state was rescued by treatment with lipoic acid, likely through a thiol/disulfide mechanism, which resulted largely in improved IIS and in synaptic plasticity.

VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans

ObjectiveReduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study. Methods92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. ResultsIn this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10−11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. ConclusionsThe results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance. Clinical Trial Registration NumberNCT01631123

Increased Brain Glucose Uptake After 12 Weeks of Aerobic High-Intensity Interval Training in Young and Older Adults

Aerobic exercise training can increase brain volume and blood flow, but the impact on brain metabolism is less known. We determined whether high-intensity interval training (HIIT) increases brain metabolism by measuring brain glucose uptake in younger and older adults. Brain glucose uptake was measured before and after HIIT or a sedentary (SED) control period within a larger exercise study. Study procedures were performed at the Mayo Clinic in Rochester, MN. Participants were younger (18 to 30 years) or older (65 to 80 years) SED adults who were free of major medical conditions. Group sizes were 15 for HIIT (nine younger and six older) and 12 for SED (six younger and six older). Participants completed 12 weeks of HIIT or SED. HIIT was 3 days per week of 4 × 4 minute intervals at over 90% of peak aerobic capacity (VO2peak) with 2 days per week of treadmill walking at 70% VO2peak. Resting brain glucose uptake was measured using 18F-fluorodeoxyglucose positron emission tomography scans at baseline and at week 12. Scans were performed at 96 hours after exercise. VO2peak was measured by indirect calorimetry. Glucose uptake increased significantly in the parietal-temporal and caudate regions after HIIT compared with SED. The gains with HIIT were not observed in all brain regions. VO2peak was increased for all participants after HIIT and did not change with SED. We demonstrate that brain glucose metabolism increased after 12 weeks of HIIT in adults in regions where it is reduced in Alzheimer's disease.

Short-term interval training alters brain glucose metabolism in subjects with insulin resistance

Brain insulin-stimulated glucose uptake (GU) is increased in obese and insulin resistant subjects but normalizes after weight loss along with improved whole-body insulin sensitivity. Our aim was to study whether short-term exercise training (moderate intensity continuous training (MICT) or sprint interval training (SIT)) alters substrates for brain energy metabolism in insulin resistance. Sedentary subjects (n = 21, BMI 23.7–34.3 kg/m2, age 43–55 y) with insulin resistance were randomized into MICT (n = 11, intensity≥60% of VO2peak) or SIT (n = 10, all-out) groups for a two-week training intervention. Brain GU during insulin stimulation and fasting brain free fatty acid uptake (FAU) was measured using PET. At baseline, brain GU was positively associated with the fasting insulin level and negatively with the whole-body insulin sensitivity. The whole-body insulin sensitivity improved with both training modes (20%, p = 0.007), while only SIT led to an increase in aerobic capacity (5%, p = 0.03). SIT also reduced insulin-stimulated brain GU both in global cortical grey matter uptake (12%, p = 0.03) and in specific regions (p < 0.05, all areas except the occipital cortex), whereas no changes were observed after MICT. Brain FAU remained unchanged after the training in both groups. These findings show that short-term SIT effectively decreases insulin-stimulated brain GU in sedentary subjects with insulin resistance.

P14 LW-AFC treatment improves learning-memory ability and brain glucose metabolism in a mouse model of Alzheimer’s Disease

Objective: Alzheimer’s disease (AD) causes progressive hippocampus dysfunctions leading to the impairment of learning and memory ability and a reduced uptake rate of glucose in the hippocampus. LW-AFC is a new formula derived from the classical traditional Chinese medicinal prescription Liuwei Dihuang decoction. In this study, we investigated the beneficial and protective effects of LW-AFC in learning-memory ability and brain glucose metabolism in a widely used AD model, the senescence-accelerated prone mouse (SAMP8). Methods: SAMP8 mice were administrated LW-AFC (1.6 g/kg) for 2 months. The Morris water maze (MWM) test, shuttle box test, and novel object recognition test, were all used to evaluate cognition abilities. Fluorodeoxyglucose positron emission tomography (FDG-PET) was employed to detect the level of glucose uptake in the mouse brain. The concentrations of ATP, ADP and AMP were determined by HPLC. Results: The results from the MWM, shuttle box, and novel object recognition tests showed impairments in object recognition memory and spatial learning and memory, and active avoidance in SAMP8 mice. Administration of LW-AFC ameliorated the impairments in learning and memory abilities. The FDG-PET results showed a decrease in the uptake of glucose in the brains of SAMP8 mice with increasing age. LW-AFC enhanced glucose uptake in the brain of SAMP8 mice. Decreases in the concentrations of ATP, ADP and AMP were also found in the brains of SAMP8 mice. Administration of LW-AFC increased the concentration of all energy substances. Conclusion: LW-AFC could ameliorate deterioration of cognition in SAMP8 mice by improving glucose metabolism.

Loss of Brain Aerobic Glycolysis in Normal Human Aging

The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow incognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.

Effects of Lipoic Acid on High-Fat Diet-Induced Alteration of Synaptic Plasticity and Brain Glucose Metabolism: A PET/CT and 13C-NMR Study

High-fat diet (HFD)-induced obesity is accompanied by insulin resistance and compromised brain synaptic plasticity through the impairment of insulin-sensitive pathways regulating neuronal survival, learning, and memory. Lipoic acid is known to modulate the redox status of the cell and has insulin mimetic effects. This study was aimed at determining the effects of dietary administration of lipoic acid on a HFD-induced obesity model in terms of (a) insulin signaling, (b) brain glucose uptake and neuronal- and astrocytic metabolism, and (c) synaptic plasticity. 3-Month old C57BL/6J mice were divided into 4 groups exposed to their respective treatments for 9 weeks: (1) normal diet, (2) normal diet plus lipoic acid, (3) HFD, and (4) HFD plus lipoic acid. HFD resulted in higher body weight, development of insulin resistance, lower brain glucose uptake and glucose transporters, alterations in glycolytic and acetate metabolism in neurons and astrocytes, and ultimately synaptic plasticity loss evident by a decreased long-term potentiation (LTP). Lipoic acid treatment in mice on HFD prevented several HFD-induced metabolic changes and preserved synaptic plasticity. The metabolic and physiological changes in HFD-fed mice, including insulin resistance, brain glucose uptake and metabolism, and synaptic function, could be preserved by the insulin-like effect of lipoic acid.

Brain metabolism in health, aging, andneurodegeneration.

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.

Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults

BackgroundKetones are the brain’s main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear. ObjectiveThe aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8. MethodsIn a crossover design, 9 participants with mean ± SD ages 34 ± 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and β-hydroxybutyrate (β-HB) analysis. ResultsC8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol ⋅ h/L and 1876 ± 772 µmol ⋅ h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses. ConclusionsIn healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at clinicaltrials.gov as NCT 02679222.

Fluoride Alteration of [3H]Glucose Uptake in Wistar Rat Brain and Peripheral Tissues

The present study was designed to investigate the role of postnatal fluoride intake on [3H]glucose uptake and transport in rat brain and peripheral tissues. Sodium fluoride (NaF) in a concentration of 10 or 50 ppm was added to the drinking water of adult Wistar rats. The control group received distilled water. After 4 weeks, respective plasma fluoride levels were 0.0541 ± 0.0135 μg/ml (control), 0.0596 ± 0.0202 μg/ml (10 ppm), and 0.0823 ± 0.0199 μg/ml (50 ppm). Although plasma glucose levels were not altered in any group, the plasma insulin level in the fluoride (50 ppm) group was elevated (0.72 ± 0.13 μg/ml) versus the control group (0.48 ± 0.24 μg/ml) and fluoride (10 ppm) group. In rats receiving fluoride for 4 weeks at 10 ppm in drinking water, [3H]glucose uptake was unaltered in all tested parts of the brain. However, in rats receiving fluoride at 50 ppm, [3H]glucose uptake in cerebral cortex, hippocampus, and thalamus with hypothalamus was elevated, versus the saline group. Fluoride intake had a negligible effect on [3H]glucose uptake by peripheral tissues (liver, pancreas, stomach, small intestine, atrium, aorta, kidney, visceral tissue, lung, skin, oral mucosa, tongue, salivary gland, incisor, molars, and jawbone). In neither fluoride group was glucose transporter proteins 1 (GLUT 1) or 3 (GLUT 3) altered in frontal cortex and striatum versus control. On the assumption that increased glucose uptake (by neural tissue) reasonably reflects neuronal activity, it appears that fluoride damage to the brain results in a compensatory increase in glucose uptake and utilization without changes in GLUT 1 and GLUT 3 expression.

Effects of tetrahydrocannabinol on glucose uptake in the rat brain

Δ9-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain. The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain. 21 male Sprague Dawley rats (12–13 w) were examined and received five different doses of THC ranging from 0.01 to 1 mg/kg. For data acquisition a Focus 120 small animal PET scanner was used and 24.1–28.0 MBq of [18F]-fluoro-2-deoxy-d-glucose were injected. The data were acquired for 70 min and arterial blood samples were collected throughout the scan. THC, THC-OH and THC-COOH were determined at 55 min p.i. Nine volumes of interest were defined, and the cerebral glucose uptake was calculated for each brain region. Low blood THC levels of < 1 ng/ml (injected dose: ≤ 0.01 mg/kg) corresponded to an increased glucose uptake (6–30 %), particularly in the hypothalamus (p = 0.007), while blood THC levels > 10 ng/ml (injected dose: ≥ 0.05 mg/kg) coincided with a decreased glucose uptake (−2 to −22 %), especially in the cerebellar cortex (p = 0.008). The effective concentration in this region was estimated 2.4 ng/ml. This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose – an effect that may be of relevance in behavioural studies.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation.

Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)-mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.

Increases in Brain 1H-MR Glutamine and Glutamate Signals Following Acute Exhaustive Endurance Exercise in the Rat.

Objective: Proton magnetic resonance spectroscopy (1H-MRS) in ultra-high magnetic field can be used for non-invasive quantitative assessment of brain glutamate (Glu) and glutamine (Gln) in vivo. Glu, the main excitatory neurotransmitter in the central nervous system, is efficiently recycled between synapses and presynaptic terminals through Glu-Gln cycle which involves glutamine synthase confined to astrocytes, and uses 60–80% of energy in the resting human and rat brain. During voluntary or involuntary exercise many brain areas are significantly activated, which certainly intensifies Glu-Gln cycle. However, studies on the effects of exercise on 1H-MRS Glu and/or Gln signals from the brain provided divergent results. The present study on rats was performed to determine changes in 1H-MRS signals from three brain regions engaged in motor activity consequential to forced acute exercise to exhaustion.Method: After habituation to treadmill running, rats were subjected to acute treadmill exercise continued to exhaustion. Each animal participating in the study was subject to two identical imaging sessions performed under light isoflurane anesthesia, prior to, and following the exercise bout. In control experiments, two imaging sessions separated by the period of rest instead of exercise were performed. 1H-NMR spectra were recorded from the cerebellum, striatum, and hippocampus using a 7T small animal MR scanner.Results: Following exhaustive exercise statistically significant increases in the Gln and Glx signals were found in all three locations, whereas increases in the Glu signal were found in the cerebellum and hippocampus. In control experiments, no changes in 1H-MRS signals were found.Conclusion: Increase in glutamine signals from the brain areas engaged in motor activity may reflect a disequilibrium caused by increased turnover in the glutamate-glutamine cycle and a delay in the return of glutamine from astrocytes to neurons. Increased turnover of Glu-Gln cycle may be a result of functional activation caused by forced endurance exercise; the increased rate of ammonia detoxification may also contribute. Increases in glutamate in the cerebellum and hippocampus are suggestive of an anaplerotic increase in glutamate synthesis due to exercise-related stimulation of brain glucose uptake. The disequilibrium in the glutamate-glutamine cycle in brain areas activated during exercise may be a significant contributor to the central fatigue phenomenon.

18F]FDG PET signal is driven by astroglial glutamate transport.

Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide the first positron emission tomography (PET) evidence that activation of the astrocytic glutamate transport via GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [18F]FDG PET data, whereby astrocytes would be recognized to contribute significantly to the [18F]FDG signal.

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability.

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.

Spatial distribution of resting-state BOLD regional homogeneity as a predictor of brain glucose uptake: A study in healthy aging

Positron emission tomography using [18F]-fluorodeoxyglucose (PET-FDG) is the primary imaging modality used to measure glucose metabolism in the brain (CMRGlu). CMRGlu has been used as a biomarker of brain aging and neurodegenerative diseases, but the complexity and invasive nature of PET often limits its use in research. There is therefore great interest in developing non-invasive metrics for estimating brain CMRGlu. We therefore investigated resting state fMRI metrics such as regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF) and regional global connectivity (Closeness) with multiple analytical approaches to determine their relationship to CMRGlu. We investigated this relation in two distinct cognitively healthy populations separated by age (27 young adults and 35 older adults). Overall, we found that both regionally and across participants, ReHo strongly correlated with CMRGlu in healthy young and older adults. Moreover, ReHo demonstrated the same age-related differences as CMRGlu throughout all cortical regions, particularly in the default network and frontal areas.

The effects of nicotine administration and drug cue on impulsivity

Several [18F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [18F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [18F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [18F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle.