•Chronic social stress (CSS) leads to increased energy need.•CSS leads to increased dependence on carbohydrate as energy source.•CSS leads to reduced insulin and slower glucose clearance.•CSS leads ...to increased ghrelin and reduced leptin.•CSS leads to lower glucose utilization by the brain.
Chronic stress leads to changes in energy status and is a major risk factor for depression, with common symptoms of reductions in body weight and effortful motivation for reward. Indeed, stress-induced disturbed energy status could be a major aetio-pathogenic factor for depression. Improved understanding of these putative inter-relationships requires animal model studies of effects of stress on both peripheral and central energy-status measures and determinants. Here we conducted a study in mice fed on a standard low-fat diet and exposed to either 15-day chronic social stress (CSS) or control handling (CON). Relative to CON mice, CSS mice had attenuated body weight maintenance/gain despite consuming the same amount of food and expending the same amount of energy at any given body weight. The low weight of CSS mice was associated with less white and brown adipose tissues, and with a high respiratory exchange ratio consistent with increased dependence on glucose as energy substrate. Basal plasma insulin was low in CSS mice and exogenous glucose challenge resulted in a relatively prolonged elevation of blood glucose. With regard to hunger and satiety hormones, respectively, CSS mice had higher levels of acylated ghrelin in plasma and of ghrelin receptor gene expression in ventromedial hypothalamus and lower levels of plasma leptin, relative to CON mice. However, whilst CSS mice displayed this constellation of peripheral changes consistent with increases in energy need and glucose utilization relative to CON mice, they also displayed attenuated uptake of 18FFDG in brain tissue specifically. Reduced brain glucose utilization in CSS mice could contribute to the reduced effortful motivation for reward in the form of sweet-tasting food that we have reported previously for CSS mice. It will now be important to utilize this model to further understanding of the mechanisms via which chronic stress can increase energy need but decrease brain glucose utilization and how this relates to regional and cellular changes in neural circuits for reward processing relevant to depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brain glucose hypometabolism is a significant manifestation of Alzheimer’s disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as factors possibly influencing the ...pathogenesis of AD. This study aimed to investigate the link between 27-OHC, the gut microbiota, and brain glucose uptake in AD. Here, 6-month-old male C57BL/6 J mice were treated with sterile water or antibiotic cocktails, with or without 27-OHC and/or 27-OHC synthetic enzyme CYP27A1 inhibitor anastrozole (ANS). The gut microbiota, brain glucose uptake levels, and memory ability were measured. We observed that 27-OHC altered microbiota composition, damaged brain tissue structures, decreased the 2-deoxy-2-18 F fluorodeoxyglucose (18F-FDG) uptake value, downregulated the gene expression of glucose transporter type 4 (GLUT4), reduced the colocalization of GLUT1/glial fibrillary acidic protein (GFAP) in the hippocampus, and impaired spatial memory. ANS reversed the effects of 27-OHC. The antibiotic-treated mice did not exhibit similar results after 27-OHC treatment. This study reveals a potential molecular mechanism wherein 27-OHC-induced memory impairment might be linked to reduced brain glucose uptake, mediated by the gut microbiota.
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•27-OHC affects gut microbiota composition and induces gut microbiota dysbiosis.•27-OHC decreases brain glucose uptake and induces memory impairment of mice.•27-OHC did not decrease brain glucose uptake in microbiota-depleted mice.•GLUT1 and GLUT4 are important factors in the regulation of brain glucose uptake.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alteration in brain glucose metabolism due to glucose uptake reduction has been described in the onset of certain neurodegenerative disorders. This study determined Harpephyllum caffrum fruit's ...potential ability to improve glucose uptake and its modulatory effects on intrinsic antioxidant, glucogenic, cholinergic, and nucleotide‐hydrolyzing enzyme activities in isolated rat brain. Consequently, the bioactive compounds of the fruits were identified with LC–MS. The fruit significantly improved brain glucose uptake following coincubation with glucose and brain tissue. The fruit extract also elevated GSH level, SOD, catalase, glycogen phosphorylase, and ENTPDase activities while simultaneously suppressing NO and malonaldehyde levels and fructose‐1,6‐bisphosphatase, ATPase, acetylcholinesterase and butyrylcholinesterase activities. LC–MS analysis revealed S‐methylcysteine sulfoxide, dihydroquercetin, 3,4‐dimethyl‐2,5‐bis(3,4,5‐trimethoxyphenyl) tetrahydrofuran (MTHF), nobiletin, puerarin, quercetin 3‐rutinoside, 8‐D‐glucosyl‐4′,5,7‐trihydroxyflavone, asperulosidic acid, 1,2,4,6‐tetragalloylglucose, and phellamurin. This study suggests the neuroprotective effects of H. caffrum fruit due to its ability to enhance glucose uptake, attenuate glucose‐induced oxidative stress while modulating glucogenic, cholinergic, and nucleotide‐hydrolyzing enzyme activities in normal brain tissues.
Practical applications
Available scientific evidence describes oxidative stress as one of the physiological processes contributing to aging‐associated neurodegeneration in humans. In this regard, commonly consumed natural products from plants have attracted much interest due to their ability to mitigate redox imbalance‐related pathologies that affect various organs in the body such as the brain. Harpephyllum caffrum or bush mango is an evergreen plant native to the South African vegetation. The fruit from the plant is consumed locally as food or specifically for improving the nutritional quality of meals as deserts or condiments. While previous findings described the high antioxidant properties of the fruits, this study reported possible mechanisms via which the plant may exhibit ameliorative effects against oxidative stress‐related neurological disorders in the brain. Hence, findings from the current work present another justification for the significance of fruits as a safer nutraceutical alternative for therapy in neurological disease management.
Harpephyllum caffrum fruits improve brain glucose uptake and utilization, with concomitant improvement of brain's antioxidant, cholinergic, and glucogenic enzyme activities.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after ...Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (
) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the
marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and
KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.
The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.
Aims
To investigate further the finding that insulin enhances brain glucose uptake (BGU) in obese but not in lean people by combining BGU with measures of endogenous glucose production (EGP), and to ...explore the associations between insulin‐stimulated BGU and peripheral markers, such as metabolites and inflammatory markers.
Materials and methods
A total of 20 morbidly obese individuals and 12 lean controls were recruited from the larger randomized controlled SLEEVEPASS study. All participants were studied under fasting and euglycaemic hyperinsulinaemic conditions using fluorodeoxyglucose‐positron emission tomography. Obese participants were re‐evaluated 6 months after bariatric surgery and were followed‐up for ~3 years.
Results
In obese participants, we found a positive association between BGU and EGP during insulin stimulation. Across all participants, insulin‐stimulated BGU was associated positively with systemic inflammatory markers and plasma levels of leucine and phenylalanine. Six months after bariatric surgery, the obese participants had achieved significant weight loss. Although insulin‐stimulated BGU was decreased postoperatively, the association between BGU and EGP during insulin stimulation persisted. Moreover, high insulin‐stimulated BGU at baseline predicted smaller improvement in fasting plasma glucose at 2 and 3 years of follow‐up.
Conclusions
Our findings suggest the presence of a brain‐liver axis in morbidly obese individuals, which persists postoperatively. This axis might contribute to further deterioration of glucose homeostasis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose (
F-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular ...in differentiating Alzheimer's disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes-two diseases characterized by systemic insulin resistance-are associated with an increased risk for AD. Along with the well-defined patterns of fasting
F-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with
F-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.
Aims
Recent clinical studies have shown enhanced brain glucose uptake during clamp and brain fatty acid uptake in insulin‐resistant individuals. Preclinical studies suggest that the brain may be ...involved in the control of insulin secretion. The aim of this study was to investigate whether brain metabolism assessed as brain glucose and fatty acid uptake is associated with the parameters of β‐cell function in humans.
Materials and methods
We analysed cross‐sectional data of 120 subjects across a wide range of BMI and insulin sensitivity. Brain glucose uptake (BGU) was measured during euglycaemic‐hyperinsulinaemic clamp (n = 67) and/or during fasting (n = 45) using 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET). In another group of subjects (n = 34), brain fatty acid uptake was measured using 18F‐fluoro‐6‐thia‐heptadecanoic acid (FTHA) PET during fasting. The parameters of β‐cell function were derived from OGTT modelling. Statistical analysis was performed with whole‐brain voxel‐based statistical parametric mapping.
Results
In non‐diabetics, BGU during euglycaemic hyperinsulinaemic clamp correlated positively with basal insulin secretion rate (r = 0.51, P = .0008) and total insulin output (r = 0.51, P = .0008), whereas no correlation was found in type 2 diabetics. BGU during clamp correlated positively with potentiation in non‐diabetics (r = 0.33, P = .02) and negatively in type 2 diabetics (r = −0.61, P = .02). The associations in non‐diabetics were not explained with whole‐body insulin sensitivity or BMI. No correlations were found between baseline (fasting) BGU and basal insulin secretion rate, whereas baseline brain fatty acid uptake correlated directly with basal insulin secretion rate (r = 0.39, P = .02) and inversely with potentiation (r = −0.36, P = .04).
Conclusions
Our study provides coherent, though correlative, evidence that, in humans, the brain may be involved in the control of insulin secretion independently of insulin sensitivity.
Preclinical studies suggest that the brain may be involved in the control of insulin secretion, but data on humans are scanty. Our study provides coherent, though correlative, evidence that, in humans, the brain may be involved in the control of insulin secretion independently of insulin sensitivity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the
gene has been ...linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here,
F-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the
gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance.
Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that ...components of the insulin‐mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin‐dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin‐dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin‐signaled GLUT4 transport. We studied hippocampal high‐energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood–brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. 31Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)‐to‐adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity.
The physiological role of insulin in brain glucose uptake has not previously been well characterized. We propose that the kinetics of insulin mediated glucose uptake are such that in the brain, it may play a role in facilitating the required acute rapid increases in neuronal glucose uptake in response to cognitive activity. We present data from a new in vivo experimental in vivo approach which supports this proposed role.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The purpose of this study was to assess the effects of four anesthetic protocols on normal canine brain uptake of 2‐deoxy‐2‐18Ffluoro‐d‐glucose (FDG) using positron emission tomography/computed ...tomography (PET/CT). Five clinically normal beagle dogs were anesthetized with (1) propofol/isoflurane, (2) medetomidine/pentobarbital, (3) xylazine/ketamine, and (4) medetomidine/tiletamine–zolazepam in a randomized cross‐over design. The standard uptake value (SUV) of FDG was obtained in the frontal, parietal, temporal and occipital lobes, cerebellum, brainstem and whole brain, and compared within and between anesthetic protocols using the Friedman test with significance set at P<0.05. Significant differences in SUVs were observed in various part of the brain associated with each anesthetic protocol. The SUV for the frontal and occipital lobes was significantly higher than in the brainstem in all dogs. Dogs receiving medetomidine/tiletamine–zolazepam also had significantly higher whole brain SUVs than the propofol/isoflurane group. We concluded that each anesthetic protocol exerted a different regional brain glucose uptake pattern. As a result, when comparing brain glucose uptake using PET/CT, one should consider the effects of anesthetic protocols on different regions of the glucose uptake in the dog's brain.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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