Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes

Shima, Takeru; Matsui, Takashi; Jesmin, Subrina; Okamoto, Masahiro; Soya, Mariko; Inoue, Koshiro; Liu, Yu Fan; Torres‐Alemán, Ignacio; McEwen, Bruce S.; Soya, Hideaki

doi:10.1007/s00125-016-4164-4

Cited by 49 publications

(30 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In adult rats, hyperglycemia is associated with increased glycogen concentration and decreased MCT2 protein expression in the hippocampus. 16,17 MCT4 expression is not altered. 16 The effect on GLUT1 seems inconsistent, with some studies reporting upregulation and others finding no alteration.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, in adult rats, hyperglycemia alters glycogen and lactate metabolism in the hippocampus. 16,17 Astrocytic glycogen breakdown and astrocyte-neuron-lactate transport has an important role in hippocampal synaptic morphology and plasticity. [18][19][20] The objective of the present study was to determine the long-term effects of recurrent neonatal hyperglycemia of graded severity on hippocampal neurochemical profile and dendritic structure in rats.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

et al. 2018

View full text Add to dashboard Cite

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p< 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

et al. 2018

View full text Add to dashboard Cite

show abstract

“…For instance, a rat model of type 2 diabetes (Otsuka Long–Evans Tokushima Fatty rat: OLETF) have been reported to accumulate ~30% higher amounts of glycogen in the hippocampus (Shima et al, ) while brain stem glycogen levels remain similar (Shima, Jesmin, Matsui, Soya, & Soya, ). Another type 2 diabetes model rat strain (Zucker Diabetic Fatty rat: ZDF) was reported to have a tendency for decreased hippocampal glycogen levels (Shima et al, ; Sickmann, Waagepetersen, Schousboe, Benie, & Bouman, ). The streptozotocin (STZ) model of type I diabetes in the rat has been reported to result in modestly higher levels of glycogen (Plaschke & Hoyer, ), whereas magnetic resonance spectroscopic measurement from the occipital lobe of type 1 diabetes patients (Öz et al, ) show a tendency for decreased glycogen amounts.…”

Section: Hippocampal Glycogen Usagesmentioning

confidence: 99%

“…The literature on brain glycogen in diabetes is somewhat confounding. For instance, a rat model of type 2 diabetes (Otsuka Long-Evans Tokushima Fatty rat: OLETF) have been reported to accumulate ~30% higher amounts of glycogen in the hippocampus (Shima et al, 2017) while brain stem glycogen levels remain similar (Shima, Jesmin, Matsui, Soya, & Soya, 2018). Another type 2 diabetes model rat strain (Zucker Diabetic Fatty rat: ZDF) was reported to have a tendency for decreased hippocampal glycogen levels (Shima et al, 2017;Sickmann, Waagepetersen, Schousboe, Benie, & Bouman, 2010).…”

Section: ;mentioning

confidence: 99%

Glycogen distribution in mouse hippocampus

Hirase

Akther

Wang

et al. 2019

J of Neuroscience Research

View full text Add to dashboard Cite

The hippocampus is a limbic structure involved in the consolidation of episodic memory. In the recent decade, glycogenolysis in the rodent hippocampus has been shown critical for synaptic plasticity and memory formation. Astrocytes are the primary cells that store glycogen which is subject to degradation in hypoglycemic conditions. Focused microwave application to the brain halts metabolic activities, and therefore preserves brain glycogen. Immunohistochemistry against glycogen on focused microwave‐assisted brain samples is suitable for both macroscopic and microscopic investigation of glycogen distribution. Glycogen immunohistochemistry in the hippocampus showed a characteristic punctate signal pattern that depended on hippocampal layers. In particular, the hilus is the most glycogen‐rich subregion of the hippocampus. Moreover, large glycogen puncta (>0.5 µm in diameter) observed in neuropil areas are organized in a patchy pattern consisting of puncta‐rich and ‐poor astrocytes. These observations are discussed with respect to distinct hippocampal neural activity states observed in live animals.

show abstract

“…Chronic exercise that enhances endurance capacity and cognitive function has also been accompanied with elevated hippocampal glycogen levels in normal rats 16 . In our very recent study, 4 weeks of moderate exercise is effective in improving the declining memory function (hippocampal) in type 2 diabetic rats, and this exercise-induced hippocampal-memory amelioration has been associated with hyper-glycogen levels in the hippocampus 23 . Indeed, recent studies have demonstrated that pharmacological or genetic inhibition of hippocampal glycogen metabolism impairs memory formation and compromises endurance capacity 19 – 22 , 24 .…”

Section: Introductionmentioning

confidence: 87%

Hyper-hippocampal glycogen induced by glycogen loading with exhaustive exercise

Soya

Matsui

Shima

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Glycogen loading (GL), a well-known type of sports conditioning, in combination with exercise and a high carbohydrate diet (HCD) for 1 week enhances individual endurance capacity through muscle glycogen supercompensation. This exercise-diet combination is necessary for successful GL. Glycogen in the brain contributes to hippocampus-related memory functions and endurance capacity. Although the effect of HCD on the brain remains unknown, brain supercompensation occurs following exhaustive exercise (EE), a component of GL. We thus employed a rat model of GL and examined whether GL increases glycogen levels in the brain as well as in muscle, and found that GL increased glycogen levels in the hippocampus and hypothalamus, as well as in muscle. We further explored the essential components of GL (exercise and/or diet conditions) to establish a minimal model of GL focusing on the brain. Exercise, rather than a HCD, was found to be crucial for GL-induced hyper-glycogen in muscle, the hippocampus and the hypothalamus. Moreover, EE was essential for hyper-glycogen only in the hippocampus even without HCD. Here we propose the EE component of GL without HCD as a condition that enhances brain glycogen stores especially in the hippocampus, implicating a physiological strategy to enhance hippocampal functions.

show abstract

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes

Cited by 49 publications

References 55 publications

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

Glycogen distribution in mouse hippocampus

Hyper-hippocampal glycogen induced by glycogen loading with exhaustive exercise

Contact Info

Product

Resources

About