State-Dependent Changes in Brain Glycogen Metabolism

DiNuzzo, Mauro; Walls, Anne B.; Öz, Gülin; Seaquist, Elizabeth R.; Waagepetersen, Helle S.; Bak, Lasse K.; Nedergaard, Maiken; Schousboe, Arne

doi:10.1007/978-3-030-27480-1_9

Cited by 10 publications

(9 citation statements)

References 254 publications

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“…During intense brain activity, glycogen converted to lactate and released from astrocytes can be used by neurons as mitochondrial fuel. Meanwhile, rapid glycogenolytic generation of ATP may be important for astrocytic energy demands (Dienel and Rothman, 2019) and thus glycogenolysis, by reducing the astrocytic requirement for blood-borne glucose, can spare an equivalent amount of glucose for neuronal utilization (Dienel, 2019a;DiNuzzo et al, 2019). The estimated glucose equivalent of glycogen concentration in astrocytes is up to 40-100 mM.…”

Section: Glycogen Production In Astrocytesmentioning

confidence: 99%

“…The estimated glucose equivalent of glycogen concentration in astrocytes is up to 40-100 mM. Considering the high rate of glycogenolysis, the amount of glucose that can be released via glycogen breakdown is very significant (Dienel, 2019a;DiNuzzo et al, 2019). Unfortunately, glycogen levels in the human brain during KD have yet to be investigated.…”

Section: Glycogen Production In Astrocytesmentioning

confidence: 99%

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Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Zilberter

Zilberter²

2020

eNeuro

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The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that glucose’s functions span beyond its role as an energy substrate, and in most of these functions, glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

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Section: Glycogen Production In Astrocytesmentioning

confidence: 99%

Section: Glycogen Production In Astrocytesmentioning

confidence: 99%

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Zilberter

Zilberter²

2020

eNeuro

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“…Furthermore, artificial tissue hypoxia has been reported in mice following cervical dislocation 33 , decapitation 34 , and CO2 euthanasia 35 . Brain tissue collection through conventional routes results in glycogen degradation and changes in global protein phosphorylation status 36,37 . A deeper understanding of neuronal function hinges on expanded metabolic pathway coverage, creating a critical need to establish an accurate baseline brain metabolome that excludes residual non-physiological metabolism that occurs post-mortem brain resection.…”

Section: Introductionmentioning

confidence: 99%

In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

Juras

Webb

Young

et al. 2022

Preprint

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The brain metabolome directly connects to brain physiology and neuronal function. Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. Therefore, challenges remain to capture an accurate snapshot of the physiological brain metabolome in healthy and diseased rodent models. To overcome this barrier, we employ a high-power focused microwave for the simultaneous euthanasia and fixation of mouse brain tissue to preserve metabolite pools prior to surgical removal and dissection of brain regions. We demonstrate exhaustion of glycogen and glucose and increase in lactate production during conventional rapid brain resection prior to preservation by liquid nitrogen that is not observed with microwave fixation. Next, microwave fixation was employed to define the impact of brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple regions of the mouse brain, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the TCA cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation to study terminal brain metabolism in rodent models.

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“…Astrocytes maintain the multi-branched glucose polysaccharide glycogen as a principal energy fuel alternative to blood-derived glucose. The brain glycogen depot, despite limitations in total mass, is dynamic during normal brain activity and metabolic stability ( Bélanger et al, 2011 , Stobart and Anderson, 2013 , DiNuzzo et al, 2019 ), and is an important source of lactate equivalents during states of heightened activity or hypoglycemia ( Gruetter, 2003 , Brown, 2004 ). Glycogen metabolism is controlled by opposing glycogen synthase (GS) and glycogen phosphorylase (GP) enzyme actions that correspondingly catalyze glycogen synthesis or breakdown.…”

Section: Introductionmentioning

confidence: 99%

Hindbrain catecholamine regulation of ventromedial hypothalamic nucleus glycogen metabolism during acute versus recurring insulin-induced hypoglycemia in male versus female rat

Briski

Napit

et al. 2021

Endocrine and Metabolic Science

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Ventromedial hypothalamic nucleus (VMN) glycogen metabolism affects local glucoregulatory signaling. The hindbrain metabolic-sensitive catecholamine (CA) neurotransmitter norepinephrine controls VMN glycogen phosphorylase (GP)-muscle (GPmm) and -brain (GPbb) type expression in male rats. Present studies addressed the premise that CA regulation of hypoglycemic patterns of VMN glycogen metabolic enzyme protein expression is sex-dimorphic, and that this signal is responsible for sex differences in acclimation of these profiles to recurrent insulin-induced hypoglycemia (RIIH). VMN tissue was acquired by micropunch-dissection from male and female rats pretreated by caudal fourth ventricular administration of the CA neurotoxin 6-hydroxydopamine (6OHDA) before single or serial insulin injection. 6-OHDA averted acute hypoglycemic inhibition of VMN glycogen synthase (GS) and augmentation of GPmm and GPbb protein expression in males, and prevented GPmm and -bb down-regulation in females. Males recovered from antecedent hypoglycemia (AH) exhibited neurotoxin-preventable diminution of baseline GS profiles, whereas acclimated GPmm and -bb expression in females occurred irrespective of pretreatment. RIIH did not alter VMN GS, GPmm, and GPbb expression in vehicle- or 6-OHDA-pretreated animals of either sex. VMN glycogen content was correspondingly unchanged or increased in males versus females following AH; 6-OHDA augmented glycogen mass in AH-exposed animals of both sexes. RIIH did not alter VMN glycogen accumulation in vehicle-pretreated rats of either sex, but diminished glycogen in neurotoxin-pretreated animals. AH suppresses baseline GS (CA-dependent) or GPmm/GPbb (CA-independent) expression in male and female rats, respectively, which corresponds with unaltered or augmented VMN glycogen content in those sexes. AH-associated loss of sex-distinctive CA-mediated enzyme protein sensitivity to hypoglycemia (male: GS, GPmm, GPbb; female: GPmm, Gpbb) may reflect, in part, VMN target desensitization to noradrenergic input.

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State-Dependent Changes in Brain Glycogen Metabolism

Cited by 10 publications

References 254 publications

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome

Hindbrain catecholamine regulation of ventromedial hypothalamic nucleus glycogen metabolism during acute versus recurring insulin-induced hypoglycemia in male versus female rat

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