Ketogenic diet and metabolic regulation of brain microglia

Abstract Ketogenic diet (KD) has been proposed as a coadjuvant therapy in the treatment of brain tumours. Reduction of blood glucose and increase in ketone bodies concentration are amongst the most important changes induced by KD in patients. Preliminary data collected in our lab indicates that KD induces substantial changes in the immune system in mice bearing brain tumours. Microglia are brain-resident immune cells that account for around 30% of the tumour mass and play a major role in controlling tumour progression by adopting a protumour (M2 polarisation) or antitumour (M1 polarisation) phenotype. We are interested in understating the molecular and metabolic determinants of microglia polarisation and how these can be modulated by the metabolic microenvironment and KD. We report some initial findings that indicate microglia adapt to changes in the metabolic microenvironment and that nutrient availability can modulate microglia activation and polarisation. We believe that the study of microglia metabolism and nutritional interventions like KD can provide new knowledge about the regulation of the brain immune system and unveil novel routes for brain cancer treatment.

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Ketogenic Diet, Aging, and Neurodegeneration

10.1093/med/9780190497996.003.0024 ◽

2016 ◽

Cited By ~ 1

Author(s):

Kui Xu ◽

Joseph C. LaManna ◽

Michelle A. Puchowicz

Keyword(s):

Oxidative Stress ◽

Energy Source ◽

Blood Flow ◽

Ketogenic Diet ◽

Ketone Bodies ◽

Neurovascular Unit ◽

Cerebral Metabolic Rate ◽

Downstream Effects ◽

Atp Supply ◽

The Brain

The brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α‎) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α‎.

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Ketogenic Diet and PPARgamma

10.1093/med/9780190497996.003.0020 ◽

2016 ◽

Cited By ~ 1

Author(s):

Timothy A. Simeone

Keyword(s):

Ketogenic Diet ◽

Refractory Epilepsy ◽

Ketone Bodies ◽

Peroxisome Proliferator ◽

Potential Therapeutic Target ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Transcription Factor ◽

Inflammatory Processes ◽

The Brain

The ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial function, which is thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. This chapter focuses on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews what is known concerning PPARgamma in the brain, the evidence that PPARgamma has neuroprotective and antiseizure properties, and the evidence suggesting that PPARgamma may be involved in the antiseizure mechanisms of the ketogenic diet.

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Metabolic regulation of synaptic activity

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0090 ◽

2018 ◽

Vol 29 (8) ◽

pp. 825-835 ◽

Cited By ~ 5

Author(s):

Sergei V. Fedorovich ◽

Tatyana V. Waseem

Keyword(s):

Metabolic Disease ◽

Ketogenic Diet ◽

Neuronal Death ◽

Metabolic Regulation ◽

Glutamate Release ◽

Epileptic Seizures ◽

Brain Dysfunction ◽

Synaptic Activity ◽

Brain Diseases ◽

The Brain

AbstractBrain tissue is bioenergetically expensive. In humans, it composes approximately 2% of body weight and accounts for approximately 20% of calorie consumption. The brain consumes energy mostly for ion and neurotransmitter transport, a process that occurs primarily in synapses. Therefore, synapses are expensive for any living creature who has brain. In many brain diseases, synapses are damaged earlier than neurons start dying. Synapses may be considered as vulnerable sites on a neuron. Ischemic stroke, an acute disturbance of blood flow in the brain, is an example of a metabolic disease that affects synapses. The associated excessive glutamate release, called excitotoxicity, is involved in neuronal death in brain ischemia. Another example of a metabolic disease is hypoglycemia, a complication of diabetes mellitus, which leads to neuronal death and brain dysfunction. However, synapse function can be corrected with “bioenergetic medicine”. In this review, a ketogenic diet is discussed as a curative option. In support of a ketogenic diet, whereby carbohydrates are replaced for fats in daily meals, epileptic seizures can be terminated. In this review, we discuss possible metabolic sensors in synapses. These may include molecules that perceive changes in composition of extracellular space, for instance, ketone body and lactate receptors, or molecules reacting to changes in cytosol, for instance, KATPchannels or AMP kinase. Inhibition of endocytosis is believed to be a universal synaptic mechanism of adaptation to metabolic changes.

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Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice

Nutrients ◽

10.3390/nu13072167 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2167

Author(s):

María del Carmen Blanco-Gandía ◽

Francisco Ródenas-González ◽

María Pascual ◽

Marina Daiana Reguilón ◽

Consuelo Guerri ◽

...

Keyword(s):

Gene Expression ◽

Ketogenic Diet ◽

Adult Male ◽

Ketone Bodies ◽

Standard Diet ◽

Male Mice ◽

Self Administration ◽

Nutritional Interventions ◽

Glucose Levels ◽

Gene Expression Analyses

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

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Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review

Frontiers in Nutrition ◽

10.3389/fnut.2021.807970 ◽

2022 ◽

Vol 8 ◽

Author(s):

Matthieu Lilamand ◽

François Mouton-Liger ◽

Emmanuelle Di Valentin ◽

Marta Sànchez Ortiz ◽

Claire Paquet

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Ketone Bodies ◽

Amyloid Peptide ◽

Nutritional Interventions ◽

Ketogenic Diets ◽

Age Related ◽

Β Amyloid ◽

The Brain

Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.

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Potential immunotherapy for Alzheimer disease and age-related dementia

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2019.21.1/mischwartz ◽

2019 ◽

Vol 21 (1) ◽

pp. 21-25 ◽

Cited By ~ 1

Keyword(s):

Immune System ◽

Alzheimer Disease ◽

Cross Talk ◽

Immune Checkpoint ◽

Short Review ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

New Approach ◽

Age Related ◽

The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

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Potential immunotherapy for Alzheimer disease and age-related dementia

Dialogues in Clinical Neuroscience ◽

10.31887/dnc.2019.21.1/mschwartz ◽

2019 ◽

Vol 21 (1) ◽

pp. 21-25 ◽

Cited By ~ 1

Keyword(s):

Immune System ◽

Alzheimer Disease ◽

Cross Talk ◽

Immune Checkpoint ◽

Short Review ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

New Approach ◽

Age Related ◽

The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

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