scholarly journals Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Gerwyn Morris ◽  
Michael Maes ◽  
Michael Berk ◽  
André F. Carvalho ◽  
Basant K. Puri
Keyword(s):  
Ketone Bodies ◽  
Coconut Oil ◽  
Glutamate Synthase ◽  
Acid Oxidation ◽  
Lactate Shuttle ◽  
Main Site ◽  
Therapeutic Applications ◽  
Low Carbohydrate ◽  
Glucose Restriction

Abstract Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

scholarly journals Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Senthilkumar Sivanesan ◽  
Ravi Mundugaru ◽  
Jayakumar Rajadas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ketone Bodies ◽  
Brain Regions ◽  
Pentose Phosphate ◽  
Lactate Shuttle ◽  
Carboxy Terminal ◽  
Brain Energy

Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer’s disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

scholarly journals Possible Role of Butyrylcholinesterase in Fat Loss and Decreases in Inflammatory Levels in Patients with Multiple Sclerosis after Treatment with Epigallocatechin Gallate and Coconut Oil: A Pilot Study

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3230
Author(s):  
Jose Enrique de la Rubia Ortí ◽  
Jose Luis Platero ◽  
Iván Hu Yang ◽  
Jose Joaquin Ceron ◽  
Asta Tvarijonaviciute ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pilot Study ◽  
Body Fat ◽  
Ketone Bodies ◽  
Intervention Group ◽  
Epigallocatechin Gallate ◽  
Coconut Oil ◽  
Control Group ◽  
Fat Percentage

(1) Background. Multiple sclerosis (MS) is characterised by the loss of muscle throughout the course of the disease, which in many cases is accompanied by obesity and related to inflammation. Nonetheless, consuming epigallocatechin gallate (EGCG) and ketone bodies (especially β-hydroxybutyrate (βHB)) produced after metabolising coconut oil, have exhibited anti-inflammatory effects and a decrease in body fat. In addition, butyrylcholinesterase (BuChE), seems to be related to the pathogenesis of the disease associated with inflammation, and serum concentrations have been related to lipid metabolism. Objective. The aim of the study was to determine the role of BuChE in the changes caused after treatment with EGCG and ketone bodies on the levels of body fat and inflammation state in MS patients. (2) Methods. A pilot study was conducted for 4 months with 51 MS patients who were randomly divided into an intervention group and a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, and the control group was prescribed a placebo. Fat percentage and concentrations of the butyrylcholinesterase enzyme (BuChE), paraoxonase 1 (PON1) activity, triglycerides, interleukin 6 (IL-6), albumin and βHB in serum were measured. (3) Results. The intervention group exhibited significant decreases in IL-6 and fat percentage and significant increases in BuChE, βHB, PON1, albumin and functional capacity (determined by the Expanded Disability Status Scale (EDSS)). On the other hand, the control group only exhibited a decrease in IL-6. After the intervention, BuChE was positively correlated with the activity of PON1, fat percentage and triglycerides in the intervention group, whereas these correlations were not observed in the control group (4). Conclusions. BuChE seems to have an important role in lipolytic activity and the inflammation state in MS patients, evidenced after administering EGCG and coconut oil as a βHB source.

scholarly journals Islet Health, Hormone Secretion, and Insulin Responsivity with Low-Carbohydrate Feeding in Diabetes

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 455
Author(s):  
Cassandra A. A. Locatelli ◽  
Erin E. Mulvihill
Keyword(s):  
Ketone Bodies ◽  
Hormone Secretion ◽  
Diabetes Research ◽  
Carbohydrate Restriction ◽  
Carbohydrate Feeding ◽  
Low Carbohydrate ◽  
Islet Hormone ◽  
The Usa ◽  
Preclinical And Clinical Studies

Exploring new avenues to control daily fluctuations in glycemia has been a central theme for diabetes research since the Diabetes Control and Complications Trial (DCCT). Carbohydrate restriction has re-emerged as a means to control type 2 diabetes mellitus (T2DM), becoming increasingly popular and supported by national diabetes associations in Canada, Australia, the USA, and Europe. This approval comes from many positive outcomes on HbA1c in human studies; yet mechanisms underlying their success have not been fully elucidated. In this review, we discuss the preclinical and clinical studies investigating the role of carbohydrate restriction and physiological elevations in ketone bodies directly on pancreatic islet health, islet hormone secretion, and insulin sensitivity. Included studies have clearly outlined diet compositions, including a diet with 30% or less of calories from carbohydrates.

scholarly journals Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1

2002 ◽  
Vol 366 (1) ◽  
pp. 289-297 ◽  
Author(s):  
Alícia NADAL ◽  
Pedro F. MARRERO ◽  
Diego HARO
Keyword(s):  
Ketone Bodies ◽  
Control Site ◽  
Luciferase Reporter ◽  
Acid Oxidation ◽  
Transcription Start ◽  
Forkhead Transcription Factor ◽  
The Brain

Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the use of ketone bodies for energy, thereby preserving the limited glucose for use by the brain. This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis. We decided to investigate the molecular mechanism of this inhibition. In the present study, we show that FKHRL1, a member of the forkhead in rhabdosarcoma (FKHR) subclass of the Fox family of transcription factors, stimulates transcription from transfected 3-hydroxy-3-methylglutaryl-CoA synthase promoter-luciferase reporter constructs, and that this stimulation is repressed by insulin. An FKHRL1-responsive sequence AAAAATA, located 211bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis. It binds FKHRL1 in vivo and in vitro and confers FKHRL1 responsiveness on homologous and heterologous promoters. If it is mutated, it partially blocks the effect of insulin in HepG2 cells, both in the absence and presence of overexpressed FKHRL1. These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin.

scholarly journals The impact of keto-adaptation on exercise performance and the role of metabolic-regulating cytokines

2019 ◽  
Vol 110 (3) ◽  
pp. 562-573 ◽  
Author(s):  
Matthew Sherrier ◽  
Hongshuai Li
Keyword(s):  
Exercise Performance ◽  
Refractory Epilepsy ◽  
Ketone Bodies ◽  
Adaptation Period ◽  
High Fat ◽  
Active Growth ◽  
Beneficial Effects ◽  
Low Carbohydrate ◽  
The Impact

ABSTRACTThe ketogenic diet (KD) is a normocaloric diet composed of high-fat, low-carbohydrate, and adequate protein that induces fasting-like effects and results in the production of ketone bodies. Initially used widely for children with refractory epilepsy, the KD gained popularity due to its beneficial effects on weight loss, diabetes, and cancer. In recent years, there has been a resurgence in interest surrounding the KD and exercise performance. This review provides new insights into the adaptation period necessary for enhancement in skeletal muscle fat and ketone oxidation after sustained nutritional ketosis. In addition, this review highlights metabolically active growth factors and cytokines, which may function as important regulators of keto-adaptation in the setting of exercise and the KD.

scholarly journals Lithium and Not Acetoacetate Influences the Growth of Cells Treated with Lithium Acetoacetate

2019 ◽  
Vol 20 (12) ◽  
pp. 3104 ◽  
Author(s):  
Silvia Vidali ◽  
Sepideh Aminzadeh-Gohari ◽  
Renaud Vatrinet ◽  
Luisa Iommarini ◽  
Anna Maria Porcelli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Lines ◽  
Ketone Bodies ◽  
Acid Oxidation ◽  
Antiproliferative Effects ◽  
Future Studies ◽  
Low Carbohydrate ◽  
Li Ion

The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control.

scholarly journals Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions

2019 ◽  
Vol 116 (47) ◽  
pp. 23813-23821 ◽  
Author(s):  
Junki Miyamoto ◽  
Ryuji Ohue-Kitano ◽  
Hiromi Mukouyama ◽  
Akari Nishida ◽  
Keita Watanabe ◽  
...  
Keyword(s):  
Alternative Energy ◽  
Ketone Bodies ◽  
Expression System ◽  
Intermittent Fasting ◽  
Alternative Energy Sources ◽  
Low Carbohydrate ◽  
Weight Decrease ◽  
G Protein Coupled ◽  
Deficient Mice

Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.

Control of food intake by fatty acid oxidation

1986 ◽  
Vol 250 (6) ◽  
pp. R1003-R1006 ◽  
Author(s):  
E. Scharrer ◽  
W. Langhans
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Food Intake ◽  
Fatty Acid Oxidation ◽  
Ketone Bodies ◽  
Acid Oxidation ◽  
Dark Phase ◽  
Fat Level ◽  
Plasma Ffa

The role of fatty acid oxidation in the control of food intake was studied using mercaptoacetate (MA), an inhibitor of fatty acid oxidation. Food intake, plasma free fatty acids (FFA) and ketone bodies, and blood glucose were measured. Rats were fed either a low-fat (LF, 3.33% fat) or a medium-fat (MF, 18% fat) diet. At the onset of the dark phase of the lighting cycle, MA did not affect food intake in LF rats but increased it 74% in MF rats in comparison to control. Four hours after the injection the effect of MA on food intake disappeared. In the middle of the bright phase of the lighting cycle, MA increased food intake in MF rats approximately 120% up to 6 h postinjection. After MA, plasma FFA concentration was elevated, and plasma 3-hydroxybutyrate concentration was lowered, indicating that fatty acid oxidation had been successfully reduced. MA did not affect blood glucose. These results indicate fatty acid oxidation is involved in the control of food intake, at least when the dietary fat level is relatively high.

scholarly journals An effective medical replacement therapy: ketogenic diet for intractable childhood epilepsy

2021 ◽  
Vol 9 (4) ◽  
pp. 1234
Author(s):  
Ansh Chaudhary ◽  
Bhupendra Chaudhary
Keyword(s):  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Intractable Epilepsy ◽  
Coconut Oil ◽  
Epileptic Seizures ◽  
High Fat ◽  
Low Carbohydrate ◽  
History Of ◽  
Restrictive Diet ◽  
Long Chain Triglycerides

Ketogenic diet (KD) a high fat, adequate protein and low carbohydrate restrictive diet has a long history of its use in intractable epilepsy of childhood. The diet produces biochemical changes mimicking that of starvation. The high levels of ketone bodies produced by KD act as a major source of energy for brain replacing the usual glucose.1 Comprising the ratio of 4:1 (fat:carbohydrate and protein) by weight, the diet produces state of ketonemia or ketosis that leads to reduction in frequency of epileptic seizures by is unique mode of action. To increase the palatability medium chain triglycerides (as coconut oil) in ratio of 3:1 is used which is more efficiently absorbed and have lesser gastro intestinal side effects as compared to traditional 4:1 ratio diet with long chain triglycerides like PUFA

scholarly journals Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

2019 ◽  
Author(s):  
Jantzen Sperry ◽  
Michael C. Condro ◽  
Lea Guo ◽  
Daniel Braas ◽  
Nathan Vanderveer-Harris ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Aerobic Glycolysis ◽  
Diet Therapy ◽  
Acid Oxidation ◽  
Reduce Tumor Growth

SummaryGlioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays revealed FA utilization throughout the GBM metabolome, and growth inhibition in nearly every cell line in a broad spectrum of patient-derived glioma cells treated with FAO inhibitors. In vivo assessments revealed that knockdown of carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme for FAO, reduced the rate of tumor growth and increased survival. However, the unrestricted ketogenic diet did not reduce tumor growth, and for some models significantly reduced survival. Altogether, these data highlight important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.

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