Metatropic

METATROPIC

GET METABOLICALLY OPTIMIZED

The future of human health

Increased energy, better cognition, a reduction in fat, reduced inflammation and a healthier, better performing heart,

MetaTropic represents a quantum leap in human health nutrition. Developed exclusively by Metabolic Solutions and utilizing a proprietary formulation process, MetaTropic takes advantage of the human body’s unique energy systems and the fuels they use for sustaining life.

If the human body was a car it would be a hybrid; able to use gasoline or electricity for fuel. As we know, gasoline is a “dirty” fuel producing damaging exhaust fumes. Electricity on the other hand is a clean and powerful source of energy. MetaTropic provides the chemical signaling to “turn on” your bodies hybrid fuel system providing an amazingly bountiful and powerful fuel source for your cells. Not only does this fuel source provide better energy, it benefits numerous other body systems such as the brain, heart, lungs, blood and circulatory systems as well as numerous others.


Metatropic benefits multiple body systems…

MetaTropic’s proprietary βHB formula is the most efficient fuel for the human body.  Feel energy like never before.

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Just a single dose can increase cognitive abilities thru enhanced neuronal metabolism and protect against neurodegeneration.

Metatropic utilizes receptor signaling pathways to mobile fat from fat stores. This fat is then used by the body as energy instead of being stored.

Protects the heart from free radical damage and guards cardiac tissue from oxidative stress. Ketone bodies have been shown to increase the hydraulic efficiency of the heart by 28%.

Reduces ROS (Reactive Oxygen Species) damage and inhibits inflammatory responses thru the inhibition of NLRP3.

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Improved glycemic control, lipid markers, decreased blood glucose and a retraction of insulin and other medications needed.

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The Science Behind the Breakthrough…

R-3 Hydroxybutyrate is a water-soluble, low molecular weight compound (M.W. 104). One gram of R-3 Hydroxybutyrate has 3.8 kcal of energy. During normal metabolism, the blood level of R-3 Hydroxybutyrate is only 0-3 mg/dl and the compound is excreted in the urine and expired air without being utilized. During fasting or starvation, however, the blood level rises to 20-30 mg/dl or higher and utilization commences. R-3 Hydroxybutyrate can be substituted for glucose as an energy source during fasting and starvation. It is metabolized and utilized by vital organs and tissues excluding the liver (i.e. the heart, kidneys, brain, and muscles).

Generally D-3-hydroxybutyrate polymer when administered orally, will decompose to the monomeric forms metabolically thus partially reducing their activity. By contrast, when HPL’s D-3-hydroxybutyrate polymer is formulated for oral administration, the formulation incorporates a decomposition resistant technology that mitigates decomposition, particularly in the gastrointestinal tract. Therefore the polymeric ester will reach the therapeutic target site in vivo in an un-cleaved, non-decomposed form, therefore, no loss of activity of the administered compound will occur. Additionally the formulation incorporates a proprietary hydrolase that facilitates the monomerization for optimal metabolism.

Dosage scheduling is based on particular therapeutic intervention strategies, thus, administration can be adjusted individually to provide levels of the active compound in the blood plasma that are sufficient to maintain and obtain the desired therapeutic effects. In general, however, dose range is typically administered at 0.01 to 100 mg/kg body weight.

Based on hydroxyl radical scavenging assays the dimeric (general formula I, n = 1) and trimeric (general formula I, n = 2) molecules show more than tenfold higher antioxidant capacity against hydroxyl radicals over the known antioxidants than the monomeric compound 3-hydroxybutyric acid or ascorbic acid and thus protect ROS challenged cells effectively from oxidative damage in low concentrations. Excellent antioxidant activity will be reached, for example in ophthalmic therapy. Further, the present molecules are water-soluble or water-dispersible which allows for facile formulation and administration of them.

METATROPIC

BACKED BY RESEARCH, PROVEN BY SCIENCE…

Metatropic for Energy
  • Ketone bodies represent an important alternative energy substrate for cerebral metabolism, sparing amino acid utilization for gluconeogenesis. A Cause of Permanent Ketosis: GLUT-1 Deficiency. Alexis Chenouard ,Sandrine Vuillaumier-Barrot, Nathalie Seta, Alice Kuster 09/2014

 

  • Ketone bodies supply energy to non-hepatic tissues, mainly brain and skeletal muscles. MacDonald MJ, Dobrzyn A, Ntambi J, Stoker SW. The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells. Arch Biochem Biophys 2008;470:153–162. [PubMed: 18082128]

 

  • Consistent with the observed improvements in mitochondrial respiration, β –hydroxybutyrate increased ATP production substantially in isolated brain mitochondria and brain homogenates and acetoacetate increased phosphocreatine levels in cardiac myocytes (Suzuki et al. 2001; Squires et al. 2002 Tieu et al. 2003). These findings provide further support for the hypothesis that ketone bodies improve mitochondrial function and explain how ketone bodies increase myocardial hydraulic work and sperm motility described in previous work (Veech et al. 2001; Veech 2004). These findings also suggest that ketone bodies and calorie restriction enhance mitochondrial function through similar mechanisms. The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • Compared with fatty acid oxidation, ketone bodies are more energetically efficient, yielding more energy available for ATP synthesis per molecule of oxygen invested. Furthermore, the oxidation of ketone bodies may attenuate ROS production associated with the oxidation of fatty acids suggesting that myocardial ketone body oxidation could protect against injury and adverse ventricular remodeling responses, which promote the development of cardiomyopathy and heart failure.

 

  • Ketone bodies may be more energetically favorable substrates than fatty acids, in part through the maintenance of a favorable NAD/NADH ratio as well as their ability to maintain ubiquinone in the oxidized state, which increases redox span in the electron transport chain and thus diminishes superoxide production and increases energy available for ATP synthesis. In our study, Acetoacetate diminished the rate of superoxide production in mitochondria isolated from hearts of both SCOT-Heart-KO and control mice, which suggests that Acetoacetate-mediated suppression of mitochondrial superoxide emission is likely due to a non-oxidative role of Acetoacetate, whose mechanisms could include ROS scavenging by Acetoacetate, or diminished mitochondrial inner membrane potential through non-oxidative mechanisms.

 

  • Ketone bodies are also utilized by glial cells and are the primary substrates for glial synthesis of glutamine, where it is buffered in a large glial glutamine pool, and not highly contributing to neuronal glutamate and thus GABA.

 

  • Ketone bodies have been shown to increase cerebral blood flow and perfusion. Also, ketone bodies have been shown to increase ATP synthesis and enhance the efficiency of ATP production. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Shannon L. Kesl, et al. Kesl et al. Nutrition & Metabolism (2016) 13:9 DOI 10.1186/s12986-016-0069-y

 

  • Ketone bodies provide a metabolic fuel for extrahepatic tissues. Energy Metabolism in the Liver. Liangyou Rui. Compr Physiol. 2014 January ; 4(1): 177–197. doi:10.1002/cphy.c130024.

 

  • Metabolism of ketone bodies provides a high energy yield- roughly 23-26 ATP/one BHB molecule. Moreover, BHB is the most efficient fuel per molecule of oxygen consumed when compared to glucose, pyruvate, or free fatty acids, due to its ability to widen the redox potential gap between the respiratory complex-I (NADH/NAD) and CoQ/CoQH2. Grabacka MM, Wilk A, Antonczyk A, Banks P, Walczyk-Tytko E, Dean M, Pierzchalska M and Reiss K (2016) Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells. Front. Endocrinol. 7:5. doi: 10.3389/fendo.2016.00005

 

  • Ketone oxidation increases the redox span between complex-I and complex-III by keeping mitochondrial ubiquinone oxidized. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • Briefly, when BHB is converted to acetoacetate it generates NADH (the reduced form of nicotinamide adenine dinucleotide [NAD]), thereby reducing the mitochondrial NAD/NADH couple and increasing the oxidation of the co-enzyme Q couple. In addition, KB metabolism increases the mitochondrial pool of acetyl- CoA and succinate. The net effect of these changes is increased metabolic efficiency. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

 

  • KBs, especially BHB, can enter the TCA cycle directly in the absence of Pyruvate Dehydrogenase enzyme complex. Astroglia and neurons responded to hypoxia by enhancing KB production, and KBs produced by astroglia or neurons or both might be used as a neuronal energy substrate. The activation of astroglial ketogenesis through activated AMPK might reduce ischemic cell damage. Roles and Regulation of Ketogenesis in Cultured Astroglia and Neurons Under Hypoxia and Hypoglycemia Shinichi Takahashi, et al.  ASN Neuro July-September 2014: 1–14. DOI: 10.1177/1759091414550997

 

  • Even in the presence of glucose, the heart muscle preferentially utilizes fatty acids, ketone bodies, or lactate for an oxidative generation of ATP. The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer. Rainer Wittig and Johannes F. Coy. Perspectives in Medicinal Chemistry 2007:1 64–82

Metatropic as an Anticonvulsant
  • Anticonvulsant effects have been demonstrated for acetoacetate and acetone but not for β – hydroxybutyrate. First, both acetoacetate and acetone decreased the incidence of seizures triggered by loud auditory stimuli in Frings audiogenic-susceptible mice (Rho et al. 2002). Second, acetone suppressed seizures in several additional models of epilepsy, including the amygdala kindling, maximal electroshock and pentylenetetrazole tests (Likhodii et al. 2004).

 

  • KE supplementation delays central nervous system (CNS) oxygen toxicity seizures without the need for dietary restriction

 

  • BHB is a strongly anionic endogenous molecule and exerts anti-epileptic effects by reducing neuronal excitability via regulation of intracellular potassium cations. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • Ketone bodies protect the brain against types of intractable or refractory epilepsy. The role of monocarboxylate transporters (MCTs) in the uptake of ketone bodies into neurons and glial cells (Joachim Deitmer / Holger Becker)

 

  • Ketone bodies and PUFAs have been shown to exert neuroprotective activity in neurodegenerative conditions associated with impaired mitochondrial function. Ketone bodies appear not only to raise ATP levels in seizure-prone areas such as hippocampus, but also diminish reactive oxygen species (ROS) production through increases in NADH oxidation and inhibition of mitochondrial permeability transition. Mechanisms of Ketogenic Diet Action. Susan A. Masino, Jong M. Rho. Jasper’s Basic Mechanisms of the Epilepsies, Fourth Ed.

 

  • Ketone bodies are associated with the improvement of epilepsy in brain. The proposed mechanism is that the utilization of ketone bodies favors the production of γ-aminobutyric acid (GABA). Daikhin et al. reported that the utilization of ketone bodies in the brain produces sufficient amount of acetyl-CoA for the CAC cycle. It pulls the reaction toward the formation of citrate by the combination of oxaloacetate and acetyl-CoA. This leads to less oxaloacetate undergoing the reaction catalyzed by aspartate aminotransferase so that glutamate transamination is decreased. Relatively more glutamate is converted to more GABA by glutamate decarboxylase. Since GABA is the major inhibitory neurotransmitter and a potent anti-epileptic agent in the mammalian brain, ketone bodies in the brain have anticonvulsant effect through increasing GABA synthesis. Potential of Anaplerotic Triheptanoin for the Treatment of Long-Chain Fatty Acid Oxidation Disorders. Lei Gu.

 

  • Recent research has demonstrated that the biological action of the ketone body D-β-hydroxybutyrate extends beyond its role as metabolite. Indeed, D-β- hydroxybutyrate has been shown to act both as a signaling molecule by activating G-protein coupled receptors (GPCRs), and as a transcriptional regulator by acting as a HDAC inhibitor. Related to its properties as signaling intermediate, D-β-hydroxybutyrate has been shown to be an agonist for two GPCRs, PUMA-G (also named HCAR2, hydroxycarboxylic acid receptor 2, or Gpr109) and the free fatty acids receptor 3 (FFA3, or Grp41). Essential roles of four-carbon backbone chemicals in the control of metabolism. Sabrina Chriett, Luciano Pirola. World J Biol Chem 2015 August 26; 6(3): 223-230 ISSN 1949-8454 (online)
Metatropic for Neuroprotection
  • Ketone bodies protect neurons against multiple types of neuronal injury and the underlying mechanisms are similar to those of calorie restriction and of the ketogenic diet. Simultaneous quantification of salivary 3‑hydroxybutyrate, 3‑hydroxyisobutyrate, 3‑hydroxy‑3‑methylbutyrate, and 2‑hydroxybutyrate as possible markers of amino acid and fatty acid catabolic pathways by LC–ESI–MS/MS. Miyazaki et al. SpringerPlus (2015) 4:494 DOI 10.1186/s40064-015-1304-0

 

  • Rise in β -hydroxybutyrate concentration is associated with a more significant reduction in the vulnerability of hippocampal neurons to kainate injections.

 

  • In animal models of Parkinson’s disease, chronic subcutaneous infusion of β –hydroxybutyrate in mice conferred partial protection against dopaminergic cell loss and motor deficits induced by MPTP (Tieu et al. 2003). β -hydroxybutyrate also protected cultured mesencephalic dopaminergic neurons from the toxic effects of MPTP and rotenone, another inhibitor of mitochondrial complex I (Kashiwaya et al. 2000; Imamura et al. 2006). In patients with Alzheimer’s disease, administration of medium-chain triglycerides improved memory and the degree of improvement correlated with blood levels of β -hydroxybutyrate (Reger et al. 2004). Further, direct application of β -hydroxybutyrate protected cultured hippocampal neurons against Aβ  toxicity (Kashiwaya et al. 2000). Finally, exogenous administration of either β -hydroxybutyrate or acetoacetate reduced neuronal loss and improved neuronal function in animal models of hypoxia, hypoglycemia and focal ischemia (Suzuki et al. 2001, 2002; Massieu et al. 2001, 2003; Masuda et al. 2005). The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • A combination of β -hydroxybutyrate and acetoacetate (1 mM each) increased the survival of acutely dissociated rat neocortical neurons exposed to glutamate or hydrogen peroxide for 10 min or more (Kim et al. 2007; Maalouf et al. 2007b). Increased survival was associated with the inhibition of electrophysiological signs of neuronal injury, specifically, irreversible depolarization associated with a significantly decreased membrane resistance. Acetoacetate (also in millimolar concentrations) had a similar effect in primary hippocampal cultures (Noh et al. 2006a). In addition, the combination of β -hydroxybutyrate and acetoacetate prevented oxidative impairment of long-term potentiation in the CA1 region of the hippocampus, indicating that ketone bodies not only limited neuronal loss but also preserved synaptic function (Maalouf et al. 2007a). The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • A combination of β – hydroxybutyrate and acetoacetate (1 mM each) decreased the production of reactive oxygen species by complex I of the mitochondrial respiratory chain (Maalouf et al. 2007b). Specifically, in acutely isolated rat neocortical neurons, increases in the intracellular levels of superoxide following prolonged exposure to glutamate were inhibited by pretreatment with ketone bodies. Ketone bodies also decreased reactive oxygen species concentrations in isolated mitochondria overloaded with calcium. In a similar study, increased survival of HT22 hippocampal cell lines treated with acetoacetate was associated with decreased production of reactive oxygen species (Noh et al. 2006a). The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • In the study by Maalouf et al. (2007b), ketone bodies decreased NADH levels in intact neurons and in isolated mitochondria but did not affect glutathione levels. Furthermore, ketone bodies prevented the inhibition of mitochondrial respiration by calcium in the presence of pyruvate and malate but not succinate. Given that NADH oxidation correlates with decreased mitochondrial formation of reactive oxygen species (Duchen, 1992; Kudin et al, 2004; Sullivan et al, 2004a) and that pyruvate and malate drive mitochondrial respiration through complex I, the source of reactive oxygen species in neurons (Turrens 2003), these findings strongly suggested that ketone bodies decreased the production of reactive oxygen species by enhancing complex I-driven mitochondrial respiration rather than increase antioxidant factors such as glutathione. The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • Ketone bodies prevented neuronal injury and death caused by hydrogen peroxide or by the glutathione oxidant diamide (Kim et al. 2007). Their neuroprotective effect was replicated by inhibitors of mitochondrial permeability transition. In addition, ketone bodies elevated the threshold for calcium-induced mitochondrial permeability transition in isolated brain mitochondria. Mitochondrial permeability transition can be triggered by various pathological menchanisms, most notably oxidative stress, causing the cytoplasmic release of cytochrome c and the subsequent induction of caspase-mediated apoptosis (Mattson et al. 2003; Nicholls 2004; Balaban et al. 2005). In support of these data, ketone bodies blocked the activation of the apoptotic enzyme serine/threonine phosphatase 2A by oxidative stress (Maalouf et al. 2007a). The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • Ketone bodies were recently shown to prevent oxidative impairment of long-term potentiation, an effect that was associated with inhibition of protein phosphatase 2A (Maalouf et al. 2007a). The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • Ketosis and neuroprotection are linked through metabolic regulation via four mechanisms: 1) the “glucose sparing” effect which suggests that a decrease in glucose utilization and oxidation may be beneficial for brain function during recovery from neurological damage (LaManna et al. 2009; Zhang et al. 2013b), 2) the presence of brain ketone bodies in the reduction of glutamate neurotoxicity and promotion of GABA synthesis (Noh et al. 2006), 3) brain adaptation to chronic ketosis by induction of molecular regulatory proteins, such as monocarboxylate transporters (MCT) (Leino et al. 2001;Vannucci and Simpson 2003) and hypoxia-inducible factor (HIF1-α) that accounts for angiogenesis (Puchowicz et al. 2008), and 4) the reduction of reactive oxygen species (ROS) and subsequent oxidative stress in mitochondria (Bough and Eagles 1999; Maalouf et al. 2009; Sullivan et al. 2004). Decreased carbon shunting from glucose towards oxidative metabolism in diet-induced ketotic rat brain.  Yifan Zhang, Ph.D, Shenghui Zhang, M.S, Isaac Marin-Valencia, M.D and Michelle A. Puchowicz, Ph.D. J Neurochem. 2015 February;132(3):301–312. doi:10.1111

 

  • Ketones maintain brain metabolism and are neuroprotective during severe hypoglycemia. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Shannon L. Kesl, et al. Kesl et al. Nutrition & Metabolism (2016) 13:9 DOI 10.1186/s12986-016-0069-y

 

  • BHB offers protection from ABeta toxicity. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

 

  • Infusion of KB into rodents protects them from glutamate toxicity, ischemia, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

 

  • BHB induces AgRP expression while increasing ATP and inhibiting AMPK phosphorylation (Cheng et al., 2008). Moreover, Laeger and colleagues have recently demonstrated that under physiological conditions BHB decreases AMPK phosphorylation and AgRP mRNA expression in GT1-7 hypothalamic cells. Ketosis,ketogenic diet and food intake control: a complex relationship AntonioPaoli1*, GerardoBosco1, et al. Frontiers in Psychology. published: 02 February 2015 doi: 10.3389/fpsyg.2015.00027

 

  • (D)-3-hydroxybutyrate, a metabolite also subject to gut microbial regulation, was recently shown to antagonize GPR41-mediated SNS activation. Metabolic tinkering by the gut microbiome : Implications for brain development and function. Joel Selkrig, et al. Gut Microbes 5:3, 369-380. May/June 2014. Landes Bioscience.

 

  • BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. The physiologic and the nonphysiologic isomers of BHB (D- and L-BHB, respectively) scavenge OH in a free-cell system and reduce neuronal death and ROS production induced by glycolysis inhibition in cultured hippocampal neurons and hypoglycemia-induced lipoperoxidation in vivo. These observations support the potential of KB to prevent oxidative stress and cell death induced during energy limiting conditions or overexcitation. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • Present observations suggest that D-BHB can substitute for glucose in an in vivo model of noncoma hypoglycemia and effectively prevent ROS generation and cell death in all affected cortical areas, regardless their differential production of ROS and vulnerability to cell death. In vitro results suggest that the metabolic activity of D-BHB in combination with its antioxidant action contributes to the effective protective action of this KB, and that these actions can take place during the recovery period in the presence of glucose. These observations support the therapeutic potential of D-BHB against ischemic and traumatic insults, which are associated with energy impairment and oxidative stress and which require treatments that can be effective when administered after the insult. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • In vitro data show that D-BHB notably prevents neuronal death when incubated during glucose deprivation and glucose reperfusion, but is also effective when incubated only during glucose deprivation or only during glucose reperfusion. Consistently, ATP levels recover to the same extent when D-BHB is present only during glucose deprivation, only during glucose reperfusion or during both periods. According to these data preserving ATP concentrations at levels 30% to 40% below control values is sufficient to significantly prevent neuronal death. These observations also indicate that D-BHB can stimulate ATP production during glucose deprivation but also during glucose reperfusion likely through its metabolism by the tricarboxylic acid cycle. The present results agree with other studies showing protection by the ketogenic diet or BHB infusion against ischemic and traumatic brain injury. The improvement of mitochondrial function and ATP production has been suggested by several studies as the main mechanism involved in the neuroprotective action of KB. According to the present data, besides the stimulation of ATP production, D-BHB also reduces ROS levels. Similar results have been previously reported in cultured and isolated neurons as well as in isolated mitochondria, and this effect has been implicated in the protective action of KB against excitotoxic neuronal death. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • Some studies have suggested that there may be a bioenergetics shift taking place within neuronal metabolism prior to the onset of clinical signs of neurodegeneration, where glucose uptake and utilization become progressively reduced. This glucose hypometabolism may reflect a decline in mitochondrial function. The shift has been observed to occur long before the onset of clinical signs of neurodegeneration, suggesting the possibility that glucose hypometabolism may be the initial step leading to axonal atrophy and neuronal loss through a reduction in ATP availability. The bioenergetics shift appears to specifically affect the metabolism of glucose. No such shift is seen with ketone body metabolism. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mithu Storoni and Gordon T. Plant. Hindawi Publishing Corporation. Multiple Sclerosis International. Volume 2015, Article ID 681289, 9 pages.

 

  • Ketone bodies play a neuroprotective role in animal models of neurodegeneration. ATP-sensitive potassium channels (K ATP channels) located on the cell surface of neurons stabilize neuronal excitability. Ketones promote an “open state” of these channels and confer neuronal stability. K ATP channels also play a role in mitochondrial function and in cell death. The “open state” of K ATP channels located on the inner mitochondrial membrane prevents the formation of mitochondrial permeability transition pores (MPTPs) that can lead to mitochondrial swelling and cell death. Acetoacetate and beta-hydroxybutyrate have been shown to increase the threshold for calcium-induced MPTP formation. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mithu Storoni and Gordon T. Plant. Hindawi Publishing Corporation. Multiple Sclerosis International. Volume 2015, Article ID 681289, 9 pages.

 

  • Acetone and BHB enhanced inhibitory glycine receptors, whereas BHB alone was able to enhance GABAA -receptor mediated currents – but all of these actions were observed at highly supratherapeutic (i.e., anesthetic) concentrations, not seen during KD treatment. Mechanisms of Ketogenic Diet Action. Susan A. Masino, Jong M. Rho. Jasper’s Basic Mechanisms of the Epilepsies, Fourth Ed.

 

  • More recent work has demonstrated that BHB decreases GABA degradation, and thus could increase the available pool of GABA. Mechanisms of Ketogenic Diet Action. Susan A. Masino, Jong M. Rho. Jasper’s Basic Mechanisms of the Epilepsies, Fourth Ed.
Metatropic for Cognition
  • The single administration of MCT led to a significant correlation between performance on the paragraph recall task and serum BHB concentration, with those subjects presenting the highest BHB levels showing the most improvement. In addition, there was significant improvement in ADAS-Cog scores. The rapid (90 min) improvement seen in cognitive tasks suggests that the effect is driven by enhanced neuronal metabolism. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics
Metatropic for Fat Mobilization
  • It appears that the supply of acetyl-CoA via the transfer of acyl groups from mitochondria in the form of acetoacetate is important for de novo fatty acid synthesis, and alterations of lipid content and lipid species may influence insulin secretion in beta cells. The Neuroprotective Properties of Calorie Restriction, the Ketogenic Diet, and Ketone Bodies.. Maalouf, et al. Brain Res Rev. 2009 March ; 59(2): 293–315. doi:10.1016/j.brainresrev.2008.09.002

 

  • B-hydroxybutyrate (BHB) has been demonstrated to activate the receptor HM74a leading to reduced FFA secretion from adipocytes. HM74a is better known as the niacin receptor, a potent lipid-lowering agent. Hence, KB not only have metabolic effects but also act through receptor signaling pathways. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

 

  • Ketones (mainly BHB) can act both orexigenically or anorexigenically. In the orexigenic mechanism, it increases the circulating level of adiponectin, increasing brain GABA and AMPK phosphorylation and decreasing brain ROS production. The anorexigenic mechanism triggers a main normal glucose meal response, increasing circulating post-meal FFA (thus reducing cerebral NPY), maintaining CCK meal response and decreasing circulating ghrelin. It can be postulated that the net balance of the contrasting stimuli results in a general reduction of perceived hunger and food intake. Ketosis,ketogenic diet and food intake control: a complex relationship AntonioPaoli1*, GerardoBosco1, et al. Frontiers in Psychology. published: 02 February 2015 doi: 10.3389/fpsyg.2015.00027

 

Metatropic for the Heart
  • Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. The oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Schugar, et al.

 

  • Forsey et al. reported that ketone bodies competed with fatty acids and inhibited the oxidation of oleate and octanoate in isolated perfused heart. Similarly, Vanoverschelde et al. reported that the infusion of BHB competed with palmitate and decreased myocardial palmitate oxidation in humans and dogs. In perfused rat heart, ketone bodies inhibit glucose uptake and oxidation. Potential of Anaplerotic Triheptanoin for the Treatment of Long-Chain Fatty Acid Oxidation Disorders. Lei Gu.

 

Metatropic as an Antioxidant/Anti-inflammatory
  • Procession of ketone bodies through the SCOT enzyme toward terminal oxidation attenuates ROS production from oxidation of fatty acids.

 

  • In some cell types, increased delivery of the ketone body D-betahydroxybutyrate increases histone acetylation, which ameliorates oxidative stress through an ability to increase transcription of Foxo3a and Mt2 via inhibition of Class I histone deacetylases.

 

  • A novel and exciting research field has finally recently emerged with the discovery that D-β-hydroxybutyrate can be a key regulator of gene expression by acting as an endogenous HDACs inhibitor. The HDACs inhibitory activity of D-β-hydroxybutyrate brings changes in histone acetylation and gene expression that seem to protect cells from oxidative stress. Essential roles of four-carbon backbone chemicals in the control of metabolism. Sabrina Chriett, Luciano Pirola. World J Biol Chem 2015 August 26; 6(3): 223-230 ISSN 1949-8454 (online)

 

  • On one hand, absorption and utilization of bHB decreases the intracellular NAD to NADH ratio and therefore affects the activity of sirtuins, but on the other hand, bHB is an inhibitor of class I histone deacetylases (HDAC 1, 2, 3, 8) and class IIa histone deacetylases (HDAC 4, 5, 7, 9) that bind zinc atoms at the active site. The suppression of HDAC activity leads to various epigenetic modulations associated with global histone hyperacetylation. In this way, bHB exerts pleiotropic effects. For example, it induces the stress response gene FOXO3A, which is a tumor suppressor gene responsible for cell cycle arrest, reactive oxygen species detoxification, and apoptosis in various stressogenic conditions. Grabacka MM, Wilk A, Antonczyk A, Banks P, Walczyk-Tytko E, Dean M, Pierzchalska M and Reiss K (2016) Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells. Front. Endocrinol. 7:5. doi: 10.3389/fendo.2016.00005

 

  • BHB, inhibits the NLRP3 inflammasome in macrophages independently of binding to surface Gpr109a receptors or mitochondrial oxidation, which may avoid competition for receptor occupancy and a requirement of ATP generation. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • BHB, but neither acetoacetate nor structurally-related short chain fatty acids, butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to several structurally unrelated NLRP3 activators, without impacting NLRC4, AIM2 or non-canonical caspase-11 inflammasome activation. Mechanistically, BHB inhibits NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 were not dependent on chirality or classical starvation regulated mechanisms like AMPK, reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocked NLRP3 inflammasome without undergoing oxidation in TCA cycle, independently of uncoupling protein-2 (UCP2), Sirt2, receptor Gpr109a and inhibition of NLRP3 did not correlate with magnitude of histone acetylation in macrophages. BHB reduced the NLRP3 inflammasome mediated IL-1β _and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β _secretion in mouse models of NLRP3-mediated diseases like Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS) and urate crystal induce body cavity inflammation. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • BHB, but not butyrate, inhibited monosodium urate (MSU) crystal or particulate matter-induced caspase-1 activation. Furthermore, BHB blocked inflammasome activation by five additional NLRP3 activators nigericin, silica particles, lipotoxic fatty acids palmitate, ceramides and sphingosine. BHB also inhibited processing of IL-1β _in response to the TLR4 pathogen associated molecular pattern (PAMP) agonist lipid A, the TLR1/2 ligand Pam3-CSK4 and the TLR2 agonist lipoteichoic acid (LTA). Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • It has been suggested that BHB can act as signaling molecule by binding the G protein coupled receptor GPR109a or by serving as a histone deacetylase (HDAC) inhibitor. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • BHB prevented the decline in intracellular K+ in response to incubation with the NLRP3 activators ATP, MSU and ceramides. Furthermore, the NLRP3-dependent ASC nucleation-induced polymerization or oligomerization is considered a common mechanism of NLRP3 inflammasome activation. BHB prevents ATP-induced ASC oligomerization and speck formation. Data suggest that BHB blocks NLRP3 inflammasome activation by controlling an unknown upstream event that reduces K+ efflux from macrophages and by inhibiting ASC polymerization, speck formation and assembly of the inflammasome. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • BHB dose-dependently inhibited IL-1β _and IL-18 secretion in LPS-stimulated human monocytes without significantly affecting the TNFα _production. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • In states of extreme energy deficit such as starvation, metabolic signals like BHB can dampen innate immune responses, sparing ATP for functioning of ketone-dependent organs such as the brain and heart (Supplementary Figure 8a). These findings provide insight into immunological functions of metabolic signals such as BHB and suggest that dietary or pharmacological approaches to elevate BHB, without inducing the generalized starvation response, holds promise in reducing the severity of multiple NLRP3 mediated chronic inflammatory diseases. Ketone Body β-hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease. Yun-Hee Youm, et al. Nat Med. 2015 March; 21 (3): 263-269. DOI:10.1038/nm.3804

 

  • Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • In agreement, in vivo studies have shown that BHB reduces the increase in lipoperoxidation induced by brain ischemia and hypoglycemia. An antioxidant action of KB can result from the increase in NADH oxidation and/or the improvement of mitochondrial function. In addition, in a previous study we reported in a free cell system that both isomers of BHB can scavenge the hydroxyl radical with an IC50 of 2 to 3 mmol/L. We also showed that both isomers reduce the number of Et-positive hippocampal cells during glycolysis inhibition, suggesting that they retain their capacity to scavenge ROS in a cellular system. We now show that both BHB isomers reduce ROS production induced by the exposure to Xa/Xo, which produces superoxide and the hydroxyl radical after superoxide dismutation to H2O2 in the presence of Fe2+. Similarly, D- and L-BHB reduce the Et fluorescence induced by cell exposure to H2O2. The ROS production in these conditions is not initiated by energy failure and therefore the effect of D-BHB would be more related to an antioxidant rather than a metabolic action. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • The systemic administration of BHB effectively and significantly reduces ROS levels in all cortical and hippocampal regions and completely prevents cell death in the cortex. Results from cortical cultures show that D-BHB, the physiologic isomer of BHB, efficiently preserves ATP production, reduces ROS generation, and notably prevents neuronal death induced by glucose deprivation, while the nonphysiologic isomer, L-BHB also reduces ROS production and partially prevents neuronal death, but has no effect on ATP levels. D- and L-BHB also reduced DHE oxidation in cells exposed to xanthine/xanthine oxidase (Xa/Xo), a superoxide producing system, and to H2O2 further suggesting the antioxidant action of BHB. These results support the protective action of BHB against neuronal damage induced by energy failure, and suggest that the preservation of energy levels in combination with reduced ROS production accounts for the protective action of BHB. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. Alberto Julio-Amilpas, et al. Journal of Cerebral Blood Flow & Metabolism (2015) 35, 851–860

 

  • BHB specifically inhibits the NLRP3 inflammasome but not its relatives NLRC4 or AIM2. BHB turns off NLRP3 activation of caspase-1 by inhibiting potassium efflux from cells, similar to its putative active function in quieting neuronal excitability in epilepsy. Quelling Inflammation with Ketosis and Steric Chemistry. Michael W. Gleeson, MD, PhD1 and Rolland C. Dickson, MD1. Clinical and Translational Gastroenterology (2016) 7, e145; doi:10.1038/ctg.2016.6; published online  February 18 2016

 

  • Ketone bodies have been linked to ROS reduction in vivo. Due to tumor cells’ metabolic dependence on glucose and glutamate, elevated levels of ketone bodies in the intracranial region diminish glycolytic levels and inhibit angiogenesis. This study demonstrated that an increased saturation of BHB, which was observed in the oil-fed mice, hindered the proliferation of malignant cells in culture. The Efficacy of Ketogenic Diet and Associated Hypoglycemia as an Adjuvant Therapy for High-Grade Gliomas: A Review of the Literature Kunal Varshneya, et al. DOI: 10.7759/cureus.251

 

  • The ketone betahydroxybutyrate has a direct, dose-dependent inhibitory activity on class I histone deacetylases (HDACs) including HDAC1, HDAC3, and HDAC4. The ketone acetoacetate has also been shown to inhibit class I and class IIa HDACs. Beta-hydroxybutyrate’s inhibition of HDAC promotes the acetylation of histone H3 lysine 9 and histone H3 lysine 14 and increases the transcription of genes regulated by FOXO3A. These include genes leading to the expression of the antioxidant enzymes mitochondrial superoxide dismutase and catalase. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mithu Storoni and Gordon T. Plant. Hindawi Publishing Corporation. Multiple Sclerosis International. Volume 2015, Article ID 681289, 9 pages.

 

  • The anti-inflammatory effect of a ketogenic diet may partly be explained through the inhibition of the NLRP3 inflammasome by beta-hydroxybutyrate in a manner that is independent of starvation-induced mechanisms such as AMPK, autophagy, or glycolytic inhibition. The NLRP3 inflammasome is responsible for the cleavage of procaspase-1 into caspase-1 and the activation of the cytokines IL-1? and IL-18. Its inhibition prevents IL-1?  and IL-18 generation and their downstream effects. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mithu Storoni and Gordon T. Plant. Hindawi Publishing Corporation. Multiple Sclerosis International. Volume 2015, Article ID 681289, 9 pages.

 

  • Recent studies suggest that many of the benefits of the Ketogenic Diet (KD) are due to the effects of ketone body metabolism. Interestingly, in studies on Type 2 Diabetic patients, improved glycemic control, improved lipid markers, and retraction of insulin and other medications occurred before weight loss became significant. Both β Hydroxybutyrate and Acetoacetate have been shown to decrease mitochondrial reactive oxygen species (ROS) production. Veech et al. have summarized the potential therapeutic uses for ketone bodies; they have demonstrated that exogenous ketones favorably alter mitochondrial bioenergetics to reduce the mitochondrial NAD couple, oxidize the co-enzyme Q, and increase the Δ G’ (free enthalpy) of ATP hydrolysis. Ketone bodies have been shown to increase the hydraulic efficiency of the heart by 28 %, simultaneously decreasing oxygen consumption while increasing ATP production. Thus, elevated ketone bodies increase metabolic efficiency and as a consequence, reduce superoxide production and increase reduced glutathione. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Shannon L. Kesl, et al. Kesl et al. Nutrition & Metabolism (2016) 13:9 DOI 10.1186/s12986-016-0069-y

 

  • Shimazu et al. reported that β HB is an exogenous and specific inhibitor of class I histone deacetylases (HDACs), which confers protection against oxidative stress. Ketone bodies have also been shown to suppress inflammation by decreasing the inflammatory markers TNF-a, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Therefore, it is thought that ketone bodies themselves confer many of the benefits associated with the ketogenic diet. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Shannon L. Kesl, et al. Kesl et al. Nutrition & Metabolism (2016) 13:9 DOI 10.1186/s12986-016-0069-y
Metatropic for Blood Glucose
  • Ketone supplementation causes a significant decrease of blood glucose

 

  • Recent studies suggest that many of the benefits of the Ketogenic Diet (KD) are due to the effects of ketone body metabolism. Interestingly, in studies on Type 2 Diabetic patients, improved glycemic control, improved lipid markers, and retraction of insulin and other medications occurred before weight loss became significant. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Shannon L. Kesl, et al. Kesl et al. Nutrition & Metabolism (2016) 13:9 DOI 10.1186/s12986-016-0069-y
Other benefits of Metatropic
  • BHB and acetoacetate (ACA) were found to increase sperm motility, while at the same time decreasing oxygen consumption 10 to 29%. Ketone Bodies as a Therapeutic for Alzheimer’s Disease. Samuel T. Henderson. Accera, Inc., Broomfield, Colorado 80021. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

 

  • Observations indicate that under certain physiological conditions where colonic SCFA production is enhanced, or (D)-3-hydroxybutyrate production is increased, gut microbial-regulated metabolites in the circulation are capable of directly mediating effects on host cells via GPCR signaling. Metabolic tinkering by the gut microbiome : Implications for brain development and function. Joel Selkrig, et al. Gut Microbes 5:3, 369-380. May/June 2014. Landes Bioscience.

 

  • There is also some evidence that ketones in their own right are directly toxic to cancer (Magee et al., 1979; Skinner et al., 2009; Fine et al., 2009) and can improve the immune system’s ability to target cancer (Husain et al., 2013). Starvation of Cancer via Induced Ketogenesis and Severe Hypoglycemia. Adam Kapelner and Matthew Vorsanger. arXiv:1407.7622v2 [q-bio.OT] 8 Dec 2014.

 

  • Ketone bodies that are elevated when insulin and blood glucose levels are low have been found to have a negative effect on proliferation of many tumor cell types in vitro. Ketone bodies have also been shown to exhibit positive effects against reactive oxygen species and cytotoxicity, especially in the brain, in this way providing an opportunity for enhancing the therapeutic ratio in radio- and chemotherapy. Abstracts of the 15th International Hamburg Symposium on Tumor Markers. Edited by R. Klapdor. 29-31 May, 2011. Anticancer Research 31: 1957-2016 (2011)

 

  • Beta-hydroxybutyrate attenuates the decrease in ATP production caused by a defect in complex I of the electron transport chain. It is thought to increase levels of the TCA intermediate succinate, which bypasses complex I when entering the TCA cycle. This carries considerable implications for MS, since defects in complex I within the electron transport chain have been observed in white matter lesions as well as in “normal” regions of the motor cortex. Ketones can also preserve ATP levels if complex II of the electron transport chain is inhibited, but this effect shows some regional specificity. The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mithu Storoni and Gordon T. Plant. Hindawi Publishing Corporation. Multiple Sclerosis International. Volume 2015, Article ID 681289, 9 pages.

 

  • Supplementation with ketones to induce ketosis has also shown an acceptable safety and tolerability profile. 23
  • Except for the role of preferential use for energy supply, another function of ketone bodies in the brain is to provide AcAc-CoA and acetyl-CoA for the synthesis of cholesterol and lipids, which are important for brain development. Potential of Anaplerotic Triheptanoin for the Treatment of Long-Chain Fatty Acid Oxidation Disorders. Lei Gu.