Induced Ketosis as a Treatment for Neuroprogressive Disorders: Food for Thought?

Abstract

Induced ketosis (or ketone body ingestion) can ameliorate several changes associated with neuroprogressive disorders, including schizophrenia, bipolar disorder, and major depressive disorder. Thus, the effects of glucose hypometabolism can be bypassed through the entry of beta-hydroxybutyrate, providing an alternative source of energy to glucose. The weight of evidence suggests that induced ketosis reduces levels of oxidative stress, mitochondrial dysfunction, and inflammation-core features of the above disorders. There are also data to suggest that induced ketosis may be able to target other molecules and signaling pathways whose levels and/or activity are also known to be abnormal in at least some patients suffering from these illnesses such as peroxisome proliferator-activated receptors, increased activity of the Kelch-like ECH-associated protein/nuclear factor erythroid 2-related factor 2, Sirtuin-1 nuclear factor-κB p65, and nicotinamide adenine dinucleotide (NAD). This review explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders and ameliorate abnormal levels of molecules and signaling pathways that also appear to contribute to the pathophysiology of these illnesses. This review also examines safety data relating to induced ketosis over the long term and discusses the design of future studies.

Figure 1.

The biochemistry of ketogenesis. Prolonged glucose restriction leads to an increased glucagon insulin ratio, relieving the inhibition of adipose triglyceride lipase and hormone-sensitive lipase, which are key enzymes in the production of free fatty acids (FFAs) in adipocytes and their subsequent release into the peripheral circulation. Decreased levels of insulin and glucose also combine to relieve the inhibition of carnitine acyltransferase 1 in the liver, which governs the uptake of FFAs into mitochondria, and to increase levels of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) while reducing levels of oxaloacetate, as it is used as a precursor for the manufacture of glucose. The net effect of these changes is increased glucagon-mediated transport of FFAs into the liver and increased uptake into mitochondria where they are used for the manufacture of acetyl coenzyme A (acetyle-CoA). In normal conditions, this would enter the tricarboxylic acid (TCA) cycle, but in an environment of reduced oxaloacetate the only metabolic pathway open to the molecule is ketogenesis involving the formation of ketone bodies via a series of steps. In the first of these reactions, Acetyl-CoA (AcCoA) is converted to acetoacetyl CoA in a reaction enabled by 3-Ketothiolase. This molecular intermediate is then converted to HMG CoA by HMG-CoA synthase, which is constitutively expressed in mitochondria. The final reaction in this pathway is the cleavage of HMG-CoA by HMG-CoA Lyase to produce acetoacetate. beta-hydroxybutyrate (BHB) may then be formed by the reversible reduction of acetoacetate mediated by 3-hydroxybutyrate dehydrogenase, and acetone may be produced by the thermodynamically favorable decarboxylation of aceoaetic acid (AA). Egress of these ketone bodies from the liver is facilitated by the transporter Solute Carrier Family 16, Member 6 (SLC16A6). Their subsequent entry into peripheral tissues and brain facilitated by monocarboxylic acid transporters ultimately serves as a source of AcCoA for the TCA cycle. Once in situ, BHB may be reconverted to acetoacetate in a reaction enabled by the same enzyme. However, from that point, ketolysis and utilization of ketone bodies display major biochemical differences compared with ketogenesis. In particular, Succinyl-CoA transfers its CoA group to acetoacetate to produce acetoacetyl-CoA in a reaction enabled by the enzyme succinyl-CoA:3-ketoacid coenzyme A transferase (also known as OXCT1 or SCOT), bypassing the irreversible step in ketogenesis catalyzed by HMG-CoA synthase and thereby preventing the development of a futile cycle of hepatic BHB synthesis and utilization.

Figure 2.

Mitochondrion. Glucose restriction and BHB oxidation leads to an increase in NAD+ and upregulated AMP-activated protein kinase (AMPK), with “downstream” activation of silent mating type information regulation 2 homologue 1 and 3 (SIRT1 and 3), peroxisome proliferator-activated receptor γ (PPARy), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), forkhead box O 3a (FOXO3a), and nuclear factor erythroid-derived 2-like 2 (NFE2L2). The cooperative activity of these enzymes and signalling systems ultimately result in increased transcription of genes related to oxidative capacity, mitochondrial uncoupling, and antioxidant defenses as detailed in the text. Fatty acid oxidation subsequent to ketolysis in an environment of glucose restriction decreases the ratio of NADH/FADH₂, leading to the overreduction of the CoQ/CoQH2 couple due to an excess of electrons entering the ETC at complex II. This scenario may provoke increases in reverse electron transport and increased ROS production in the form of superoxide radicals at complex I of the ETC. The subsequent dismutation of superoxide to hydrogen peroxide in the mitochondrial matrix and “spill over” into the cytoplasm offer another mechanism whereby mitochondria to nuclear signaling activates a transcriptional response almost identical to the one initiated by glucose restriction and BHB formation described above. This response is likely to be a major player in increasing the cellular antioxidant response in stressed mitochondria characteristic of neuroprogressive disorders.