The Evolution of Ketosis: Potential Impact on Clinical Conditions

Abstract

Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies' brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.

Keywords: anti-inflammatory; beta-hydroxybutyrate; evolution; ketogenesis.

Figure 1

Schematic Diagram of the metabolic pathways of key energy sources in the human body. NAD: nicotinamide adenine dinucleotide; FADH: reduced flavin adenine dinucleotide; NADH: nicotinamide adenine dinucleotide (NAD) + hydrogen (H); PDH: pyruvate dehydrogenase; LDH: lactate dehydrogenase; CPT: carnitine palmitoyl transferase; ß HOB: beta hydroxybutyrate; BDH: D-3-hydroxybutyrate dehydrogenase; SCOT: succinyl-CoA acetoacetate transferase; AcAc: acetoacetate; CoA: coenzyme A; CoA-SH: coenzyme A with sulfhydryl functional group; CO2: carbon dioxide; H2O: water; ADP: adenosine diphosphate; ATP: adenosine triphosphate; Pi: phosphorylated forms of phosphatidylinositol; NH3: ammonia; NH4: ammonium; H+: hydrogen ion; HMG-CoA: ß-hydroxy-ß-methylglutaryl-CoA; MCT: monocarboxylate transporters; GLUT: glucose transporter; AAT: amino acid transporter; ALT: alanine amino transferase; PC: pyruvate carboxylase; MPC: mitochondrial pyruvate carrier.

Figure 2

Endogenous and exogenous metabolic pathways. NAD: nicotinamide adenine dinucleotide; FADH: reduced flavin adenine dinucleotide; NADH: nicotinamide adenine dinucleotide (NAD) + hydrogen (H); CPT: carnitine palmitoyl transferase; ß HOB: beta hydroxybutyrate; BDH: D-3-hydroxybutyrate dehydrogenase; SCOT: succinyl-CoA acetoacetate transferase; AcAc: acetoacetate; CoA: coenzyme A; ADP: adenosine diphosphate; ATP: adenosine triphosphate; Pi: phosphorylated forms of phosphatidylinositol; H+: hydrogen ion; HMG-CoA: ß-hydroxy-ß-methylglutaryl-CoA; MCT: monocarboxylate transporters.

Figure 3

Molecular pathways involved in ketone bodies effect on oxidative stress, inflammation, and epigenetic control. HDAC: histone deacetylase; BDNF: brain-derived neurotrophic factor; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; FOXO3A: forkhead box O3; Mt2: mammalian metallothionein-2; UCP: uncoupling protein; PPARγ: peroxisome proliferator-activated receptor γ; p53: protein 53; Ku70: DNA repair subunit protein; GSK3: serine/threonine protein kinase; mTOR: mammalian target of rapamycin.

Figure 4

Scheme illustrating the relationship between brain metabolism of ketone bodies and that of glutamate and GABA, where the metabolism of ketone bodies of acetyl-CoA induces the increase of glutamate and GABA. 3-OH_Butyrate: β-hydroxybutyrate; Succ-CoA: succinyl-CoA; AcAc-CoA: acetoacetyl-CoA; Ac- CoA: acetyl-CoA; CoA: coenzyme A; NADH/NAD: nicotinamide adenine dinucleotide; GOT: glutamate-oxaloacetate transaminase; GABA: gamma-aminobutyric acid.

Figure 5

The six hallmarks of ketonic action. ATP: Adenosine triphosphate; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROX: chemical reduction oxidation; GABA: gamma-aminobutyric acid; HDAC: histone deacetylase.