**1. Introduction**

Ketone bodies are small compounds created from fatty acids that serve as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise [1].

The most important ketone bodies in humans are acetoacetate (AcAc) and β-hydroxybutyrate (BHB), in particular, the R-enantiomer of BHB. Ketone bodies are believed to be adaptive molecules secreted by the liver and quickly distributed to vital organs as a part of an integrated survival mechanism evolved and conserved to provide bioenergetic and signaling advantages when humans face life-threatening conditions or risk factors that could increase the likelihood of premature death [2]. During times of scarce glucose, for example, during fasting or strenuous exercise, BHB is the currency by which energy stored in adipose tissue is turned into fuel that serves the cells to maintain their functions. BHB derives from fatty acids mobilized from adipose tissue and transported to the liver. BHB circulates in the blood to all tissues. After being absorbed into a cell, BHB is broken down in the mitochondria to generate acetyl-CoA, which is further metabolized into ATP. This is the canonical "energy currency" function of BHB.

By reducing carbohydrate ingestion, there is an exhaustion of the body's glucose reserve, shifting the metabolism into ketogenesis, inducing hepatic oxidation of fatty acids, and producing ketones as an important alternative to glucose as the body's energy source [3].

**Citation:** Dilliraj, L.N.; Schiuma, G.; Lara, D.; Strazzabosco, G.; Clement, J.; Giovannini, P.; Trapella, C.; Narducci, M.; Rizzo, R. The Evolution of Ketosis: Potential Impact on Clinical Conditions. *Nutrients* **2022**, *14*, 3613. https:// doi.org/10.3390/nu14173613

Academic Editors: Omorogieva Ojo and Amanda R Amorim Adegboye

Received: 7 August 2022 Accepted: 30 August 2022 Published: 1 September 2022

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Ketosis is a physiological metabolic state characterized by an increased serum ketone body level from ~0.2 mM to above 3.0 mM [4], caused by exercise [5], fasting/starvation [6], or diabetes [7,8]. In peculiar conditions, the ketosis might develop into overt ketoacidosis, with a decreased serum bicarbonate level and pH, causing serious illness and hospitalization. Ketoacidosis is mainly associated with alcoholism and diabetes mellitus type I, starvation, particularly during malnutrition, and poor dietary intake in people following low-carbohydrate and/or low-caloric diets [9].

In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. Ketone bodies are involved in epigenetic changes [10–12], controlling cellular signaling metabolites [13], gut microbiota, and butyrogenesis [14]. The epigenetic changes regulate cellular gene expression and metabolism, with an implication for physiological and pathological conditions [15,16]

In this review, we discuss not only the metabolic effect of ketone bodies but also their implication in clinical conditions, suggesting possible future research fields in the use of these molecules as a clinical approach.
