Ketosis

Ketosis is a metabolic state characterized by elevated levels of ketone bodies—specifically beta-hydroxybutyrate (BHB), acetoacetate, and acetone—in the blood, which occurs when the body utilizes fat as its primary fuel source instead of glucose [14, 18]. While often discussed in pharmacological contexts, ketosis is a physiological process rather than a specific protein or receptor target; however, it exerts its therapeutic effects through the activation of specific molecules, most notably the Hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) [1, 2, 10]. In this state, BHB serves as an alternative energy substrate for the brain and functions as a signaling ligand that can inhibit histone deacetylases (HDACs) and reduce systemic inflammation [6, 17]. Therapeutic ketosis is clinically established as a treatment for refractory epilepsy and is being actively explored for neurodegenerative conditions like Alzheimer's and Parkinson's disease due to its neuroprotective properties [2, 13, 19]. Drugs such as sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., empagliflozin) can pharmacologically induce a ketotic state, as can the administration of exogenous ketone esters or medium-chain triglycerides [7, 16, 18]. Despite its benefits, therapeutic ketosis requires careful monitoring to prevent complications like diabetic ketoacidosis, particularly in patients with insulin deficiencies [5, 14].

Other names

Nutritional ketosisPhysiological ketosisTherapeutic ketosisKetonemia

Induction of hepatic ketogenesis via carbohydrate restriction or pharmacological inhibition of glucose reabsorption, leading to the production of ketone bodies (BHB, acetoacetate) that serve as alternative energy substrates and signaling ligands for receptors such as HCAR2/GPR109A.