The Impact of Ketogenic Nutrition on Obesity and Metabolic Health: Mechanisms and Clinical Implications

Abstract

The ketogenic diet (KD) has recently gained increasing popularity. This high-fat, adequate-protein, and carbohydrate-poor eating pattern leads to nutritional ketosis. The KD has long been known for its antidiabetic and antiepileptic effects and has been used therapeutically in these contexts. Recently, the KD, due to its effectiveness in inducing weight loss, has also been proposed as a possible approach to treat obesity. Likewise, a KD is currently explored as a supporting element in the treatment of obesity-associated metabolic disorders and certain forms of cancer. Here, we discuss the metabolic and biochemical mechanisms at play during the shift of metabolism to fatty acids and fatty acid-derived ketone bodies as main fuel molecules, in the substitution of carbohydrates, in ketogenic nutrition. Different sources of ketone bodies and KDs as alternatives to glucose and carbohydrates as main energy substrates are discussed, together with an attempt to weigh the benefits and risks posed by the chronic use of a KD in the context of weight loss, and also considering the molecular effects that ketone bodies exert on metabolism and on the endocrine system.

Keywords: beta-hydroxybutyrate; inflammatory response; ketogenic diet; ketone bodies; lipid metabolism; obesity.

Figure 1.

Metabolism of Fatty Acids (FAs). (A) Ketogenesis is initiated in order to make available energy stored in fatty acids. Once formed in the mitochondria, acetyl coenzyme A (acetyl-CoA) is reversibly converted to acetoacetyl-CoA, what is catalyzed by acetyl-CoA transferase 1 (ACAT1). Next, HMG (hydroxymethylglutaryl)-CoA synthase condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA. HMG-CoA lyase catalyzes the formation of acetoacetate from HMG-CoA. The acetoacetate (AcAc) is then reversibly converted to β-hydroxybutyrate (BHB) by β-hydroxybutyrate dehydrogenase 1 (BDH1). (B) Fatty acids are present in the blood due to prior disruption of lipids (lipolysis) and are used as substrates in the β-oxidation process. Following hepatic ketogenesis, the ketone bodies are transferred back to the blood, where BHB as a signaling metabolite can be further transferred to extrahepatic tissues and AcAc can be degraded spontaneously into acetone (Ac), which will then be exhaled. (C) Ketolysis encompasses a set of reactions designed to recover energy through the oxidation of ketone bodies, which takes place in the mitochondria. The main ketone body distributed to the extrahepatic tissues—BHB—undergoes the reversible conversion to AcAc by BDH1. AcAc is then incorporated into acetoacetyl-CoA in a reaction catalyzed by succinyl-CoA-3-ketoacid-coenzyme A transferase (SCOT). Acetoacetyl-CoA can be reversibly converted by ACAT1 to acetyl-CoA, which is used in the tricarboxylic acid (TCA) cycle. The figure was created with BioRender.com

Figure 2.

Changes in the Ketone Body Levels Depending on Ketone Body Sources and Metabolic Conditions. In the physiological state, concentrations of BHB are below 1 mmol/L. Overnight fasting and 24-hour fasting generate physiological ketonemia. Longer fasting, from 3 to 7 days, results in overt ketosis and the induction of ketosis through the ketogenic diet may increase the concentration of ketone bodies to up to 7 mmol/L. Starvation leads to an approximately 6–8 mmol/L blood BHB concentration, when maintained for more than 10 days. Beyond this range (up to 20 mmol/L), pathological conditions, such as untreated diabetes and ketoacidosis, occur. The figure was created with BioRender.com

Figure 3.

Molecular Responses to Induction of Ketosis. Abbreviations: IL, interleukin; GPR109A, hydroxycarboxylic acid receptor 2, niacin receptor 1; MCFA, medium-chain fatty acid; NF-κB, nuclear factor–kappa B; NLR, Nod-like receptor protein family; NLRP3, NLR pyrin domain-containing protein 3; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha; TLR4, Toll-like receptor 4. The figure was created with BioRender.com