Ketone body metabolism and cardiometabolic implications for cognitive health

Abstract

Cardiometabolic complications of obesity present a growing public health concern and are associated with poor outcomes, mediated in part by an increased risk for cardiovascular disease, metabolic dysfunction-associated fatty liver disease, and systemic insulin resistance. Recent studies support that both insulin resistance and obesity are also associated with aberrant brain metabolism and cognitive impairment similar to what is observed in neurodegenerative diseases. Central to these pathological outcomes are adverse changes in tissue glucose and ketone body metabolism, suggesting that regulation of substrate utilization could be a mechanistic link between the cardiometabolic outcomes of obesity and the progression of cognitive decline. Here, we review ketone body metabolism in physiological and pathological conditions with an emphasis on the therapeutic potential of ketone bodies in treating cardiometabolic diseases and neurodegenerative diseases that lead to cognitive decline. We highlight recent findings in the associations among cardiometabolic disease, ketone body metabolism, and cognitive health while providing a theoretical framework by which ketone bodies may promote positive health outcomes and preserve cognitive function.

Fig. 1. Regulation of ketone body metabolism in normal and pathological states.

Schematic depicting key regulators of hepatic ketogenesis and extrahepatic utilization (A). Hepatic ketogenesis is regulated by levels of circulating insulin and glucagon, with overall capacity influenced by adiposity (B) and the overall rate influenced by liver disease (C) and circulating concentrations (D). HSL hormone-sensitive lipase, Sk =skeletal, MASLD metabolic dysfunction-associated steatotic liver disease, MASH metabolic dysfunction-associated steatohepatitis. Created with BioRender.com

Fig. 2. Ketogenic interventional strategies and effects on neuronal metabolism.

Schematic highlighting the effects of ketogenic diet, exercise, and certain medications (e.g. SGLT2i) on endogenous ketogenesis and neuronal metabolism. Exogenous ketone supplementation includes ketone esters and salts that may increase circulating ketone bodies independent of classical, hepatic ketogenesis. Neuronal uptake of ketone bodies could reduce glucose oxidation and spare glucose-derived carbon for biosynthesis. Created with BioRender.com