Exogenous ketosis, a nutritional strategy to preserve brain health?

The prevalence of obesity (BMI ≥ 30 kg m−2) has reached epidemic proportions in recent decades. According to the World Health Organization (2016), 650 million people can be considered obese. Obesity is a global health concern as it increases the risk of developing cardiometabolic diseases, cancer and cognitive disorders. In addition, obese adults are more prone to developing insulin resistance, leading to hyperglycaemia and type II diabetes mellitus (T2D). Both acute and chronic hyperglycaemia are associated with cognitive dysfunction resulting from cerebral glucose hypometabolism and a reduction in cerebral blood flow (CBF) (Walsh et al. 2021a). Proper regulation of CBF is critical for supporting brain function via the delivery of oxygen and energy substrates and the disposal of metabolic waste products. Moreover, circulating levels of brain-derived neurotrophic factor (BDNF) are reduced in adults with impaired glucose tolerance (Walsh et al. 2021a). BDNF is a key regulator of synaptic plasticity and important for the survival and maturation of neurons in the nervous system (Miranda et al. 2019). Given the harmful effects of hyperglycaemia on brain metabolism and cognitive function, it is important to seek therapeutic interventions that can increase glucose tolerance in obese adults. Previous studies have shown that a low-carbohydrate, high-fat, ketogenic diet is an effective approach for lowering blood glucose levels in humans and improving cognitive abilities in animal models (Hernandez et al. 2018). A ketogenic diet results in increased fat oxidation and stimulates the production of the ketone bodies β-hydroxybutyrate (βHB) and acetoacetate by liver mitochondria. These ketone bodies can bypass neuronal glycolysis to meet brain energy demands under conditions of limited glucose availability (Hernandez et al. 2018). However, due to the restrictive nature of a ketogenic diet, compliance is often poor. An alternative nutritional approach is the intake of ketone esters (KE), which induces a safe, rapid and transient increase in the concentration of circulating ketone bodies without the need of adhering to a specific diet. The glucose-lowering potential of exogenous ketosis has been demonstrated in humans (Walsh et al. 2021b) and is at least partly attributed to decreased availability of l-alanine for gluconeogenesis. In addition, ketone bodies have been shown to serve as an alternative fuel in brain cells with compromised glucose metabolism, to induce neuroprotective effects, and even to improve cognitive function in patients with T2D (Jensen et al. 2020). Interestingly, infusion of βHB increases CBF in humans and upregulates the concentration of BDNF in neurons. However, these effects have all been observed under acute ketosis. Therefore, the potential beneficial effects of longer term, intermittent elevation of ketone bodies on brain metabolism and function in obese adults are unclear. Accordingly, the recent article by Walsh et al. (2021a) published in The Journal of Physiology aimed to investigate the effects of short-term (14 days) KE supplementation in a cross-over design on CBF, circulating BDNF and cognitive function in obese adults. Subjects (n = 14) consumed 12 g of ketone monoester prior to breakfast, lunch and dinner. Apart from the intake of KE (∼175 kcal/day), food intake was standardized throughout the study period and matched between both experimental conditions. CBF, BDNF and cognitive performance were measured before and after the intervention period in the fasted state, thus under normal physiological ketone body concentrations (e.g. <0.5 mM).