Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study

Abstract

Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, C-AcAc andF-fluorodeoxyglucose (F-FDG), respectively. During the KD, plasma ketones increased 8-fold ( p = 0.005) while plasma glucose decreased by 24% ( p = 0.005). CMRa increased 6-fold ( p = 0.005), whereas CMRglc decreased by 20% ( p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p < 0.0001). After four days on the KD, CMRa represented 17% of whole brain energy requirements in healthy adults with a 2-fold difference across brain regions (12-24%). The CMR of ketones (AcAc and β-hydroxybutyrate combined) while on the KD was estimated to represent about 33% of brain energy requirements or approximately double the CMRa. Whether increased ketone availability raises CMR of ketones to the same extent in older people as observed here or in conditions in which chronic brain glucose hypometabolism is present remains to be determined.

Intermittent metabolic switching, neuroplasticity and brain health

“…Moreover, Castellano et al recently reported that a 3-month aerobic training (brisk walking) programme increased brain cell ketone utilization in patients with AD threefold without affecting cerebral glucose utilization 144 , which may be one reason that aerobic exercise can protect the brain against AD. That IF may be another approach for subjects at risk of or with AD is suggested by a study using 11 C-acetoacetate positron emission tomography (PET) imaging that showed that within 48 hours of the onset of fasting, there is a sevenfold to eightfold increase in brain uptake of ketones 4,145 . Moreover, whereas brain cell uptake of glucose is severely impaired in patients with AD, the cells remain capable of utilizing ketones 146 .…”

“…Every time they eat, the glycogen stores in their liver are replenished; liver glycogen provides 700–900 calories of glucose or energy, an amount that will last 10–14 hours in individuals who are not exercising. Subsequently, liver energy stores are depleted, circulating glucose levels remain low and adipose cells release fatty acids, which are converted in the liver to the ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc), which are released into the blood and are used as energy substrates by neurons 4,5 (FIG. 1).…”

Ketones, omega-3 fatty acids and the Yin-Yang balance in the brain: insights from infant development and Alzheimer’s disease, and implications for human brain evolution

“…usually 3% of brain energy requirements. Nevertheless, ketones are still the adult brain's preferred fuel so they spare brain glucose uptake for other uses (Courchesne-Loyer et al, 2017). Fourth, production of glucose and ketones from endogenous substrates is governed by insulin but insulin appears to have little or no effect on ketone production from exogenous MCT.…”

“…Our PET protocol involves sequentially assessing brain ketone uptake first (because 11 C is a short-lived radiotracer) followed by assessing brain glucose uptake with the tracer -18 F-flurodeoxyglucose. This provides a measure of brain uptake of both fuels within a three hour period in the same person on the same day, which is as comparable an assessment of both brain glucose and ketone metabolism as possible (Roy et al, 2012(Roy et al, , 2013Castellano et al, 2017;Courchesne-Loyer et al, 2017;Croteau et al, 2017).…”

Automated synthesis of 1-[11C]acetoacetate on a TRASIS AIO module

“…PET imaging using [ 11 C]acetoacetate ([ 11 C] AcAc ) can provide quantitative analysis of brain ketone utilization that can help uncover the role of ketone metabolism in early AD; such information could potentially lead to new preventive and therapeutic strategies (Authier et al, 2008; Courchesne-Loyer et al, 2016; Nugent et al, 2013). These promising translational imaging applications of [ 11 C] AcAc stimulated efforts for the development of a more robust and simple automated radiochemistry procedure.…”