Can ketone esters support an appetite to perform and recover?

The ability of endurance athletes to train consistently and intensely is of paramount importance. The transient exercise-induced decrements to performance elicited by overload training appear necessary to promote sustained and meaningful physiological adaptations that eventually improve performance (i.e. functional overreaching). However, a persistent inability to completely recover from the multi-faceted demands of exercise can predispose athletes to a variety of negative outcomes. Numerous terms have been proposed to describe the cardiovascular, hormonal and psychological maladaptations that can arise due to a persistent imbalance between training and recovery. At its mildest, non-functional overreaching is defined by a stagnation in training-specific performance which may progress to sustained impairments. If untreated, this can lead to an increase in symptom severity or injury (i.e. overtraining), requiring months or even years to recover from (Fry et al. 1992). Several points of intervention exist (e.g. rest, nutrition, tapering) that require further exploration as researchers unravel the physiological basis and temporal nature of these maladaptations. Accordingly, research is ongoing towards potential nutritional strategies to mitigate the onset of non-functional overreaching or provide a performance-enhancing effect. Recently, ketone ester (KE) supplementation has gained considerable attention as a potential ergogenic and recovery aid by providing a well-tolerated alternative energy substrate (Evans et al. 2017; Holdsworth et al. 2017). As such, a role for KE supplementation in modifying the response to training and subsequently altering symptoms of overreaching is plausible, particularly if supplementation is over the duration of training or immediately post-exercise. A recent article by Poffé et al. in The Journal of Physiology uncovers a previously unrecognized ability for KE supplementation to blunt symptoms of overreaching in fit, male participants (Poffé et al. 2019). It was observed that daily KE ingestion prior to sleep and following bouts of mixed exercise training (3 weeks of high intensity intervals, intermittent endurance, and constant-load endurance bouts designed to induce a state of non-functional overreaching) can: (1) help athletes better match energy intake to the increased energetic demands of an intensive training regimen, (2) blunt symptoms of overreaching, including heightened nocturnal catecholamines and reduced heart rate responses to exercise, (3) increase training load, as evidenced by a 15% increase in total work output in the final week of training, and (4) significantly increase cycling power output during the final 30 min of a 2 h endurance task. The results of the present study propose a new role for KE supplementation in maintaining whole-body energy homeostasis and the prevention of overreaching symptoms. A common symptom of overreaching is the suppression of appetite that leads to improper nutrition, inadequate recovery and ultimately impaired performance (Fry et al. 1992). Interestingly, only the KE group compensated for the increased demands of training by increasing total (self-reported) caloric intake (by week 2). Poffé et al. explored the contribution of appetite hormones to the observed changes in dietary intake in the KE group. However, negative regulators of appetite, including growth differentiation factor 15 (GDF15) and leptin, as well as the orexigenic peptide ghrelin all remained unaltered in the KE group throughout much of the intervention. It was not until the third week of training that GDF15 significantly increased in the KE group (although to a lesser extent than in the control group); however, KEs’ protective effect on energy homeostasis was maintained. Conversely, leptin levels significantly declined in the control group, despite their inability to match dietary intake to the increasing training workload. It is important to note that there was no reported change in the subjective rating of appetite in the KE group compared to placebo, at least when assessed immediately prior to standardized breakfasts. Taken together, this suggests that chronic KE intake protects against the dysregulation between perceived hunger, hormonal signals for satiety and energy intake during overload training. Given the difficulty in interpreting single time point measures of appetite hormones (e.g. ghrelin has an ultradian rhythm), future studies could investigate the daily temporal responses of GDF15, leptin and ghrelin during a period of overtraining with KE supplementation. Additionally, given that total ghrelin was not different between placebo and KE groups, it is important to distinguish the two bioactive ghrelin isoforms. Acylated ghrelin (AG) is accepted as the orexigenic and growth hormone-stimulating peptide, which is more likely to significantly affect both energy balance and exercise recovery. It is tempting to attribute the beneficial effects of KE supplementation to a better matching of caloric intake and energy output. The 20% rise in energy intake in the KE group (but not the control) suggests a greater ability to maintain energy balance during overreaching. Importantly, the increased energy intake was fully accounted for by an increase in carbohydrate, potentially explaining the 20% decline in resting muscle glycogen content throughout the training programme in the control, but not the KE group. It may be that KE supplementation acts in part by preserving muscle glycogen content during overload training (independent of blunting overreaching symptoms). Resting muscle glycogen was similar between control and KE groups at the end of the third week of training but was not assessed prior to or during this final week in order to draw firm conclusions regarding its role as a contributor to the 15% increase in total work completed in the endurance training sessions. Poffé et al. addressed that the blunting of specific overreaching symptoms (i.e. reduced heart rate responses to exercise and elevated nocturnal urinary adrenaline) began in the first week of training, prior to the increased caloric intake (i.e. second week of training) and presumably improved recovery. Unfortunately, it is difficult to tease apart the independent contributions of intensive training and nutritional deficit on symptoms of overreaching. It is unclear if the beneficial effects of chronic KE supplementation require changes in dietary intake, as participants were able to consume food ad libitum. Therefore, it is intriguing to speculate on whether an abolishment of the protective effects of KE supplementation would be observed in the context of strict dietary control. Poffé and colleagues assessed cycling performance in four ways: (1) total work output during training, (2) a weekly 90 s sprint, (3) a weekly simulated 30 min time trial (TT), and (4) a 30 min TT following 90 min of endurance cycling pre-load. Intensive overload training was employed to elicit non-functional overreaching. To that end, the overload cycling protocol led to a significant reduction in mean power output during the 90 s all-out sprint in both control and KE groups in the final week of training. Although non-functional overreaching typically requires weeks to overcome, sprint performance returned to baseline after only 3 days of recovery. Furthermore, the mean power output during the 30 min TT was not reduced in either group over the course of the training regimen. Thus, it is possible that this 3-week programme had only begun to induce a state of non-functional overreaching. Though speculative, ethical concerns may have limited the researchers’ ability to prolong training. Finally, the lack of net utilization (in both control and KE groups) in quadriceps muscle glycogen content following the 30 min TT is surprising, highlighting an inability to utilize muscle glycogen in overreached athletes. Considering the duration and intensity of the TT, mechanisms behind this observation remain unclear. While impairments to skeletal muscle adrenergic sensitivity have been demonstrated in the literature, circulating catecholamines were not assessed during the TT in the present study to allow for a definitive conclusion. Given that many intramuscular stimulators of glycogenolysis would increase during intensive exercise (e.g. Ca2+, ADP, AMP), underlying mechanisms for these altered physiological responses during overreaching should be pursued. It is uncertain whether overreached skeletal muscle becomes resistant solely to the effects of catecholamines, or also to those of other endogenous metabolic regulators. It has been suggested that acute KE supplementation may improve TT performance in endurance trained athletes, implying that a prolonged adaptation period to ketones is not necessary for performance benefits (Cox et al. 2016). However, Poffé et al. are the first to show that chronic KE supplementation also has benefits during overload training in humans. Interestingly, the evidence presented suggests that KE supplementation is specifically beneficial for prolonged endurance exercise (i.e. >30 min) during mixed modality, intensive training. The physiological mechanism(s) by which KE supplementation exerts its acute and chronic ergogenic effects requires further exploration. It is interesting to consider whether skeletal muscle adapts to uptake and utilizes ketones, or whether ketones act as signalling molecules for metabolic adaptation when administered over the course of training. To that end, future work may also warrant a lead-in period whereby participants are given KEs prior to the commencement of training to delineate the chronic effects of KE supplementation on skeletal muscle metabolism and its implications for prolonged endurance performance. In conclusion, the present investigation has made a significant contribution towards understanding the effects of KE supplementation during intensive training in humans and suggests that many of the beneficial effects could be attributable to its ability to regulate energy balance. It is exciting to consider the future work that will stem from this single research endeavour, opening the door for multiple approaches to study the action of KEs in the nutritional, exercise and recovery-related physiological processes surrounding intense training regimes. None declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. D.T.C. (PGS-D) and K.A.W. (CGS-D) hold scholarships from the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors would like to thank Dr David Dyck and Dr David Mutch for editing the manuscript.

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