Short-term metabolic responses to overnight-fasted v. fed-state exercise

Energy production during sustained aerobic exercise performed in the overnight-fasted state (i.e. 8–12 h) is supported primarily by the oxidation of endogenous fat and carbohydrate stores. Fat oxidation predominates during low-intensity exercise (<45 % VO_2max), both fat and carbohydrate oxidation increase to support moderate-intensity exercise (45–65 % VO_2max), while under most conditions carbohydrate oxidation predominates at higher exercise intensities (>65 % VO_2max). A recent systematic review and meta-analysis clearly demonstrated that as compared with performing exercise in the overnight fasted-state, the consumption of a carbohydrate-containing meal between 0·5 and 3 h before exercise reduces fat oxidation (and increases carbohydrate oxidation) during exercise performed for up to 2 h duration at <70 % VO_2max ^{(Reference Vieira, Costa and Macedo12)}. The suppression of fat oxidation during fed-state exercise occurred regardless of exercise duration, participant sex, BMI, exercise training status, duration between feeding and exercise or meal carbohydrate content. Plasma NEFA concentrations did not significantly differ between exercise performed in the fed v. overnight-fasted state. A clear effect of fed-state exercise on blood glucose and insulin concentrations points towards increases in glycolytic flux as the dominant regulator of fuel metabolism in these conditions⁽Reference Coyle, Jeukendrup and Wagenmakers¹³⁾. Further, previous research has established that the increased fat oxidation observed during exercise in the overnight-fasted state appears to be supported by both increased plasma long-chain fatty acid oxidation and type 1 skeletal muscle fibre intramuscular TAG utilisation at least in lean individuals⁽Reference Coyle, Jeukendrup and Wagenmakers^13, Reference De Bock, Richter Erik and Russell Aaron¹⁴⁾. There does not appear to be any modulation of liver fat during exercise regardless of whether this was performed in the overnight-fasted or fed-state⁽Reference Bilet, Brouwers and van Ewijk¹⁵⁾.

Whether the increased fat oxidation when exercise is performed in the overnight-fasted state can impact upon daily fat oxidation, which would be more representative of long-term potential to alter fat balance, is of paramount importance. Traditionally, despite exercise increasing fat oxidation during the exercise bout itself, increases in fat oxidation and reductions in fat balance over a 24 h period measured using whole-room indirect calorimetry have not been observed when studied under conditions of energy balance⁽Reference Melanson, Gozansky and Barry¹⁶⁾. This has been attributed to the effects of insulin as a consequence of consuming carbohydrate-containing meals suppressing lipid utilisation throughout the day. However, it is notable that exercise in these studies was not undertaken in the overnight-fasted state. Iwayama et al. demonstrated recently in lean healthy men that 1 h moderate-intensity exercise results in increased 24 h fat oxidation measured using whole-room indirect calorimetry when exercise was performed before (i.e. in the overnight-fasted state) breakfast, but not after lunch or dinner, even when participants remained in overall energy balance⁽Reference Iwayama, Kurihara and Nabekura¹⁷⁾. The same group have also shown improved 24 h fat oxidation and fat balance with pre-breakfast exercise in women⁽Reference Iwayama, Kawabuchi and Nabekura¹⁸⁾. Exercise performed in the overnight-fasted state would appear necessary to alter 24 h fat oxidation. While this area has not received extensive mechanistic investigation, negative correlations between energy balance or carbohydrate balance with 24 h fat oxidation suggests transient energy and/or carbohydrate deficits may be driving the response⁽Reference Iwayama, Kurihara and Nabekura¹⁷⁾.

The study of nutrient–exercise interactions in the context of substrate oxidation is important because links between fat oxidation during exercise and daily fat oxidation have been made⁽Reference Robinson, Hattersley and Frost¹⁹⁾, as have associations between daily fat oxidation and obesity risk⁽Reference Zurlo, Lillioja and Puente²⁰⁾. Of potentially equal importance is consideration of how timing of food intake around exercise modulates other risk factors for cardio-metabolic diseases, such as circulating lipid and glucose concentrations. With regard to blood lipid profiles, a study by Enevoldsen et al. is insightful⁽Reference Enevoldsen, Simonsen and Macdonald²¹⁾. This group determined blood metabolite and hormone responses across the course of 5·5 h in young healthy men who undertook exercise either before or after mixed macronutrient meal ingestion. Over the duration of the study period, a more favourable response of circulating markers of lipid availability (e.g. lower plasma TAG and VLDL-TAG concentrations) was observed when exercise was performed before as compared to after meal ingestion. A similar result was observed more recently in a study of overweight men, whereby exercise followed by food intake but not food intake followed by exercise significantly lowered plasma TAG concentrations as compared with a non-exercise control trial⁽Reference Farah and Gill²²⁾. Collectively, the afore-mentioned studies imply a potentially beneficial impact of overnight-fasted v. fed-state exercise on the aspects of body fat regulation and lipid metabolism at least in the context of single bouts of exercise.

The impact of overnight-fasted v. fed-state exercise on the aspects of glycaemic control has been subject to considerable recent debate⁽Reference Chacko²³⁾. Provision of carbohydrate-containing meals increases blood glucose and insulin concentrations, but when this is followed by exercise glucose uptake into skeletal muscle is enhanced leading to a lowering effect on blood glucose. This has been argued to be of particular importance in the context of diabetes, with the commencement of exercise 30–90 min post-prandial suggested to be optimal in accelerating meal-derived glucose disposal thus avoiding hyperglycaemia but also minimising risk of post-exercise hypoglycaemia⁽Reference Chacko²³⁾. This glucose-lowering effect of fed-state exercise in type 2 diabetes does appear to be most pronounced in those with the highest pre-exercise blood glucose concentrations⁽Reference Poirier, Tremblay and Catellier²⁴⁾. Taking subsequent meals into account can present a different picture. For example, feeding prior to exercise in lean, healthy individuals has been observed to increase the post-exercise postprandial glucose response to mixed macronutrient ingestion as compared with fasted-state exercise⁽Reference Gonzalez²⁵⁾. Furthermore, when glycaemic control was assessed in individuals with prediabetes over the course of a full day after overnight-fasted or fed-state exercise using continuous glucose monitoring, interstitial glucose variability but not total interstitial glucose exposure (area under the curve) was improved with fed-state exercise⁽Reference Nygaard, Rønnestad and Hammarström²⁶⁾. It would seem that the reported influence of a single bout of overnight-fasted v. fed-state exercise on short-term glycaemic control can be affected by the experimental conditions (e.g. when assessed over single v. multiple meals), the time frame of measurement and possibly the populations studied. However, as will be discussed in a later section, it is critically important to consider the difference between the acute effects of a single exercise bout and the adaptive response to chronic exercise training resulting from the culmination of those single exercise bouts.

Short-term energy balance behaviour responses to overnight-fasted v. fed-state exercise

Exercising in the overnight-fasted v. fed-state will clearly lead to a longer period of energy deficit, and from an energy balance perspective, it is important to understand the extent to which compensation of this energy deficit may occur during the post-exercise period.

This was initially investigated in a study by Gonzalez et al. who had twelve young physically active men undertake 1 h moderate-intensity treadmill running exercise performed in the overnight-fasted state or 2 h after breakfast consumption⁽Reference Gonzalez, Veasey and Rumbold²⁷⁾. After exercise, all participants consumed a standardised mixed-macronutrient drink, followed 90 min later by provision of an ad libitum test lunch, allowing for calculation of energy and macronutrient intake. Indirect calorimetry was conducted during the experiment to calculate energy expenditure and substrate oxidation. This group reported that despite the absence of breakfast in the overnight-fasted exercise, energy intake during the test lunch was similar when exercise was performed in the fed-state. Accordingly, energy intake and energy balance across the entire study period was significantly less when exercise was performed in the overnight-fasted v. fed-state. Interestingly, the lower energy balance with overnight-fasted exercise was attributable to reduced fat but not carbohydrate balance, the importance of which are 2-fold. First, greater reductions in fat balance may be more likely to induce favourable effects on body fat loss if sustained over time. Secondly, it is possible that the maintenance of carbohydrate balance is more important and tightly regulated than fat balance possibly due to finite carbohydrate storage capacity as has been previously suggested⁽Reference Jean-Pierre²⁸⁾. In support of this assertion, it has been reported that individuals who utilise more carbohydrate during exercise are more likely to compensate for the energy expended during exercise with greater post-exercise energy intake⁽Reference Hopkins, Blundell and King²⁹⁾, and mice overexpressing hepatic protein targeted to glycogen (resulting in increased liver glycogen concentrations under fasted and fed conditions) display reduced energy intake and increased energy expenditure⁽Reference López-Soldado, Fuentes-Romero and Duran³⁰⁾. As such, interventions that minimise carbohydrate oxidation during exercise (such as overnight-fasted exercise) may serve to limit subsequent energy intake.

More recently, the effects of overnight-fasted v. fed-state exercise (i.e. breakfast) on energy intake was examined over the course of an entire day, which may be more reflective of the potential for long-term impact on energy balance⁽Reference Bachman, Deitrick and Hillman³¹⁾. The study by Bachman et al. reported that ad libitum food (and energy) intake over a 24 h period was lower when exercise was performed prior to breakfast consumption. Interestingly, reduced energy intake was not simply a function of breakfast omission but food intake during meals and snacks consumed later in the day suggesting more prolonged effects of overnight-fasted exercise on regulation of food intake. At this stage, the involvement of metabolic (e.g. carbohydrate status) and/or modulation of appetite hormone regulatory mechanisms in explaining this lower energy intake with overnight-fasted exercise has not been resolved. The possibility of simply having less time in the day to consume food should also not be excluded, and while speculative, if this is relevant then aspects of the purported benefits of time-restricted feeding may be worthy for consideration⁽Reference Hutchison, Wittert and Heilbronn³²⁾. Importantly, the study by Bachman et al. did not quantify energy expenditure across the entire study period, thus the overall impact of the interventions on energy balance was not reported. This may be particularly important, as in conditions where free-living expenditure has been quantified, omission of breakfast per se (i.e. without exercise intervention) may transiently lower physical activity energy expenditure which would impact on energy balance⁽Reference Betts, Chowdhury and Gonzalez³³⁾. These collective studies suggest that short-term studies that encompass and allow for the behavioural responses to overnight-fasted v. fed-state exercise to occur may be particularly useful for understanding the potential for long-term impacts upon metabolism and health outcomes. However, the impact of altering carbohydrate oxidation on all components of energy balance (including physical activity) in the post-exercise period currently remains unknown, as do the mechanisms that link carbohydrate balance to any behavioural responses in human subjects.

Longer term metabolic and health outcomes in response to overnight-fasted and fed-state exercise

It is clear from the previous sections that overnight-fasted v. fed-state exercise can modulate metabolic and behavioural responses to a single bout of exercise. A relevant question is the extent to which such short-term responses translate into long-term modifications in biomarkers or risk factors for cardio-metabolic disease. If the feeding status around single exercise bouts is influential in determining long-term adaptive responses to exercise, then it may in part explain why some individuals do not always adapt to exercise training as would be predicted. The implication would be that if all exercise training sessions within a training study were undertaken with standardisation of pre-exercise nutrition, adaptive responses may be more consistent. However, to our knowledge, there are no studies investigating overnight-fasted v. fed-state exercise training on the consistency or variability of exercise adaptation. Indeed, with a few exceptions described below, the vast majority of aerobic exercise training intervention studies focus on the exercise component rather consideration of nutritional control or timing of food intake around exercise bouts.

The effects of overnight-fasted v. fed-state exercise on total body mass and indices of body composition have been investigated in training studies conducted under differing states of energy balance. Under isoenergetic and hypoenergetic conditions, when the state of energy balance is matched between intervention groups, responses of total body mass, fat mass or fat-free mass did not differ as a function of short-term (i.e. 4–6 weeks) overnight-fasted v. fed-state exercise training⁽Reference De Bock, Richter Erik and Russell Aaron^14, Reference Gillen, Percival and Alison^34–Reference Schoenfeld, Aragon and Wilborn³⁶⁾. While the effects on total body mass may be predictable, the lack of difference in body fat reduction contrasts what could theoretically be expected based on previously observed increases in daily fat oxidation and less positive (more negative) fat balance as a result of conducting overnight-fasted exercise in acute studies. One of the afore-mentioned studies utilised a high-intensity interval training programme⁽Reference Gillen, Percival and Alison³⁴⁾, which may not be favourable for increasing fat oxidation during exercise. As well, in all studies, the duration of training (i.e. 4–6 weeks) may have been insufficient to realise the theoretical advantages of overnight-fasted exercise training on body fat mass. Previous studies of exercise training per se would indicate that at least 12 weeks is necessary to induce measurable reductions in body fat⁽Reference Ross, Dagnone and Jones^37, Reference Ross, Janssen and Dawson³⁸⁾. Thus, to date, experimental conditions may not have been optimised to conclusively study if body composition can be improved with regular overnight-fasted v. fed-state exercise training in iso and hypoenergetic conditions. Indeed it could be that any short-term changes in daily substrate oxidation and storage are balanced out over periods of days and weeks such that body composition remains unaltered over the long term unless there are clear perturbations to long-term energy balance⁽Reference Hall and Guo³⁹⁾.

In contrast, a study conducted by Van Proeyen and colleagues indicated that effects of overnight-fasted exercise training on body composition may be revealed during conditions of hyperenergetic feeding⁽Reference Karen, Karolina and Henri⁴⁰⁾. These researchers subjected three groups of lean, healthy men to 6 weeks of 30 % excess of habitual energy intake in the form of a fat-rich (50 % dietary energy) diet. Participants either performed no exercise (control, Con), overnight-fasted (Fast) or fed-state (Fed) exercise four times per week. In Con and Fed, body mass significantly increased as compared with pre-diet values by about 3 and 1·4 kg, respectively, while no significant changes were observed in Fast. While interesting, it should be noted that despite apparent within-group differences in body mass gain, no significant between-group differences were observed between Fed and Fast. Incidentally, body fat assessed using skinfold thickness measurements increased in Con, but did not change significantly in Fed or Fast. Overall, there is a paucity of evidence to support a clear influence of overnight-fasted v. fed-state exercise training on body weight and composition, at least when studied over a short duration of training and in the state of energy balance is matched between intervention arms. However, as we discuss later, a more fruitful approach in the context of body weight and composition may be to not clamp energy balance between interventions and allow natural alterations in energy balance behaviours to occur outside of the specific controlled fasted or fed-exercise prescription.

Exercising in the overnight-fasted v. fed-state has been linked to a number of responses that could plausibly translate to long-term improvements in lipid and glucose metabolism. Adipose tissue plays a critical role in the storage of ingested dietary fats with relevance for post-prandial lipemia and minimising ectopic lipid storage. Indeed, high turnover of adipose tissue lipid stores has been associated with improved metabolic health⁽Reference Arner, Bernard and Salehpour^41, Reference Frayn, Bernard and Spalding⁴²⁾ suggesting that frequent oxidation of adipose tissue fatty acids increases the ability of adipose tissue to buffer lipid flux. Feeding status may therefore alter adipose tissue physiology with resultant implications for health. Consistent with this line of reasoning, a single bout of fed-state exercise blunts the effects typically seen with overnight-fasted exercise on the expression of genes related to lipid metabolism, insulin sensitivity and glucose uptake in adipose tissue⁽Reference Chen, Travers and Walhin⁴³⁾. In a similar manner, fed-state exercise tends to blunt acute exercise-related responses in skeletal muscle molecular pathways associated with the up-regulation of oxidative, lipid and carbohydrate metabolism (e.g. gene expression of FAT/CD36, CPT1, UCP3, PDK4, GLUT4, AMPKα2)⁽Reference Civitarese, Hesselink and Russell^44, Reference Cluberton, McGee and Murphy⁴⁵⁾. As well, in young lean men, overnight-fasted but not fed-state exercise increased utilisation of intramuscular TAG in type 1 skeletal muscle fibres⁽Reference De Bock, Richter Erik and Russell Aaron¹⁴⁾; high rates of intramuscular TAG turnover (i.e. storage and breakdown for NEFA oxidation) have been implicated in the maintenance of muscle insulin sensitivity⁽Reference Shaw, Clark and Wagenmakers⁴⁶⁾. Finally, while not unequivocal⁽Reference Proeyen, Szlufcik and Nielens^35, Reference Bock, Derave and Eijnde⁴⁷⁾, greater long-term changes in markers of skeletal muscle training adaptation such as the protein contents of GLUT4, FAT/CD36 and FABP and the maximal activities of the mitochondrial enzymes citrate synthase and β-hydroxyacyl-coA dehydrogenase have been observed with overnight-fasted exercise training⁽Reference Proeyen, Szlufcik and Nielens^35, Reference Karen, Karolina and Henri⁴⁰⁾.

In general, the afore-mentioned evidence points to the potential for overnight-fasted exercise to promote greater benefits to metabolic health outcomes than conducting regular exercise in the fed-state, although the number of investigations in this area is remarkably limited. Summarising the evidence that is available to date, Hansen et al. concluded that there does not appear to be clear impact of short-term fed v. fasted-stated exercise training on overnight-fasted resting blood markers such as glucose, insulin and NEFA; notably studies have generally been performed in young lean individuals⁽Reference Hansen, De Strijcker and Calders⁹⁾. Only the study by Van Proeyen and colleagues described previously, which adopted 6 weeks of hyperenergetic fat-rich feeding, has addressed the impact of overnight-fasted v. fed-state exercise training on a dynamic measure of metabolic function⁽Reference Karen, Karolina and Henri⁴⁰⁾. These authors found that the Matsuda Insulin Sensitivity Index (calculated from an oral glucose tolerance test) was higher in the group that performed overnight-fasted exercise training as compared with the no exercise control trial. No significant differences were reported between fed-state exercise and no exercise control, with the implication that fasted-state exercise improves glucose tolerance during a fat-rich diet. The authors rightly acknowledge that body mass gain in the control (and fed-exercise) trial but not the fasted-exercise trial could contribute to the observed differential responses to insulin sensitivity. Nonetheless, these data provide promising proof of concept for a role for overnight-fasted training in enhancing benefits of exercise on glucose tolerance at least under conditions of excess energy intake, which could have relevance within obesogenic environments.

As stated earlier, there is a clinical view that post-prandial exercise is preferable over fasted-state exercise for the acute control of blood glucose, at least in patients living with type 2 diabetes⁽Reference Chacko²³⁾. However, if an individual performs fasted-state exercise, it is not clear if the subsequent post-prandial rises in blood glucose are pathological. As well, we also highlighted earlier that as compared with fasted-state exercise, fed-state exercise can result in a worsening of subsequent post-prandial glucose control⁽Reference Gonzalez²⁵⁾. Again, the question arises as to whether this is potentially pathological or simply reflecting short-term adaptive physiology. Our recent work examining post-prandial glucose fluxes after no exercise, exercise performed in the overnight-fasted or fed-state would suggest the latter⁽Reference Edinburgh, Hengist and Smith⁴⁸⁾. Specifically, we observed in healthy young men that fed-state exercise increases glucose appearance rates into the circulation during subsequent glucose ingestion, and this was explained by increases in the appearance of the ingested glucose. However, this was met with increases in whole body glucose disposal, such that the increased influx of glucose was appropriately cleared. Whether this applies in other study populations remains to be determined, but it does lend support to the notion that the responses of blood glucose to single bouts of exercise performed in the fed or fasted state are part of normal physiology. What is perhaps more important is the adaptive stimulus provided by acute bouts of exercise, for example, in skeletal muscle, that when accrued over time results in chronic changes in the capacity to manage postprandial excursions in blood glucose (and lipids). In this respect, the work from Van Proeyen and colleagues showing that the aspects of glucose control may be preferentially affected by consistent exercise training in the overnight-fasted v. fed-state (under conditions of excess energy intake) is perhaps most revealing⁽Reference Karen, Karolina and Henri⁴⁰⁾, although clearly there is a need to follow-up this work in patients at risk of or living with disturbances in glucose control such as type 2 diabetes.