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Fuel Selection and Metabolic Function

The body primarily relies on carbohydrate and fat oxidation as the main sources of ATP for skeletal muscle contraction. The utilization of either carbohydrate or fat resources will depend on the intensity and duration of the exercise (Loon et al., 2001). However, Lei et al. (2015) contend that the ability of the body to switch from glucose metabolism to fatty acid metabolism (metabolic flexibility) is essential in determining exercise tolerance. The authors further note that the inability of the body to switch from glucose to fatty acids can lead to metabolic disorders such as cardiometabolic syndrome, diabetes, and insulin resistance, while metabolic flexibility is associated with enhanced fatty acid oxidation, which preserves existing glucose reserves (Lei et al., 2015). In this paper, the writer will reflect on the best diet for increasing exercise tolerance and potential issues with the selection of the appropriate fuels.

Metabolic Inflexibility

According to Lei et al. (2015), metabolic inflexibility occurs in individuals whose beta-oxidation is impaired. These disorders associated with beta-oxidation impairment also contribute to other problems such as cardiomyopathy, hepatic steatosis. However, the authors contend that the mechanism through which skeletal muscles switch from one fuel to another, and its impact on exercise is not well known. In their study involving laboratory mice, Lei et al. (2015) found that Acyl-CoA Synthetase Long-Chain Family Member 1 (ACSL1) is critical for fat oxidation in muscles. In the absence of the factor, the body increasingly relies on glucose for APT production, which can lead to hypoglycemia. The inability of skeletal muscles to switch from glucose to fatty acids leads to suboptimal exercise performance, and low endurance. As such, any mutation that affects the availability of ACSL1 can limit metabolic flexibility of an individual, and therefore reduce their ability to endure intense exercise.

Metabolic inflexibility may also occur due to other factors, other than ACSL1. During exercise, the body will first oxidate glucose that is available in the liver or muscles. As the intensity and duration of exercise increase, the body will draw on fat reserves. Loon et al. (2001) contend that the oxidation levels of either carbohydrates or fats will depend on serum levels of free fatty acids (FFAs). They argue that a high level of FFAs can lead to a reduction in oxidation levels of carbohydrates, as the free fatty acids suppress pyruvate dehydrogenase complex activation. In their study of eight cyclists, Loon et al. (2001) found that a reduction of fat oxidation in cyclists was due to the downregulation of carnitine palmitoyltransferase I. The scholars concluded that it was likely that a decline in intracellular pH and free carnitine availability could explain the findings. As such, it is likely that a change in pH and carnitine available could lead to metabolic inflexibility since the body is unable to oxidate fats. It is likely that similar mechanisms could explain the impairment of fat oxidation in people who are obese or those who are diabetic.

A mismatch between oxidation and availability of lipids might induce lipotoxicity due to ectopic fat deposition. Lipotoxicity occurs when lipid metabolites interfere with insulin signaling pathways, leading to insulin resistance (Feerbabdez-Verdejo et al., 2018). In such a context, high levels of oxidation may prevent ectopic fat deposition and thus reduce the risk of lipotoxicity, which would prevent insulin resistance. However, in people with type two diabetes (TD2), high levels of circulating non-esterified fatty acids (NEFA) impede fat oxidation, which can lead to lipotoxicity (Feerbabdez-Verdejo et al., 2018). Accordingly, the presence of high levels of serum NEFA impairs metabolic flexibility and thus can lead to lipotoxicity. The mechanisms through which these fatty metabolites contribute to the condition are not unknown. However, there is evidence that skeletal mechanisms are implicated in the problem.

Fuel Selection and Exercise Tolerance

Selection of the appropriate fuel can be difficult. In their study, Cox et al. (2016) suggest that nutritional ketones could increase resilience in individuals. The body produces ketones in response to an energy deficit or calorie deprivation. Such conditions occur when an individual either has a clinical manifestation of ill-health or when an individual is undergoing prolonged starvation or exercise. Starvation ketones differ from nutritional ketones in that nutritional ketones are produced when the body oxides fats instead of glucose. All tissues in the body can easily oxidize ketones, with the exception of the liver, since it lacks succinyl-CoA:3-ketoacid CoA transferase (Cox et al., 2016). The latter enzyme is responsible for the oxidative disposal of ketones. Athletes or other individuals engaging in high-intensity exercise can benefit from a direct intake of d-β- hydroxybutyrate. However, direct intake of the monoester is not recommended. Rather a ketonic diet or ketone esters can raise serum ketone levels (Cox et al., 2016).

The most appropriate diet for exercise remains nutritional ketones. There are several reasons for the conclusion. First nutritional ketones are easily oxidated by all tissues, including skeletal muscles, with the exception of the liver (Cox et al., 2016). Secondly, ketones yield more ATP energy per mol of oxygen relative to fatty acids and glucose. Thirdly, ketones produce less reactive oxygen species compared to other energy sources. Furthermore, ketones regulate their own production by directing fuel oxidation, inhibiting spare glycogen oxidation, and lipolysis (Soto-Mota & Clarke, 2020) The role of ketones in starvation makes it an important fuel for the high duration and intensity of exercise. d-β- hydroxybutyrate, a ketone body, plays a key role in starvation by suppressing oxidative stress, increasing histone acetylation, and diminishing inflammation response. The ketone body also plays a key role in diminishing sympathetic nervous system activity. It also diminishes total energy expenditure by blocking short-chain fatty acid signaling (Soto-Mota & Clarke, 2020).

Cox et al. (2016) contend that nutritional ketosis can play the same role as glucose in ATP production. The reason is that ketosis plays a key role in survival mechanisms, where maintenance of normal homeostasis is essential. When competition for energy sources is high, ketones can fulfil the energy demands of the body. Unlike other energy sources, ketones do not lead to the production of reactive metabolites such as those that are produced by fatty acid oxidation. In their findings, Cox et al. (2016) found that nutritional ketones were associated with higher levels of skeletal muscle oxidation levels. On the other hand, intake of CHO did not affect the oxidation levels of skeletal muscles. It is likely that nutritional ketones inhibited the oxidation of fatty acids, thus increasing skeletal muscles oxidation levels.

While nutritional ketones can improve performance, it is critical for athletes or other individuals engaging in high duration and intensity exercise to take time to recover. In their study, Stander et al. (2020) reported that metabolic recovery of marathon athletes occurs within 48 hours. The reason for the recovery is due to a reduction in substrate catabolism. According to the authors, a reduction in energy requirement after exercise reduces the need for fuel substrate catabolism, which triggers intracellular glycemic flux and glycogenesis. Glycogenesis, on the other hand, triggers cellular repair and re-esterification (Stander et al., 2020). Stander et al. (2020) note that energy use during high duration exercise begins with carbohydrate oxidation, followed by lipid oxidation, and then ketone oxidation. In the absence of these fuel sources, the body will resort to amino acid metabolism. Generally, these fuel sources will recover after 48 hours.


Enhancing the endurance of athletes remains a challenge. From the reviewed literature, it seems that ketones are the best fuel source for people engaging in high intensity and long duration exercise. Unlike other fuel sources, such as fatty acids, and carbohydrates, ketones produce more energy per mole of oxygen. Furthermore, ketones produce less reactive oxygen species. The role of ketones in reducing energy expenditure during starvation makes them a particularly useful resource for athletes. As such, a nutritional diet comprising of ketones or a ketonic diet is recommended.


Cox, P., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., . . . Clarke, K. (2016). Nutritional ketosis alters fuel preference and thereby endurance performance of athletes. Cell Metabolism, 24(2), 256-268.

Feerbabdez-Verdejo, R., Bajpeyi, S., Ravussin, E., & Galgani, J. (2018). Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivit. Endocrinology and Metabolism, 315(4), E715-E722.

Lei, L., Grevengoed, T., Paul, D., Illkayeva, O., Koves, T., Pascual, F., . . . Coleman, R. (2015). Compartmentalized Acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. Diabetes, 64(1), 23-35.

Loon, L., Greehaff, P., Teodosiu, D., Saris, W., & Wagenmakers, A. (2001). The effects of increasing exercise intensity on muscle fuel utilisation in humans. The Journal of Physiology, 536(1), 295-304.

Soto-Mota, N. N., & Clarke, K. (2020). Why a d-β-hydroxybutyrate monoester? Biochemical Society Transactions, 48(1), 51-59.

Stander, Z., Luies, L., Mienie, L., Reenen, M., Howatson, G., Keane, K., . . . Loots, D. (2020). The unaided recovery of marathon-induced serum metabolome alterations. Scientific Reports, 10(11060), 1-11.


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