Prehabilitation: Do We Need Metabolic Flexibility?

Prehabilitation involves enhancing a patient’s physiological and functional capacity before surgery to improve resilience and to improve postoperative outcomes [1]. Today’s surgical candidates are often older, physically deconditioned, frail, malnourished, or living with multiple comorbidities, all factors known to increase perioperative risk [2‒6]. Cardiorespiratory fitness, in particular, has been widely accepted as an indicator of “surgical fitness.” Greater cardiorespiratory capacity is associated with a variety of protective factors thought to help patients withstand the metabolic and inflammatory demands of surgery [7].

Traditionally, the association between reduced exercise capacity and adverse outcomes has been attributed to an inability of the cardiovascular system to meet the immediate metabolic demands of surgery, creating what has been termed an oxygen debt [8]. This concept has been central to interventions such as perioperative goal-directed therapy and has been implicit in prehabilitation interventions such as high-intensity interval training, intended to increase oxygen uptake (VO₂) peak in the preoperative period, based partly on the premise that this would increase the ability to augment cardiac output to meet the metabolic demands of the early postoperative period. However, in the majority of individuals, aerobic deconditioning, especially at its most severe, is consequent to reduced mitochondrial capacity rather than a failure of oxygen delivery [9]. When stratified by fitness, interventions to improve oxygen delivery have not demonstrated improved outcomes [10]. Furthermore, most individuals are able to augment oxygen delivery to preoperative targets [11]. In critical illness, a clear phenotype has been described where capacity to utilise oxygen at the cellular level in combination with substrates for bioenergetic purposes influences outcome trajectories [12].

Many patients with low cardiorespiratory fitness also exhibit metabolic dysfunction, manifesting as an impaired ability to maintain metabolic homeostasis under varying conditions – a phenotype increasingly known as metabolic inflexibility. Metabolic inflexibility is reflected in the reduced ability of cells, particularly muscle cells, to switch between fuel sources, such as carbohydrates and fats, in response to changes in energy demand [13]. Under healthy conditions, the body adjusts its fuel utilisation based on energy needs, diet, and activity levels. For example, in periods of fasting or low activity, the body primarily uses fat as an energy source, while during exercise or after a carbohydrate-rich meal, it shifts towards glucose usage. Metabolic inflexibility, conversely, is often characterised by a preference for glucose oxidation, limited fat utilisation, and impaired adaptation to dietary or energetic shifts [14]. It is most commonly found in individuals with obesity, insulin resistance, and type 2 diabetes, where normal regulatory mechanisms are disrupted. Mitochondrial dysfunction and inflammatory pathways are frequently implicated in the development of metabolic inflexibility [15].

Prehabilitation and preoptimisation targeting metabolic flexibility may support an enhanced ability to regulate substrate usage and respond effectively to changes in perioperative metabolic demand. We will discuss mechanisms underlying this relationship and examine strategies within exercise and nutritional prehabilitation that aim to improve metabolic flexibility.

Metabolic dysregulation is frequently observed in the perioperative period and is often exacerbated by the physiological stress of surgery and related treatments. The preoperative period offers a critical opportunity to identify metabolically inflexible patients and to implement prehabilitation strategies to improve resilience. Several factors present in surgical patients are associated with metabolic inflexibility (Fig. 1).

Cancer cells exhibit altered metabolism, typically favouring glycolysis over fatty acid oxidation – a phenomenon known as the Warburg effect. Glucose is preferentially converted into lactate even when oxygen is abundantly present [16]. This altered energy production preference, while beneficial for tumorigenesis by optimising the cancer microenvironment, disrupts whole-body metabolic homeostasis [17, 18]. Cancer-driven metabolic disruptions impact systemic energy balance and promote chronic inflammation, catabolism, and cytokine profiles that drive reduced metabolic flexibility [14].

Obesity, reduced cardiorespiratory fitness, insulin resistance, diabetes, and frailty are endemic in patients undergoing cancer surgery, are associated with adverse outcomes [3, 19‒24], and all further contribute to metabolic inflexibility [13‒15, 25, 26]. In the UK, approximately one-third of patients presenting for surgery are obese [27], a state marked by chronic low-grade inflammation and lipid toxicity. This lipid toxicity generates signalling intermediates which interfere with local and systemic immune responses, causing a vicious cycle of immune-metabolic degradation [28]. Excess visceral fat releases pro-inflammatory cytokines like tumour necrosis factor alpha and interleukin 6 which interfere with insulin signalling, promote insulin resistance, and disrupt lipid metabolism. At the cellular level, nutrient overload, inactivity, and heightened substrate competition result in mitochondrial indecision, impaired fuel switching, and energy dysregulation [15].

Sedentary behaviour, exacerbated by cancer-related fatigue, muscle atrophy, and treatment side effects, is a major driver of metabolic inflexibility [26]. Frailty, often accompanied by age-related sarcopenia and cancer-related cachexia, compounds this problem by accelerating muscle loss through mechanisms such as the ubiquitin-proteasome pathway, resulting in proteolysis of myofibrillar proteins [29]. Reduced muscle mass limits fuel stores within skeletal muscle and compromises the body’s ability to oxidise fatty acids, leading to a heightened dependence on glucose during metabolic stress [30].

Perioperatively, many non-diabetic patients exhibit insulin resistance, which may be exacerbated by the stress of surgery [20], adversely impacting mitochondrial bioenergetics [31]. In type 2 diabetes, insulin resistance results in elevated insulin levels, promoting lipogenesis while reducing lipolysis through inhibition of hormone-sensitive lipase in adipose tissue and ultimately limiting fatty acid oxidation [14].

Severe malnutrition, affecting up to 33% of patients with gastrointestinal cancers [5], significantly contributes to metabolic inflexibility through depleting essential nutrient reserves and disrupting key pathways in nutrient sensing. Protein malnutrition, in particular, reduces leptin and insulin-like growth factor 1 levels, impairing muscle repair and promoting protein breakdown to release essential amino acids [32]. Inadequate nutrition exacerbates insulin resistance, reinforcing bioenergetic dysfunction and oxidative stress [31]. Malnutrition reduces total energy expenditure by downregulating metabolic processes as an adaptive response to conserve energy and delay wasting. This suppression limits substrate availability and reduces enzymatic activity involved in fuel utilisation. This cycle of energy inefficiency and cellular damage reinforces metabolic inflexibility impairing an organism’s capacity for adaptation to fasting or stress.

Metabolic inflexibility may be implicated in the ability to respond to surgical trauma potentially increasing the risk of postoperative complications (Fig. 2). Surgery imposes multiple metabolic stressors, encompassing tissue damage, immune activation, drug exposures, physical inactivity, and intermittent caloric deprivation; these require rapid and efficient metabolic adjustments to maintain homeostasis [33, 34]. The ability to respond effectively to these demands likely hinges on metabolic flexibility.

In the early postoperative period, the stress response activates the hypothalamic-pituitary-adrenal axis resulting in release of counter-regulatory hormones like cortisol, glucagon, growth hormone, and catecholamines [33, 34]. These hormones reduce insulin secretion and increase insulin resistance, driving hepatic glycogenolysis [20, 34]. For patients with pre-existing metabolic inflexibility, this may exacerbate hyperglycaemia, complicate postoperative glucose control, and increase the risks associated with poor wound healing and infection [21].

Efficient immune function in the postoperative period relies on metabolic flexibility, which enables immune cells to adjust substrate use to meet varying energetic and functional demands. Monocytes, macrophages, and T cells dynamically switch substrates, supporting activation, proliferation, migration, and inflammatory responses depending on the prevailing nutrient conditions [35]. Pro-inflammatory cells, such as M1 macrophages and effector T cells, primarily depend on glycolysis for rapid energy during acute inflammation. Conversely, anti-inflammatory cells, including M2 macrophages and regulatory T cells, rely on oxidative phosphorylation and fatty acid oxidation to facilitate tissue repair and to support resolution of inflammation [14]. Monocyte function in particular is central to the early dynamic postoperative immune responses [36]. Emerging evidence indicates monocyte flexibility (decreased postoperative glycolytic capacity) may be implicated in the development of morbidity [37].

Periods of prolonged fasting, whether pre- or postoperative, place additional demands on surgical patients. In metabolically inflexible individuals, the inability to efficiently mobilise and oxidise fat stores during caloric deficit can lead to functional decline and prolonged recovery. Postoperative shifts in substrate utilisation from carbohydrates to lipids occur [38] and are challenging for patients with reduced ability to oxidise fat and impaired access to glucose as a fuel driven by insulin resistance and inadequate intake, potentially resulting in increased muscle catabolism [32]. Postoperative protein metabolism also differs by insulin resistance status. Stable isotope analysis shows a blunted anabolic response despite nutrient intake in non-diabetic insulin-resistant individuals, while insulin-sensitive individuals maintain preoperative anabolic capacity [39]. Studies on inactivity highlight the rapid impact of short-term inactivity to vulnerable individuals on skeletal muscle wasting, insulin resistance, aerobic fitness, and lipid accumulation [24, 40] with metabolic inflexibility implicated in the development of dysfunction [26]. Excessive intramuscular lipid accumulation is linked to skeletal muscle degradation, leading to weakness and prolonged recovery [41].

In the context of surgery, assessment and perioperative improvement of metabolic flexibility may be especially important, since treatments such as surgery and neoadjuvant chemotherapy impose significant energy demands that many patients may struggle to meet. Several methods can be used to assess aspect components of metabolic flexibility. Indirect calorimetry (IC) measures gas exchange under fasted and fed conditions providing estimates of fat and carbohydrate oxidation (CHOox) rates. Assessment of substrate changes in the fed state is often time-consuming and requires strict adherence to fasting and feeding protocols [25]. IC can assess protein utilisation, but requires 24-h urine collection, which is often impractical in outpatient settings. Postoperatively, IC may be more useful for assessing resting substrate regulation changes in the early postoperative period where patients are admitted, food intake is monitored, and urine collection is feasible. Stable isotope tracers allow for precise quantification of metabolic fluxes and substrate utilisation from both endogenous and exogenous sources. Despite their accuracy, they are costly, invasive, and technically demanding, which limits their routine clinical application. The Oral Glucose Tolerance Test (OGTT) is a relatively simple test that assesses insulin sensitivity and, indirectly, metabolic inflexibility by tracking the glucose response over time after ingestion. However, while practical, it is time-consuming and does not directly evaluate the capacity to switch between substrates or to upregulate lipid oxidation. While these methods have their individual advantages, they generally offer limited insight into the dynamic ability of the body to switch substrates under physiological stress. In contrast, cardiopulmonary exercise testing (CPET) is already widely accepted in many perioperative risk assessment clinics, providing an integrated measure of metabolic flexibility under dynamic stress conditions.

CPET can be used to assess metabolic flexibility by evaluating shifts in substrate use during incremental exercise (Fig. 3). CPET measures VO₂, VCO₂, relative to workload, with the respiratory exchange ratio reflecting (the ratio carbon dioxide production/VO₂) the balance between fat oxidation and CHOox [42]. At rest or during low-intensity exercise, fat oxidation dominates; however, with increasing exercise intensity, CHOox, first aerobic and then anaerobic, becomes dominant reflected in a rising respiratory exchange ratio and an accumulation of blood lactate. As glycolytic flux increases with exercise intensity, more pyruvate is reduced to lactate, saturating mitochondrial lactate clearance capacity of monocarboxylate transporters, resulting in blood lactate accumulation and the inhibition of lipolysis and β-oxidation [16]. Since fatty acids and lactate are both mitochondrial substrates, patterns of blood lactate accumulation and substrate shifts provide indirect, non-invasive indicators of metabolic flexibility which might be applied to predict metabolic resilience to surgery [43].

Exercise and nutrition work synergistically in prehabilitation [44]. Targeting metabolic flexibility through nutrition and exercise supports improved metabolic health, immune resilience, and adaptation to perioperative stress. A structured multidisciplinary team approach to identify, assess, optimise, and monitor individuals with metabolic inflexibility throughout the perioperative period should be considered (Fig. 4).

Reducing sedentary behaviour is among the most effective strategies to enhance metabolic flexibility [26]. Aerobic exercise enhances mitochondrial biogenesis, improves mitochondrial efficiency and resistance training, and enhances muscle mass and glycaemic control by improving muscle-organ metabolic crosstalk [13‒15, 45, 46]. Muscle is a primary site for glucose metabolism, so increased muscle mass improves insulin sensitivity, and improved glucose regulation. The effects of aerobic exercise may be more nuanced in populations that are sarcopenic or malnourished. The general beneficial effects of aerobic exercise are still present but reduced due to impaired mitochondrial function, reduced muscle oxidative capacity, and insufficient energy reserves; malnourished/sarcopenic individuals often exhibit a blunted anabolic response. This means that aerobic exercise alone might be insufficient to rebuild or maintain the muscle mass which is crucial for overall metabolic flexibility. The effectiveness of prehabilitation training regimens may be additionally reduced or even reversed if insufficient nutrients are available to support performance and adaptation [47]. Multimodal interventions including tailored nutrition and individualised aerobic and resistance exercise are, therefore, key to optimising metabolic and functional improvements. Resistance training stimulates myofibrillar protein synthesis, aiding lean mass preservation, while aerobic exercise maintains mitochondrial function and lowers inflammatory markers, protecting against catabolic pathways [29]. Exercise-induced myokines, such as interleukin 6 and irisin, activate adenosine monophosphate-activated protein kinase (AMPK) which promote fatty acid oxidation and glucose uptake, while also facilitating the browning of adipose tissue resulting in increased energy expenditure and lipid usage [46]. Enhanced muscle mass supports greater glycogen storage, while mitochondrial adaptations allow for better nutrient sensing, storage, and utilisation [15]. Overall, increased muscle mass allows for greater glycogen storage capacity, while improved mitochondrial function and enzyme activity in muscle fibres support more efficient substrate oxidation.

Preoperative exercise training can be tailored to pre-defined individualised oxidation thresholds, to stimulate shifts in substrate metabolism [45]. Interval training above and below work-rate derived from the maximal fat oxidation threshold on preoperative CPET can be used to help guide personalised metabolic exercise training regimens (Fig. 5). Repeated low-level stress through exercise supports cross-stressor adaptation (hormesis), resulting in upregulation of key pathways – such as AMPK, sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha – that improve the ability to handle metabolic demands [14]. Training protocols based on this concept are easy to implement and accepted in very sedentary patients and have shown benefits such as reduced fat mass, preserved muscle mass, improved lipid oxidation, and enhanced glycaemic control [45].

Nutritional assessment and supplementation are essential to prehabilitation, particularly to address any imbalances between intake and metabolic demands. Tailored nutritional support helps maintain adequate fuel reserves, optimise muscle glycogen stores, promote muscle protein synthesis, and mitigate the negative effects of reduced calorie intake or catabolism [29, 32]. Fat oxidation, often upregulated in the postoperative period [38], relies on adequate intake of essential fatty acids and carnitine, both of which support mitochondrial function. Studies in muscle-specific carnitine acetyltransferase knockout mice, primary human skeletal myocytes, and human subjects (age ≥60, BMI 25–35.4, fasting blood glucose 5.6–6.9 mmol/L) undergoing 2 g/day oral l-carnitine supplementation for 6 months supported improved metabolic flexibility and enhanced insulin action [48]. In a randomised, placebo-controlled, double-blind crossover design trial in non-active, overweight older adults (age ∼62 years, BMI ∼29.7), 2 g/day supplementation for 36 days in individuals with impaired glucose tolerance (plasma glucose level between 7.8 and 11.1 mmol/L 2 h after an OGTT) demonstrated benefit. l-carnitine supplementation improves acetyl carnitine formation and rescues metabolic flexibility [49].

Controlled periods of energy restriction (time-restricted feeding [TRF]) and exercise may enhance fuel switching from glucose to fat as liver glycogen is depleted. TRF adjusts food intake timing rather than overall caloric intake. Most commonly, an 8-h eating window is used, accompanied by a 16-h fast. Most available studies on fasting in cancer are preclinical, conducted in vitro or in animals, with limited large-scale human interventional trials in oncology. Preclinical studies show TRF, without caloric restriction, slows obesity-driven breast cancer growth and metastasis in mice [50]. TRF also appears feasible, with adherence typically >80% among sedentary, in older adults (≥65 years) with obesity, diabetes, or metabolic syndrome and mobility impairments when meeting an 8- to 9-h eating window for short durations of <12 weeks [51]. A systematic review of TRF compared to ad libitum eating or alternative diets in people with cancer demonstrated that TRF is feasible, well accepted with high adherence, and may offer oncological benefits related to reductions in tumour markers and recurrence rates. TRF positively influenced cancer risk factors, improving BMI, adiposity, glucose regulation, and inflammation within as little as 8 weeks [52]. In previously diagnosed breast cancer patients, periods of fasting reduced chemotherapy-induced DNA damage and augmented optimal glycaemic regulation, improving serum glucose, insulin, and insulin-like growth factor 1 concentrations, although studies were small and large heterogeneity in time-restriction windows is reported [53].

During energy deficits and exercise, pathways like AMPK, SIRT1, and peroxisome proliferator-activated receptor alpha (PPAR-α) are activated, encouraging fat oxidation, mitochondrial biogenesis, and flexibility [13]. However, excess nutrient availability, regulated by mammalian target of rapamycin (mTOR), can impair flexibility by promoting glycolysis over β-oxidation [14]. PPAR-α is a key regulator of lipid metabolism, controlling fatty acid transport, lipogenesis, and β-oxidation. Activation under fasting conditions increases β-oxidation in adipocytes, hepatocytes, myocytes, and cardiomyocytes [54]. Consequently, activation of PPAR-α may contribute to reduce lipid toxicity accumulation and metaflammation which interferes with insulin signalling and reduces glucose uptake capacity [28]. Stimulating these pathways with exercise and controlled nutrient-intake timing appears mechanistically beneficial. However, given the prevalence of altered metabolism, malnutrition, and muscle wasting in cancer patients, further investigation is needed to assess the safety and efficacy of combining exercise prehabilitation and TRF interventions in this population. Regular assessment of nutritional status and ensuring individuals participating in TRF meet caloric needs are essential for patients at risk of malnutrition. Given the current lack of evidence in the preoperative population, it is too soon to recommend this approach as part of routine care.

Enhancing metabolic flexibility may also positively influence immune function, particularly within the tumour microenvironment. Key nutrient-sensing pathways activated by exercise and TRF to enhance metabolic flexibility also regulate immune function [35]. Prehabilitation during chemotherapy has shown benefits in terms of tumour regression and immune preservation [55]. Metabolic flexibility allows CD8+ T cells to switch substrates and sustain energy production, crucial for their anti-tumour function and prevention of T-cell exhaustion [56].

Refining established tools to identify the metabolically inflexible phenotype is an important start to preparing patients for surgery. A detailed understanding of perioperative metabolic responses and their relationship to surgical outcomes is essential for developing targeted, personalised prehabilitation interventions. One ongoing study is the Peri-Operative Medicine – Metabolic Profiling (POM-MP) study (CPMS ID: 50998) which is investigating longitudinal metabolic responses to major intra-abdominal surgery to better characterise metabolic inflexibility and its link to postoperative morbidity. Advancements in biomarker technology and “omics” approaches (metabolomics, proteomics, lipidomics) hold promise for more precise profiling of metabolic flexibility and for evaluating the impact of specific prehabilitation strategies. Future research should aim to test the effectiveness of various interventions designed to enhance metabolic flexibility within the perioperative setting.

The growing understanding of metabolic flexibility and its role in surgical recovery highlights the importance of including metabolic considerations into prehabilitation and preoptimisation programs. Metabolic inflexibility is highly prevalent in the perioperative context because of the impacts of cancer metabolism, obesity, insulin resistance, sedentary behaviour, and frailty. Enhancing metabolic flexibility could better prepare an individual to meet the demands of surgery, reduce perioperative morbidity, and improve postoperative recovery. Strategies such as targeted exercise, nutritional interventions, and potentially novel pharmacological agents are emerging as tools to support this adaptive capacity, particularly for individuals who may have metabolic inflexibility due to conditions like obesity, diabetes, or chronic inactivity.

Despite promising insights, further research is needed to fully understand how metabolic flexibility impacts surgical resilience and to establish effective, evidence-based interventions. Integrating metabolic assessments into preoperative evaluations and tailoring prehabilitation strategies to enhance metabolic flexibility represent valuable future directions for surgical care. As research continues, metabolic flexibility may prove to be a vital component in preoperative optimisation, advancing patient care and setting new standards in perioperative medicine.

N.T. and J.W. are supported in part by the UCLH NIHR BRC perioperative medicine and critical care theme.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

N.T.: design, drafting, and final review. J.W.: design, revision, and final review.