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. 2024 Feb 2;7(3):560–569. doi: 10.1021/acsptsci.3c00301

Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer

Reshmi Akter ∥, Muhammad Awais ∥, Vinothini Boopathi ∥, Jong Chan Ahn ∥, Deok Chun Yang ∥, Se Chan Kang ∥, Dong Uk Yang ‡,*, Seok-Kyu Jung §,*
PMCID: PMC10928896  PMID: 38481689

Abstract

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Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg’s pioneering work in 1920. Warburg’s discovery of the “Warburg effect”, wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the “reverse Warburg effect” emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the “inversion of the Warburg effect”. This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the “inversion of the Warburg effect” as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.

Keywords: Obesity, Cancer, Warburg effect, Reverse Warburg effect, Inversion of Warburg effect

Over the past few decades, there has been a concerning surge in the prevalence of obesity, leading to its emergence as a critical global health crisis. As per the recent data furnished by the NCD Risk Factor Collaboration, in the year 2016, an estimated 39% of the global adult population, corresponding to roughly 2 billion individuals, were categorized as overweight.1 The 2022 World Obesity Atlas, distributed by the World Obesity Federation, predicts that by 2030, about 1 billion people worldwide will be described as obese, including 20% of all women and 14% of all men.2 This underscores a substantial tripling in the prevalence of obesity since 1975, signifying a considerable elevation over the preceding decades.3 With its associated risks of cardiovascular disease, diabetes, and hypertension, obesity has become a subject of intense scientific scrutiny. Beyond its correlation with metabolic disorders, obesity has been rigorously correlated with an elevated susceptibility to various malignancies.4 Notably, an increase in body weight has been estimated to have a contributory role in approximately 5% of cancers among adult males and 10% of cancers among adult females within the United States.5 According to recent reports, obesity increases cancer risk in 13 anatomic sites, such as the breast, prostate, endometrium, colon, and gallbladder, which have been identified to have a notable hormonal foundation for this association.6 Epidemiological studies have established a correlation between obesity and cancer; however, the precise pathophysiological mechanisms underlying this relationship remain unclear. In the case of breast cancer, a tumor type frequently associated with obesity, considerable research has been devoted to investigating pro-inflammatory processes and endocrine abnormalities specific to obesity.7 However, our understanding of similar pathways in other types of cancers remains limited. Researchers have dedicated significant efforts to unraveling the complex mechanisms underlying this multifactorial condition. Amidst this ongoing quest for understanding, an intriguing phenomenon has emerged—a surprising connection between obesity and a metabolic phenomenon known as the Warburg effect (WBE) wherein glucose consumption is accelerated and its catabolism is redirected toward the reduction of pyruvate to lactate, even in the presence of oxygen and irrespective of mitochondrial dysfunction.8 Remarkably, recent studies have begun to reveal an unexpected parallel between the metabolic characteristics of cancer cells found in an obesogenic environment. Nonetheless, the metabolic interrelationships of cancer cells in an obese microenvironment are not yet understood.

Understanding the behavior of cancer cells in an obesogenic microenvironment opens up a new avenue of research with significant implications for both metabolic disorders and cancer biology. In this Review, we aim to explore this intriguing connection, shedding light on the mechanistic underpinnings and potential consequences for human health.

Impact of Obesity on Cancer Incidence and Outcomes

“Overweight” is defined as a body mass index (BMI, defined as a person’s weight in kilograms divided by their height in meters squared) of 25–29.9 kg/m2, and “obese” is defined as a BMI of 30 kg/m2 or higher. Excess adiposity from being overweight or obese has been extensively studied in relation to its impact on the incidence of various types of adult cancers. Several studies indicate that nearly 40% of cancer incidences can be attributed to person being overweight or obese.5 As reported by the International Agency for Research on Cancer, the prevalence of obesity in Europe has been identified as the underlying factor in 11% of colon cancer cases, 9% of postmenopausal breast cancer cases, 39% of endometrial cancer cases, 25% of kidney cancer cases, and 37% of esophageal cancer cases.9 According to data provided by the American Cancer Society, there is a notable rise in the mortality rate associated with pancreatic cancer, hepatocellular carcinoma, multiple myeloma, and Hodgkin’s lymphoma which can be attributed to excessive body weight.10 Furthermore, numerous systematic reviews and meta-analyses have been conducted to examine the effect of excess weight on the prognosis of patients with obesity-related cancers. These studies consistently indicate that patients who are overweight or obese at the time of a cancer diagnosis experience worse outcomes. For instance, in colorectal cancer patients, those with excess body weight have been found to have a 22% higher risk of colorectal-cancer-specific mortality compared to patients with normal weight.11 Similarly, in patients with pancreatic cancer, those with a BMI of 35 kg/m2 or higher have shown a 53% decreased survival rate compared to those with a BMI below 25 kg/m2.12 Additionally, obesity has a significant association with breast cancer, leading to a 35–40% increased risk of cancer recurrence and mortality.13 Moreover, in comparison to the reference BMI category, overweight individuals have an estimated 28% higher risk of chronic kidney disease (CKD), whereas obese individuals face a substantially elevated risk of 77% in developing CKD.14 In the context of gallbladder cancer, a comprehensive meta-analysis comprising 15 studies encompassing a total of 5902 cases revealed that for every 1 kg/m2 increment in BMI above the threshold of 25 kg/m2, the risk escalated by 4%.15 According to a report, a significant rise of 36% in the susceptibility to ovarian cancer was detected among individuals who were categorized as obese.16 Obesity not only elevates the risk of developing cancer but also has detrimental effects on patient prognosis. It poses challenges in determining appropriate chemotherapy doses and can negatively impact the effectiveness of anticancer treatments, potentially leading to an increased likelihood of metastasis and reduced treatment efficacy, while also heightening the risk of adverse effects. Additionally, obesity contributes to an elevated mortality rate associated with malignant tumors, accounting for approximately 20% of female deaths and 14% of male deaths.16

Altered Metabolic Landscape in Obesity

Obesity is a complex metabolic disorder characterized by excessive accumulation of body fat, which can have profound effects on various aspects of metabolism.17 The altered metabolic landscape in obesity involves multiple interconnected processes, including changes in the energy balance, adipose tissue function, insulin resistance, inflammation, and hormonal dysregulation. Adipose tissue, or body fat, plays a crucial role in energy storage and metabolism. However, in obesity, excessive accumulation of adipose tissue leads to dysfunction and contributes to various metabolic health issues.18 Adipocytes make up the majority of the cell population in adipose tissue, but it also contains a variety of stromal cells, such as endothelial cells, pericytes, macrophages, and adipocyte progenitor cells. Adipocytes and the stromal vascular cells in adipose tissue are both considered to play an active role in the tumor microenvironment (TME). Mature adipocytes are the main cell type in white adipose tissue (WAT), containing a small number of mitochondria. In addition, mature adipocytes function by secreting various adipocytokines and are characterized by a round shape with only one large lipid droplet. Adipocytokines are signaling molecules secreted by adipocytes that regulate various physiological processes, including metabolism and inflammation.19 In obesity, there is a shift toward increased secretion of pro-inflammatory adipokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This pro-inflammatory state further exacerbates adipocyte dysfunction and impairs the normal process of adipocyte differentiation.20 Macrophages, the primary inflammatory response cells, are also abundant in adipose and TMEs, where they play roles in the initiation, growth, and progression of cancer.21 The presence of inflammatory cells (lymphocytes and macrophages) that produce reactive oxygen species (ROS) indicates that adipose tissue in obesity is in a state of low-grade chronic inflammation. These ROS are potentially tumor promoters since they exhibit mitogenic characteristics at low concentrations.22 Moreover, in obesity, a long-term positive energy balance, where energy intake exceeds expenditure, causes an increase in both the number and size of adipocytes (adipocyte hypertrophy). As adipocytes enlarge, they undergo disturbances in lipid metabolism, leading to an imbalance in the production and storage of lipids.23 This imbalance increases the release of free fatty acids (FFAs) into the bloodstream and triggers inflammatory signaling pathways in macrophages and adipocytes. FFAs, through the adaptor protein fetuin-A, bind to toll-like receptors 2 and 4, activating nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, promoting inflammation.24 These pathways contribute to insulin resistance (IR) and pro-inflammatory macrophage infiltration by increasing the synthesis and secretion of chemokines like MCP-1(CCL2) in adipocytes.25 JNK and NF-κB pathways play a crucial role in inflammation-induced IR.26 Evidence suggests that as WAT expands due to hypertrophic adipocytes, there is a relative reduction in perfusion or an increase in oxygen utilization, leading to the development of hypoxia. Hypoxia serves as a critical trigger for initiating adipose tissue inflammation, a common characteristic in obesity and the TME (Figure 1). Cellular hypoxia activates the hypoxia-inducible factor 1-alpha (HIF-1α) gene program, which is involved in the inflammatory response.27 Adipocyte hypertrophy, excessive nutrient accumulation, absorption of antigens from the digestive system, oxygen deprivation (hypoxia), and various stresses within fat tissue can trigger an inflammatory response either directly or through a series of pathological mechanisms. Additionally, obesity is associated with alterations in several hormones involved in appetite regulation, energy expenditure, and metabolism. For example, leptin, a hormone produced by adipose tissue, plays a crucial role in regulating the energy balance and appetite. In obesity, there is often a state of leptin resistance where the body becomes less responsive to the appetite-suppressing effects of leptin.28 According to one study, estrogen receptor-positive breast cancer patients who are obese have excessive leptin in their TME.29 Additionally, other hormones involved in metabolism, such as insulin, ghrelin, and adiponectin, may also be dysregulated in obesity.20 Adipocytes possess the capability to produce significant quantities of estrogens through the expression of aromatase.30 This enzymatic activity allows them to synthesize estrogens, which subsequently exert various effects on cellular processes. Specifically, estrogens promote the proliferation of cells, enhance invasiveness, and reduce cell apoptosis, thereby fostering the development of aggressive tumors.31 Thus, these changes in the metabolic environment have been determined to be important mediators of the obesity–cancer link.

Figure 1.

Figure 1

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Hypothesized mechanisms that connect obesity to cancer. The accumulation of excess fat in white adipocytes compromises their normal function, ultimately leading to apoptosis, or cell death, triggered by factors like hypoxia and increased extracellular matrix stiffness. During this apoptotic phase, cellular contents are released from dying adipocytes. These released contents, including free fatty acids, initiate receptor-mediated activation of Toll-like receptor 4 (TLR4) in resident macrophages. TLR4 activation prompts the secretion of pro-inflammatory cytokines, chemokines, and growth factors by these macrophages through the activation of the nuclear factor-kappa B (NF-κB) pathway. Subsequently, there is an intensified intracellular signaling cascade in macrophages involving NF-κB, STAT3, and JNK-related pathways, resulting in the sustained release of pro-inflammatory cytokines, thereby creating a state of chronic inflammation. The heightened secretion of pro-inflammatory cytokines and hormones by white adipocytes due to obesity further enhances the metastatic potential of cancer cells. Additionally, the obesity-related increased release of pro-inflammatory cytokines amplifies the expression of aromatase in white adipocytes. This enzyme is responsible for converting androgens into estrogens within adipose tissues, which, in turn, promotes the initiation and growth of mammary tumors by stimulating the proliferation of cancer cells. Moreover, adipocyte-released free fatty acids in cases of obesity direct cancer cells toward β-oxidation as an energy source, providing the necessary fuel for sustaining the progression of cancer.

What Is the Warburg Effect?

The WBE, also known as aerobic glycolysis, refers to a phenomenon observed in cancer cells where they preferentially utilize glycolysis (the breakdown of glucose) to generate energy, even in the presence of oxygen. This metabolic alteration was first described by the German biologist Otto Warburg in the 1920s.32 Normally, in the presence of oxygen, cells generate energy through oxidative phosphorylation, a process that occurs in the mitochondria. This process is highly efficient and produces a large amount of adenosine triphosphate (ATP), which is the energy currency of the cell. However, cancer cells exhibit a shift toward glycolysis, which is less efficient in terms of ATP production compared to oxidative phosphorylation (Figure 2).

Figure 2.

Figure 2

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Schematic diagram depicting the distinctions among oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (including the Warburg effect). In the presence of oxygen, non-proliferating (differentiated) tissues primarily utilize glucose through glycolysis, converting it into pyruvate, and subsequently, most of that pyruvate is thoroughly oxidized in the mitochondria to produce CO2 via the process known as oxidative phosphorylation. This metabolic pathway relies on oxygen as the ultimate electron acceptor, making oxygen an essential component. However, when oxygen levels are low, cells have a backup plan. They can reroute the pyruvate generated by glycolysis away from the mitochondria, leading to the production of lactate (anaerobic glycolysis). This allows glycolysis to continue by recycling NADH back into NAD+ but results in much less ATP production compared to oxidative phosphorylation. Dr. Warburg observed that cancer cells tend to convert most of the glucose into lactate, regardless of oxygen availability (aerobic glycolysis). Interestingly, this behavior is also seen in normal rapidly dividing cells. While both cancer cells and rapidly dividing normal cells still have functional mitochondria and some oxidative phosphorylation activity, aerobic glycolysis is less efficient than oxidative phosphorylation at generating ATP.

The WBE is characterized by increased glucose uptake by cancer cells and increased conversion of glucose to lactate, even in the presence of sufficient oxygen. This reliance on glycolysis provides several advantages for cancer cells. First, it allows them to rapidly generate ATP, which is essential for their enhanced proliferation and growth. Second, the glycolytic pathway generates metabolic intermediates that can be used for the synthesis of building blocks required for cell division.33 Finally, the shift to glycolysis helps cancer cells adapt to their hypoxic (low oxygen) microenvironment, which is commonly found in solid tumors.7

The exact reasons behind the WBE are not fully understood, but it is thought to result from a combination of genetic, epigenetic, and microenvironmental factors. Various oncogenes and tumor suppressor genes, as well as signaling pathways such as the PI3K/AKT/mTOR pathway, play a role in regulating the metabolic reprogramming seen in cancer cells.34

Understanding the WBE has significant implications for cancer research and therapy. Exploiting the metabolic vulnerabilities of cancer cells, including their reliance on glycolysis, is a promising approach for developing new cancer treatments. Researchers are investigating ways to selectively target the altered metabolism of cancer cells while sparing normal cells, with the aim of developing more effective and less toxic therapies.

Reverse Warburg Effect vs Inversion of Warburg Effect

The WBE provides only a partial explanation for tumor metabolism. However, the WBE offers several advantages to cancer cells, including the generation of biosynthetic precursors for cell growth and proliferation. Additionally, the upregulation of glycolysis is closely linked to the increased expression of lactate transporters. Consequently, lactate assumes a significant role in sustaining the energy demands of oxidative cancer cells. Thus, the occurrence of oxidative stress induced by cancer cells leads to several molecular changes, including the upregulation of HIF-1α, stimulation of transforming growth factor-beta (TGF-β), and downregulation of the Caveolin (Cav-1) protein, which normally inhibits TGF-β signaling. These alterations contribute to the transformation of stromal cells into cancer-associated fibroblasts (CAFs).35 CAFs, as a consequence of these molecular changes, exhibit a metabolic shift toward glycolysis, even in the presence of sufficient oxygen. Importantly, CAFs act as an energy source for adjacent cancer cells by supplying them with metabolic substrates through this process of aerobic glycolysis.36

In 2009, a modernized perspective of the Warburg hypothesis was introduced, termed the “reverse WBE”. This concept proposes a two-compartment model that describes the metabolic symbiosis between cancer cells and neighboring stromal cells or CAFs.37 Recent experiments have further highlighted the significant role of the TME in carcinogenesis and the epithelial–mesenchymal transition (EMT).38 Stromal cells, particularly CAFs, constitute a dominant component of the microenvironment and profoundly impact TME homeostasis. The interactions between cancer cells and surrounding CAFs significantly influence the growth, metabolism, metastasis, and progression of carcinomas (Figure 3).39 Similarly, when tumor cells are present within an obesity environment, researchers have observed contrasting metabolic behaviors. Instead of relying on glucose consumption via glycolysis, these cells appear to engage in gluconeogenesis, producing glucose using lactate as a substrate.40 This hypothesis is known as “inversion of the WBE”. The authors propose that this metabolic shift occurs due to the increased availability of nutrients within an obese organism. In such an environment, tumor cells derive energy from more-calorically-dense nutrients, such as fatty acids, which undergo complete oxidation through the Krebs cycle, followed by oxidative phosphorylation. By harnessing these pathways, the tumor cells in an obese state adopt a metabolic strategy that deviates from the conventional WBE, reflecting the altered nutrient availability and utilization in the context of obesity.

Figure 3.

Figure 3

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Reverse Warburg effect. In the concept of the reverse Warburg effect, different groups of cancer cells can exchange and utilize substances among themselves. More specifically, cancer cells that predominantly rely on oxidative processes can absorb lactate produced by hypoxic cancer cells engaged in aerobic glycolysis to power their oxidative phosphorylation (OXPHOS). On the other hand, hypoxic cancer cells can also take in reactive oxygen species (ROS) produced by oxidative cancer cells. This uptake triggers the activation of hypoxia-inducible factor 1α (HIF-1α) and promotes aerobic glycolysis. This provides cancer cells with an additional mechanism that boosts their ability to proliferate and survive.

Understanding the complex relationship among cancer cells, stromal cells, and the TME is essential for unraveling the mechanisms involved in tumor growth and advancement. This knowledge is vital for developing targeted therapies that can disrupt the metabolic collaboration between cells and hinder the progression of cancer.

Behavior of Cancer Cells under Hyperglycemia

Hyperglycemia, which is characterized by high levels of glucose in the bloodstream, is closely associated with obesity and type 2 diabetes. It occurs when there is insufficient insulin in the body or when the body’s ability to use insulin is impaired.41 Elevated glucose levels provide nourishment for cancer cells, promoting their growth and accelerating the progression of cancer. The concept that “glucose levels fuel the expansion of tumors” helps to clarify why high blood sugar promotes the development of cancer.42 This is attributed to the WBE, where tumor cells undergo glycolysis to convert glucose into energy, and this metabolic adaptation allows tumor cells to generate energy efficiently. Due to the reduced production of ATP through glycolysis, tumor cells increase their uptake of glucose to enhance the energy-generating glycolytic pathway. Elevated glucose levels play a significant role in supporting tumor progression through various mechanisms, such as promoting tumor cell proliferation, facilitating invasion and migration, and conferring resistance to apoptosis and chemotherapy.43 Long-term hyperglycemia can lead to the production of various pro-inflammatory factors such as IL-6, TNF-α, and cyclooxygenase-2. These factors have been implicated in the development of tumors.44 Additionally, matrix metalloproteinase-2 (MMP-2), a member of the protein family involved in breaking down extracellular matrices, plays a role in tumor invasion. In the context of cholangiocarcinoma cells, elevated glucose levels have been shown to enhance the activation of signal transducer and activator of transcription 3 (STAT3) and increase the expression of MMP-2 downstream of STAT3. This effect may be mediated by increased hydrogen peroxide (H2O2) levels resulting from the up-regulation of manganese superoxide dismutase. The activation of extracellular signal-regulated kinase and protein 38 mitogen-activated protein kinase pathways is also involved in this mechanism. The increased H2O2 production induced by hyperglycemia contributes to the migration and invasion of pancreatic cancer cells.45 Furthermore, hyperglycemia has been shown to inhibit the pro-apoptotic properties of p53, a protein that suppresses cell canceration and activates tumor cells’ response to anticancer drugs. This inhibition is achieved by reducing p53 phosphorylation of serine 46 (Ser46).46 Homeodomain-interacting protein kinase 2, a nuclear serine/threonine kinase, regulates the p53-dependent apoptotic pathway and tumor cell apoptosis (Figure 4). Studies have indicated that elevated blood glucose levels during chemotherapy can increase the chemoresistance of tumor cells, implying that hyperglycemia may impact the effectiveness of cancer treatment.47 Nevertheless, additional mechanisms are likely involved in the complex process.

Figure 4.

Figure 4

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Mechanisms underlying hyperglycemia-promoted cancer progression. Elevated blood sugar levels (hyperglycemia) bring about specific metabolic changes within cancer cells, influencing their cellular functions. Abbreviations: GLUT1, glucose transporter 1; PPP, pentose phosphate pathway; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HIF, hypoxia-inducible factor-1; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TCA, tricarboxylic acid cycle.

Shift Pattern of Cancer under Adiposity

Research has primarily focused on targeting glucose and glutamine addiction in cancer treatment. However, recent studies suggest that this dependency varies among cancer types due to cancer cells’ ability to adapt metabolically. For instance, if glutamine is blocked, cancer cells may switch to using glucose and vice versa. In essence, cancer cells can adapt their nutrient preferences, which has important implications for designing effective cancer therapies.48 Regarding the metabolic shift pattern observed in cancer under adiposity, it appears that the substrates involved in the WBE may be altered. Adiposity refers to excess accumulation of body fat, which can create a unique metabolic environment. In this context, cancer cells may exhibit the ability to produce glucose de novo from pyruvate (gluconeogenesis). This means that they can synthesize glucose internally rather than relying solely on the uptake of glucose from the extracellular environment.49 In the presence of excess body fat within an adiposity microenvironment, cancer cells face additional metabolic challenges and opportunities. A study conducted by Luis et al.50 examined the metabolic behavior of MCF-7 breast cancer cells under conditions simulating normal and increased glucose concentrations, as well as obesity. The findings revealed that cancer cells exhibit heightened aggressiveness in conditions of obesity, potentially leading to an increased risk of breast cancer recurrence. Notably, the cancer cells demonstrated the capacity to produce glucose de novo from pyruvate, suggesting an enhanced metabolic adaptability in adiposity. The metabolic adaptability observed in cancer cells within an obese microenvironment carries significant implications for tumor progression and therapeutic strategies. The ability to produce glucose de novo provides cancer cells with a survival advantage, enabling them to overcome glucose limitations. While the exact mechanisms underlying the inversion of the WBE are still being investigated, several factors have been proposed to contribute to this phenomenon. Here are some potential mechanisms:

Lactate to Pyruvate

In the presence of adiposity, there was a downregulation of glycolytic metabolism, as evidenced by the simultaneous increase in the level of glucose and pyruvate release, accompanied by a decrease in lactate levels. Lactate plays a crucial role in the metabolic dynamics of hypoxic cancer cells and CAFs. Hypoxic cancer cells and CAFs produce lactate, which is then transported from the cancer cells to the extracellular space (ECS) via the lactate transporter MCT4. Subsequently, MCT1 facilitates the uptake of lactate from the ECS and its distribution to cancer cells. Therefore, MCT1 is recognized as the primary importer of lactate, while MCT4 serves as the primary lactate exporter. The accumulated lactate is metabolized through oxidative phosphorylation (OXPHOS) in the cancer cells, resulting in the generation of ATP. This metabolic process allows lactate to become a critical fuel source for cancer cells.51 Lactate, which is the end product of glycolysis, can be converted back to pyruvate through a process called lactate-to-pyruvate conversion. This conversion is catalyzed by the enzyme lactate dehydrogenase (LDH).52 In the context of the inversion of the WBE, the reversion to a more oxidative metabolic state involves increased utilization of pyruvate through oxidative phosphorylation in the mitochondria. The conversion of lactate to pyruvate is a reversible reaction, and the direction of the reaction is governed by the NADH/NAD+ ratio. In cancer cells with high glycolytic activity, the ratio of NADH to NAD+ is elevated due to the increased production of lactate. Under such conditions, the lactate-to-pyruvate conversion is favored in the direction of pyruvate formation. However, in cells that undergo the inversion of the WBE, there is a shift toward a more oxidative metabolism. This shift is often accompanied by a decrease in the glycolytic activity and a reduction in lactate production. As a result, the NADH/NAD+ ratio decreases, favoring the conversion of pyruvate to lactate rather than the reverse reaction.

It is important to note that the inversion of the WBE is a complex phenomenon that can involve various molecular and genetic alterations in cancer cells. While the lactate-to-pyruvate conversion is part of the metabolic changes associated with the inversion, it is just one aspect of a broader metabolic rewiring that occurs in these cells.

Glutaminolysis

Tumor cells rely on glutamine not only for energy but also for lactate and macromolecule production, challenging the previous assumption that lactate production was predominantly tied to glucose metabolism. Even though glutamine is not categorized as an essential amino acid, it becomes essential under specific conditions of increased cell proliferation and growth.53 Cancer cells often exhibit a heightened consumption of glutamine, an amino acid, which is associated with increased cancer aggressiveness and progression. Nonetheless, in an anaplerotic pathway that experiences heightened activity in numerous cancer cells, glutamine can undergo conversion to α-ketoglutarate and be integrated into the TCA cycle, functioning as an additional carbon source. Intriguingly, when confronted with conditions of oxygen deprivation or impaired mitochondrial function, glutamine can emerge as the primary supplier of acetyl-CoA for lipogenesis through a process known as reductive carboxylation. These metabolic processes result in elevated pyruvate production, facilitating the replenishment of the tricarboxylic acid (TCA) cycle (Figure 5).54

Figure 5.

Figure 5

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Representative model of the central energetic metabolism of cancer cells under different nutritive statuses in which, under an obesity microenvironment, the Warburg effects invert with lowering lactate and de novo synthesis of glucose. Increased pyruvate in adiposity benefits from the contribution not only from lactate but also from amino acid catabolism. The cancer Krebs cycle under adiposity is fed from lipid and amino acid catabolism, in particular lipolysis and beta-oxidation, but also from deamination of glutamine (glutaminolysis).

Furthermore, it has been established that the secretome derived from obesity exerts a potent influence on cancer cell aggressiveness, promoting their growth and migration with a higher consumption of glutamine, confirming the high metabolic status of breast cancer in obesity-mimicking conditions.

De Novo Glycolysis

The initial step in the process of gluconeogenesis involves the conversion of pyruvate to phosphoenolpyruvic acid (PEP). This conversion requires the involvement of several enzymes, namely, pyruvate carboxylase, PEP carboxykinase, and malate dehydrogenase. Pyruvate carboxylase is primarily located in the mitochondria and facilitates the conversion of pyruvate to oxaloacetate. Since oxaloacetate cannot freely traverse the mitochondrial membranes, it undergoes a subsequent conversion to malate through the action of malate dehydrogenase. The resulting malate molecule can then traverse the mitochondrial membrane into the cytoplasm, where it is converted back to oxaloacetate by another malate dehydrogenase. Finally, oxaloacetate is transformed into PEP with the aid of PEP carboxykinase. The subsequent steps of gluconeogenesis mirror those of glycolysis, albeit in a reverse fashion.

The following step that distinguishes gluconeogenesis from glycolysis is the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate, catalyzed by the enzyme fructose-1,6-phosphatase. Likewise, the conversion of fructose-6-phosphate to glucose-6-phosphate employs the enzyme phosphoglucoisomerase, which is shared with the glycolytic pathway.51

The final step that sets gluconeogenesis apart from glycolysis is the conversion of glucose-6-phosphate to glucose, facilitated by the enzyme glucose-6-phosphatase. This particular enzyme is localized within the endoplasmic reticulum. Glucose gets released into the bloodstream, where it travels back to erythrocytes and exercises the skeletal muscle to be broken down again by anaerobic glycolysis, forming lactate. This process is called the Cori cycle. The major substrates of gluconeogenesis are lactate, glycerol, and glucogenic amino acids.

Cholesterol and Triglycerides

Several studies have demonstrated a significant link between higher levels of triglycerides and cholesterol in the bloodstream and a more unfavorable prognosis in breast cancer patients. Increased cholesterol uptake by cells plays a role in the synthesis of cellular membranes, promoting cell division and proliferation, particularly in the presence of obesity. Extensive research has shed light on the crucial functions of cholesterol in the advancement of various types of cancer, indicating that cholesterol accumulation is a shared characteristic of tumors.50 In tumor cells, triglyceride metabolism serves as a source of fatty acids, which are utilized for energy production. Fatty acids are further broken down into acetyl-CoA, resulting in the heightened production of acetate in adipose (fat) tissues. The elevation of acetate levels and the consumption of triglycerides have been proposed as indicators of fatty acid catabolism, providing a fuel source for cancer cells.

Lipids

Nieman et al.55 proposed a hypothesis stating that adipocytes play a significant role in supplying energy-dense lipids to ovarian cancer cells, facilitating their rapid growth. In a noteworthy finding, the researchers observed an abundance of lipids within the ovarian cancer cells located at the interface between adipocytes and cancer cells in omental metastasis tissue obtained from women. Interestingly, when ovarian, breast, or colon cancer cells were co-cultured with adipocytes, the cancer cells exhibited an accumulation of lipid droplets within their cytoplasm. This led the authors to investigate whether the lipids detected in the cancer cells during co-culture originated from adipocytes rather than being produced de novo through lipogenesis. To address this, the authors conducted experiments where cancer cells were co-cultured with adipocytes that had been preloaded with fluorescently labeled lipids. The researchers observed the transfer of fluorescent lipids from adipocytes to SKOV3ip1 cells, a human ovarian cancer cell line. This finding supports a model wherein adipocytes serve as a source of lipids to support tumor growth.

Conclusion

In an environment characterized by adiposity, cancer cells demonstrate a catabolic pattern of lipid and amino acid metabolism, resembling the phenomenon known as the reverse WBE. Regarding lipid metabolism, elevated levels of triglycerides present in the proximity of tumor cells promote lipolysis, followed by subsequent beta-oxidation. This metabolic cascade generates considerable amounts of acetate. Consequently, cancer cells exposed to an adipose-rich environment experience augmented energy production through aerobic respiration as well as an accumulation of substrates for gluconeogenesis. These findings are noteworthy because, contrary to the reverse WBE, which heavily relies on the stromal microenvironment, cancer cells adapt their metabolic patterns within a high-adiposity context, effectively reversing their metabolic routes independent of stromal contributions. However, the metabolic behavior under adiposity is so far observed for breast tumor growth. Therefore, additional research is necessary to elucidate the precise events occurring in tumor cells exposed to an adiposity environment.

Glossary

Abbreviations

WBE

Warburg effect

BMI

body mass index

CKD

chronic kidney disease

WAT

white adipose tissue

TNF-α

tumor necrosis factor-alpha

IL-6

interleukin-6

TME

tumor microenvironment

ROS

reactive oxygen species

NF-κB

nuclear factor-kappa B

ATP

adenosine triphosphate

TGF-β

transforming growth factor-beta

CAF

cancer-associated fibroblast

EMT

epithelial–mesenchymal transition

ECS

extracellular space

OXPHOS

oxidative phosphorylation

H2O2

hydrogen peroxide

STAT3

signal transducer and activator of transcription 3

MMP-2

matrix metalloproteinase-2

Author Contributions

† Reshmi Akter and Muhammad Awais contributed equally to the work. The concept originated from Reshmi Akter. Reshmi Akter and Muhammad Awais were responsible for the original writing, drafting, and figure preparation, while Vinothini Boopathi contributed to figure corrections. Fund acquisition was spearheaded by Jong Chan Ahn, with support from Deok Chun Yang, Dong Uk Yang, and Seok-Kyu Jung.

This work was supported by a grant from Sejong Creative Economy Innovation Center (Project Name: Metabolic Syndrome Prediction Model Artificial Intelligence Engine Development Using Intestinal Microbial Big Data).

The authors declare no competing financial interest.

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