Cancer-associated cachexia (CAC) is a “multifactorial syndrome” characterized by increased catabolism, weight loss, and decreased skeletal muscle mass and strength (with or without adipose tissue loss) (1). CAC associates with almost all types of cancer and accounts for a quarter of cancer-related deaths (2). Prevalence of cachexia ranges 50 to 80% in advanced cancer (3). CAC is a continuum with three stages of clinical relevance: precachexia, cachexia, and refractory cachexia. Patients who have more than 5% loss of stable body weight over the past 6 months, or a body-mass index (BMI) less than 20 kg/m² and ongoing weight loss of more than 2%, or sarcopenia and ongoing weight loss of more than 2%, but have not entered the refractory stage, are classified as having cachexia (1). Early CAC can also occur in patients with curable cancer and can be reversed by appropriate treatment (4). However, we often do not diagnose CAC in cancer patients until weight loss has occurred, and there are still few methods for early diagnosis of CAC.

CAC is due to the negative energy balance metabolic changes caused by higher energy demand from the tumor and reduced calorie intake of the host, including inflammation, increased catabolism and excessive energy consumption (5–7). It can lead to multi-organ functional disturbance, which is associated with increased susceptibility to infection, higher incidence of metastasis, decreased response of cancer cells to treatment, decreased quality of life, and poor prognosis (1, 8–11). CAC is affected by endogenous and environmental factors, such as complications, genetic risk factors, gender, age, and anti-tumor treatment (12–14). It has been pointed out that tumor or host derived cytokines can affect the metabolism of CAC (15). Cachexia mainly damages skeletal muscle, adipose tissue, liver, brain, intestine, pancreas, bone, and heart (16). The metabolic disorders can further aggravate this multifactorial syndrome (17).

There are many changes in adipose tissue metabolism in cancer patients. Increasing evidence demonstrates that adipose wasting occurs before muscle loss in the early stage of CAC (18). No matter what the patient’s weight is, fat loss is an adverse prognostic factor for terminal cancer (19). Studies have shown that the changes of adipose tissue morphology and function in CAC patients have important clinical significance, preserving adipose mass and correcting abnormal lipid metabolism in CAC represents a promising therapeutic strategy (20).

However, the knowledge about mechanisms of abnormal lipid metabolism in CAC is still limited. In this review, we summarized the classification and characteristics of adipose tissue and the changes of them in patients with CAC. Finally, we described existing therapeutic approaches and discussed potential new strategies that arose by targeting the link between adipose tissue and cachexia, with a view to providing directions for future clinical treatment of CAC.

Adipose tissue is a large, interactive multi-chamber organ with clear histological and anatomical structure (21). Mature adipocytes account for only one-third of adipose tissue, and the remaining two-thirds of adipose tissue are composed of nerves, blood vessels, fibroblasts, and adipocyte precursor cells (22). It was found that adipose tissue not only played multiple and complex roles in mechanical buffering and energy storage, but also had paracrine and endocrine functions as an important secretory organ (23, 24). It can regulate energy balance and homeostasis in vivo from many aspects, including appetite, inflammation, insulin sensitivity, and lipid metabolism (25). Nowadays, increasing evidence shows that there are changes in lipid metabolism in patients with CAC.

According to its distribution, adipose tissue can be divided into subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT), which have different anatomical, metabolic and endocrine characteristics. SCAT accounts for about 80% of total body fat in healthy adults (26). SCAT can be further divided into superficial SCAT and deep SCAT (27). VAT is mainly distributed in the abdominal cavity and retroperitoneum. The metabolic functions of VAT and SCAT are quite different. For example, compared with SCAT, visceral adipocytes have more active metabolism and greater lipolysis activity. Adipocytes of VAT have stronger insulin resistance than those of SCAT (28, 29). At the same time, SCAT is the main source of leptin production (26). Excess energy accumulates in adipocytes of SCAT, which acts as a metabolic pool. Visceral fat accumulation occurs only when SCAT capacity is insufficient or damaged.

According to functional characteristics, adipose tissue can be divided into three types: white adipose tissue (WAT), brown adipose tissue (BAT), or beige adipose tissue.

WAT is the most common type. White adipocytes are the main storage space of triglyceride. The main function of white adipocytes is to store fat and regulate free fatty acids (FFAs). It is mainly composed of large spherical adipocytes, in which single lipid droplets occupy the majority of the cell volume and mainly store energy in the form of triglycerides (21). WAT exists in subcutaneous and visceral tissues, and the increase of WAT quality in viscera is associated with increased metabolic risk (27, 30). WAT has important endocrine and paracrine effects (21, 31, 32).

Unlike WAT, brown adipocytes in BAT contain a large number of mitochondria and scattered lipid droplets. The main function of BAT is energy dissipation, which provides non-shivering thermogenesis to the body during energy-demanding conditions such as exercise, fasting or cold stimulus (33). BAT is mainly located in the interscapular region and perirenal regions of rodents and infants (34, 35), but BAT is normal component of several subcutaneous and visceral depots and is not exclusive to these areas (21). The development and gene characteristics of WAT and BAT are different (36–38). Classic brown adipocytes come from myogenic factor 5 (Myf-5) cell lines, while white adipocytes come from non Myf-5 cell lines (39). Thus, brown adipocytes are labeled with Myf-5 (40) and paired box 7 (41), similar to myogenic precursor cells. BAT contains rich vascular tree and dense capillary network (25). BAT consumes energy in the form of heat production (42–44), which is mainly due to the high level expression of uncoupling protein 1 (UCP1) in mitochondria and its proton leakage pathway (45–47), which is vital to lipid oxidation and thermogenesis. BAT, as an endocrine organ, regulates energy homeostasis by consuming fatty acids and glucose, and plays a key role in carbohydrate and lipid metabolism (47, 48).

Thirdly, there is a type of adipocyte, defined as “Brite” (white brown) (49) or “Beige” (50), which is derived from pre-existing white adipocytes (21). Beige adipocytes have plasticity and can be transformed from WAT by a variety of different pathways (21, 51, 52). The function of beige adipocytes is similar to that of brown adipocytes (49). In patients with CAC, beige adipocytes can develop, expand and activate under multiple environmental stimulation, which is the target of endocrine and paracrine stimulation (53, 54). The formation of beige adipocytes can be triggered by inflammatory mediators (such as interleukin-6 [IL-6] (55)) and tumor-derived compounds (such as parathyroid hormone related protein [PTHrP] (56, 57)). In mouse models, the formation of most beige adipocytes is a strong response to environmental factors, such as long-term low-temperature exposure (35).

The genetic characteristics of brown adipocytes and beige adipocytes partially overlap, except for specific markers, such as zinc finger (Zic1) in cerebellum (58). The common characteristics of brown and beige adipocytes are a large number of lipid droplets and dense accumulation of UCP1 positive mitochondria, although brown adipocytes had higher UCP1 expression level (39). Although brown and beige adipocytes are similar in morphology and biochemistry, they also have some distinct characteristics (35), because they come from different embryonic precursor cells (40). For example, brown adipocytes are mainly located in the interscapular and perirenal regions of rodents, while beige adipocytes exist in various WAT pools, especially in inguinal subcutaneous adipose tissue (59).

All three types of adipose tissue are important in the energy balance disrupted by CAC. WAT and BAT usually have opposite physiological functions. WAT is responsible for energy accumulation of lipid droplets in cells, while BAT is responsible for energy dissipation through heat production. Clinically, browning of WAT and activation of BAT are effective methods to combat obesity and metabolic syndrome, but in CAC we may need to block these mechanisms in order to preserve more adipose tissue. Changes in lipid metabolism under local or systemic stimulation make it a potential cause of CAC. In the case of congenital or acquired lipodystrophy, cachexia or any other severe malnutrition, there is almost total lack of adipose tissue, even severe multiple organ dysfunction results from the lack of leptin and other adipokines.

Lipid metabolism and adipose tissue mass are regulated by two pathways: lipolysis and lipogenesis. Lipolysis and lipogenesis balance maintain the dynamic balance of adipocytes and regulate the energy balance of CAC patients. Adipose tissue atrophy in cancer patients is attributed to increased lipolysis and lipid oxidation, decreased lipogenesis, impaired fat deposition and lipogenesis, and browning of WAT (60). Compared with non-cancer patients, the volume of adipocytes in cancer patients was smaller, but the total number of adipocytes did not change. Adipocytes isolated from patients with cachexia showed stronger catecholamine and natriuretic peptide-induced lipolysis (61). Weight loss patients also showed more sensitive characteristics to catecholamine signal (62). In addition, compared with cancer patients without cachexia, the expression of UCP1 in adipose tissue of CAC patients is higher, which may lead to adipose tissue atrophy and more heat production (55).

Patients with CAC often show systemic hypermetabolism with reduced energy intake and increased energy consumption, especially the abnormal increase of resting energy expenditure is considered to be the main cause of energy consumption. CAC, which is characterized by adipose tissue loss (60), is the terminal manifestation of metabolic changes in adipose tissue. The metabolic changes of adipose tissue have been proved to play an important role in CAC. In the context of CAC, changes in lipid metabolism and energy consumption have been shown to be harmful (16). In patients with terminal cancer, reduced adipose tissue is associated with poor prognosis (18, 19). In cachexia, fat loss is faster and earlier than lean tissue loss, especially in the period before death.

Adipose tissue contributes to weight loss in starvation, while skeletal muscle and adipose tissue mass decrease significantly in CAC patients. Lipolysis of adipocytes is the main cause of adipose tissue loss in cancer patients, and plays an important role in the course of CAC, and it is not related to malnutrition (63). The mechanism of adipose tissue loss in CAC is believed to be due to increased lipolytic activity and lipid utilization (64), while other mechanisms, such as impaired lipogenesis, may also be one of the reasons ( Figure 1 ). In the experimental model of cachexia, the decrease of adipose tissue appeared before the decrease of skeletal muscle mass and food intake (65). Studies have also shown that the decrease in adipose tissue is due to a significant decrease in adipocyte size resulting from a decrease in fat reserve, rather than a decrease in the number of cells (cell death) (64, 66). Some studies have found that lipogenesis and lipoprotein lipase (LPL) expression and activity have not been significantly down regulated in CAC patients (67, 68). A study identified the marker components of “cachectin” including Ataxin-10, which are sufficient to trigger abnormal fatty acid metabolism and cardiac atrophy. The serum level of Ataxin-10 is significantly increased in CAC patients (69).

However, the research progress in the treatment of CAC and the improvement of patients’ prognosis is relatively slow, there is also no definite treatment plan for the abnormal lipid metabolism of CAC patients. Studies have shown that CAC is often reversible if intervention is carried out in pre-cachexia or cachexia stage (10, 140). The main treatment strategies used in these stages include exercise and nutritional support, as well as the elimination of any direct cause of cancer (such as reduced food intake or malnutrition due to obstruction or compression) (140, 141). Unfortunately, many cases have been diagnosed as refractory cachexia, when CAC is usually irreversible (1, 140). At present, the main researches focus on the treatment of CAC. Several treatment options have been proposed, but have not been clinically confirmed. The treatment combination mainly involves two pathways: the anabolic pathway and the antimetabolic pathway for muscle and fat catabolism (82). Neutralization of metabolic changes is the first task to overcome cachexia, including the control of skeletal muscle protein decomposition rate, as well as the control of liver, lipid and carbohydrate protein metabolism abnormalities.

A retrospective study by Dingemans et al. included 12 phase II clinical trials involving 11 compounds. These drugs fight CAC through one of the following mechanisms: increase appetite, improve digestion, reduce systemic inflammation, and increase the ratio of muscle synthesis and degradation (142). Many other drugs have entered phase III trials, but it is difficult to achieve multiple clinical endpoints at the same time. Anamorelin, an auxin receptor agonist, has demonstrated its ability to improve lean weight in phase II clinical trials in patients with non-small cell lung cancer and CAC (143). However, the results of this phase II trial and subsequent phase III trial showed that although lean weight was improved, grip strength did not improve (143, 144), which was rejected by the European Drug Administration in 2017. Enobosarm, a selective androgen receptor regulator, showed a significant increase in total lean body weight in the phase II study (145), but it did not produce consistent end-point results in the phase III trial (146, 147). There are many influencing factors in CAC. Current studies cannot fully elucidate the pathophysiological mechanisms of CAC, so as to effectively reduce or reverse all clinical factors of CAC. Therefore, even if the development of many drugs is moving in the right direction, few of them can pass phase II and III studies.

As we mentioned above, lipopenia is an important feature of CAC, and several studies have suggested potential therapeutic strategies for lipid metabolism in CAC, which are summarized in Table 1 . Our summary shows that although so many potential strategies have been identified, they are still far from clinical practice. Based on the available evidence, nutritional strategies such as supplementing patients with unsaturated fatty acids and marine phospholipids may be effective (7, 164). Some chemotherapeutic agents, such as cytarabine, promote fat depletion, and we can intervene early in the treatment of patients using these chemotherapeutic agents (165). Exercise training may also reduce inflammation and improve the condition of muscle and adipose tissue in CAC patients (166). What’s more, the application of some new technologies may be helpful to this field. The appearance of 3D bioprinted WAT model is helpful for us to further study and understand the mechanism of adipose tissue metabolism in cachexia (167). Portable biosensors can make it easier for us to monitor lipolysis in patients (168). However, these strategies still need more clinical data to support, the treatment of CAC is still a major challenge for clinicians.

CAC is a chronic disease involving multiple organs and tissues, which requires multi-mode treatment, including drug treatment, nutritional support and physical exercise, so as to better adapt to the complex mechanisms of body consumption. While enhancing the balance of anabolism/catabolism, it can improve the physical condition and improve the quality of life (169, 170). However, the ideal drugs against CAC are still under development.

Studies have shown that adipose tissue is involved in the formation of CAC, and abnormal lipid metabolism plays an important role in the development of CAC ( Figure 2 ). In adipose tissue, WAT guides the system energy production through the balance between lipogenesis and lipolysis. BAT has been found to have important physiological and pathological functions in adults. Browning stimulates the differentiation and thermogenesis of beige adipocytes. These adipose tissues contribute differently to CAC. In the development of CAC, adipose tissue interacts with other cells or organs, showing therapeutic potential. Since abnormal lipid metabolism occurs at the early stage of CAC, correcting abnormal lipid metabolism and appropriately increasing adipose tissue may delay or even prevent the further deterioration of CAC. Therefore, it is also very important to explore related biomarkers to monitor lipid metabolism in cancer patients. In this field, we need to continue to pay attention to and think about the following questions: (1) At present, there is a lack of clinical monitoring indicators of lipid metabolism, and it is difficult for us to identify abnormal fat loss in cancer patients at an early stage. At the same time, the specific changes of each fat depot during fat loss are still not clear. (2) Some studies have shown that appropriate diet control and exercise can increase muscle strength and promote metabolic health in cancer patients. However, there is still a lack of relevant research conclusions on whether these measures are safe for patients with CAC and whether these interventions should be implemented in patients with CAC. (3) The related side effects of anti-tumor therapy may also promote the development of CAC. The effects of these therapies, including chemotherapy, radiotherapy, immunotherapy and targeted therapy, on lipid metabolism remain unclear. (4) Current animal models of CAC may not adequately simulate the actual physiological changes of CAC, many mechanistic details of abnormal lipid metabolism in CAC need to be further explored, and the interaction between different types of cancers and adipose tissue may also be different.

In this review, we systematically summarize the currently known mechanisms related to abnormal lipid metabolism in CAC. Although we have summarized a number of potential treatments for abnormal lipid metabolism in CAC in this review, most of them still require further drug development and clinical validation. CAC is still an unavoidable problem for oncologists. Through this review of abnormal lipid metabolism in CAC, we hope that drugs targeting abnormal lipid metabolism in CAC can be developed in the future, so as to effectively treat CAC and improve the prognosis of patients with CAC.

Abnormal lipid metabolism in CAC can be summarized as increased catabolism and decreased synthesis of white adipose tissue, increased browning of adipose tissue and abnormal activation of brown adipose tissue, and crosstalk between adipose tissue and non-adipose tissue further promotes adipose loss. There are a number of treatments available to prevent lipopenia, such as exercise, appetite promotion, caloric and nutrient supplementation by oral or parenteral nutrition, and NSAIDs and other drugs that may be beneficial to fat preservation, the specific items are listed in Table 1 . In clinical practice, these strategies are often used in combination to prevent the progression of CAC, and drugs targeting the above abnormal lipid metabolism need to be developed and explored in the future.

RF: Writing—Original Draft Preparation; LY, ZL: Supervision and writing — Review and Editing. All authors contributed to the article and approved the submitted version.