intensive care unit
Globally, the number of obese individuals has reached alarming proportions. According to the WHO latest estimates, approximately 500 million adults and nearly forty-three million children under the age of 5 years are considered to be obese (BMI≥30)(1). Obesity is defined as a state of excess adiposity and its cause, although multifactorial, is primarily due to prolonged positive energy balance. Several comorbidities are associated with this disease, especially immune dysfunction. Alterations in inflammation and immune cell function in the obese play a significant role in nearly all pathophysiological effects of obesity(Reference Rocha and Libby2, Reference Odegaard and Chawla3). However, few studies have directly addressed how this may affect host defence. In fact, there is striking evidence in both human subjects and mice that a state of excess adiposity greatly increases susceptibility to infections. Despite the strong epidemiological evidence in human subjects and immunological findings in rodents, much remains to be learned about obesity-related immune impairment. Furthermore, the mechanisms directly and indirectly responsible for differences in immune activity and host defence between healthy weight and obese individuals remain unclear.
In addition to an increased research focus on this topic, there may be implications for management of infections in the obese. For example, evidence is accumulating that obese individuals may respond differently to vaccination and various drugs, such as antibiotics. In combination with impaired immunity, altered responses to interventions may further affect the outcome of infection. Increased susceptibility to infection has obvious health and monetary consequences at the individual level. However, given that one out of every ten adults is obese, concerns of rising health care costs and disease transmission become a concern for all(1).
Evidence of impaired immunity in obese human subjects
Recent studies have demonstrated altered immune cell function in obese human subjects compared with those of healthy-weight. Nieman et al. reported considerable discrepancies in leucocyte number and subset counts and phagocytic and oxidative burst activity of monocytes between lean and obese individuals(Reference Nieman, Henson and Nehlsen-Cannarella4). Additionally, circulating mononuclear cells in the obese exhibit a pro-inflammatory state compared with healthy-weight persons(Reference Ghanim, Aljada and Hofmeyer5). Impaired lymphocyte proliferation to polyclonal stimulation has been reported as well(Reference Nieman, Henson and Nehlsen-Cannarella4). Type II diabetes, a common complication of obesity, is associated with impaired immune cell activity(Reference Geerlings and Hoepelman6). Individuals with a genetic mutation preventing proper synthesis of the hormone leptin, become morbidly obese and display weakened immune defences(Reference Farooqi, Matarese and Lord7). Interestingly, obesity has been shown to enhance thymic aging and reduce T-cell repertoire diversity, thus possibly impacting immune surveillance(Reference Yang, Youm and Vandanmagsar8). The reported findings of immune cell dysfunction suggest that obesity may result in impaired host defence. Indeed, studies have linked obesity with increased risk of infection(Reference Falagas and Kompoti9). Several reports have found obesity to be a significant risk factor for post-operative and surgical site(Reference Vilar-Compte, Mohar and Sandoval10), nosocomial(Reference Dossett, Dageforde and Swenson11), periodontal(Reference Ylöstalo, Suominen-Taipale and Reunanen12) and respiratory infections(Reference Jedrychowski, Maugeri and Flak13).
Infections in clinical settings
Obese patients have increased intensive care unit (ICU) length of stay(Reference Dossett, Heffernan and Lightfoot14) and are more likely to die(Reference Bochicchio, Joshi and Bochicchio15–Reference Bercault, Boulain and Kuteifan17) in the hospital. Further, several epidemiological investigations have reported that obesity increases infection susceptibility in clinical settings(Reference Falagas and Kompoti9). Obese patients are prone to developing post-operative complications. In fact, numerous studies have reported obesity to be an independent risk factor for post-operative infections(Reference Olsen, Nepple and Riew18–Reference Swenne, Lindholm and Borowiec28). In a recent secondary analysis of a large prospective observational study including critically ill and injured patients remaining in the ICU for 48 h or more, obesity was reported to be an independent risk factor for catheter and blood stream infections(Reference Dossett, Dageforde and Swenson11). A study in critically injured blunt trauma patients reported that morbid obesity (BMI≥40) was associated with increased risk of pneumonia and urinary tract infection but not with increased mortality(Reference Dowsey and Choong21).
The impact of obesity on clinical outcomes in hospitalised patients is clearly multifactorial and complex. In addition to decreased immunocompetence, there are other potential factors that may contribute to increased susceptibility to infection in the hospital setting. For example, underlying disease in the obese may inhibit proper mobility in the hospital, which can increase risk for skin breakdown(Reference Mathison29). Due to inadequate equipment or improperly trained staff, obese individuals may have prolonged visits at the hospital, thus increasing risk for acquiring nosocomial infections(Reference Falagas and Kompoti9, Reference Mathison29). Another consideration is that pharmacokinetics of antibiotics may differ in the obese, potentially affecting susceptibility to post-operative infections(Reference Hanley, Abernethy and Greenblatt30). Therefore, it is difficult to determine the direct impact of impaired immunity on severity of nosocomial infections in obese patients, but accumulating evidence suggests a significant role.
Obesity and respiratory infections
A striking number of recent studies have reported obesity to be a predictor for a worse outcome of infection with the 2009 influenza A (H1N1) pandemic strain(Reference Jain and Chaves31). In fact, several countries across the world have reported data indicating that obese individuals were disproportionately represented among influenza-related hospitalisations and deaths. Obesity or morbid obesity increased risk of ICU admission and even death among those infected with the pandemic strain(Reference Hanslik, Boelle and Flahault32–Reference Morgan, Bramley and Fowlkes35). Those admitted to ICU had a reportedly longer duration of mechanical ventilation and increased time in ICU and hospitals compared with non-obese individuals(Reference Díaz, Rodríguez and Martin-Loeches36). Before the advent of the 2009 pandemic season, there were no such reports investigating the relationship between obesity and influenza infection in human subjects. Recently, however, Kwong et al. published a study that explored the relationship between BMI and seasonal influenza infection using a series of Canada's cross-sectional population-based health surveys(Reference Kwong, Campitelli and Rosella37). The surveys covered twelve influenza seasons. Analysis of the retrospective cohort demonstrated that the obese are at greater risk for respiratory hospitalisations during the seasonal flu periods.
In contrast to the recent surge of publications highlighting a connection between influenza severity and obesity, there is very little known about obesity and other respiratory tract infections(Reference Mancuso38). A recent study by Akiyama et al. suggests that obesity may impact the response to respiratory syncytial virus infection in children(Reference Akiyama, Segawa and Ida39). A study from Poland reported that BMI was significantly related to susceptibility to respiratory infections in children(Reference Jedrychowski, Maugeri and Flak13). In critically ill trauma patients, obesity or morbid obesity was associated with respiratory infections(Reference Dossett, Dageforde and Swenson11, Reference Bochicchio, Joshi and Bochicchio15, Reference Newell, Bard and Goettler23). Conversely, a few studies have also reported obese individuals are not at greater risk for respiratory infections(Reference Dossett, Heffernan and Lightfoot14, Reference Brandt, Harder and Walluscheck40). Therefore, our understanding of the effect of obesity on risk for pulmonary infection remains unclear. However, it is important to consider that obesity can complicate lung mechanics, such as restricting lung volume (reviewed in(Reference McClean, Kee and Young41)), which could potentially increase risk for pneumonia or other infections. Although the mechanisms contributing to increased susceptibility may include impaired immunity, there may be non-immune factors to consider.
Vaccination and management of infection in the obese
Vaccination is universally recommended by public health officials to combat several types of infections. However, there is some evidence suggesting that obese individuals may not respond to vaccination to the same extent as healthy-weight individuals. Obesity was associated with a poor antibody response to hepatitis B vaccination(Reference Weber, Rutala and Samsa42, Reference Weber, Rutala and Samsa43). Additionally, overweight children displayed considerably lower anti-tetanus IgG antibodies in response to vaccination compared with healthy-weight children(Reference Eliakim, Swindt and Zaldivar44). This reduced immunogenicity in response to vaccination could be caused by several factors. One possibility is impaired generation and/or function of the antibody-secreting plasma cells. Another factor could be reduced absorption of the vaccine at the site of injection due to excess adiposity(Reference Eliakim, Swindt and Zaldivar44). Interestingly, a recent study reported that using a larger vaccine needle length resulted in considerably higher antibody titres to hepatitis B surface antigen in obese adolescents(Reference Middleman, Anding and Tung45). As mentioned, poor response to vaccination has important public health implications. Reduced protection against viral infections, such as hepatitis B, increases individual susceptibility and may increase the likelihood of transmission to others. Therefore, more research on how obesity may negatively impact vaccination response is necessary to ensure proper protection in this at risk population.
In addition to the infections mentioned earlier, increased BMI is associated with greater risk for several other bacterial infections including periodontal infections(Reference Ylöstalo, Suominen-Taipale and Reunanen12), Staphylococcus aureus nasal carriage(Reference Herwaldt, Cullen and French46) and gastric infection by Helicobacter pylori (Reference Perdichizzi, Bottari and Pallio47). Also, a recent study reported that obesity was significantly associated with herpes simplex virus 1 infection, which was determined by seropositivity(Reference Karjala, Neal and Rohrer48). Despite increased risk for several types of microbial infections, there is little known about how obesity may alter the pharmacokinetics of antimicrobial drugs (reviewed in(Reference Hanley, Abernethy and Greenblatt30)). Studies assessing dosing of the antibacterial drug, vancomycin, suggest that obese patients may require different dosages(Reference Bearden and Rodvold49) and different dosing intervals(Reference Bauer, Black and Lill50) compared with non-obese individuals. An additional study of the antimicrobial drug, linezolid, reported diminished serum concentrations in the obese compared with healthy-weight volunteers receiving the same dose(Reference Stein, Schooley and Peloquin51). As pointed out previously, there is greater risk of skin breakdown in obese individuals in clinical settings due to restricted mobility, improperly sized rooms and equipment and the special challenges of caring for patients undergoing or post-bariatric surgery(Reference Falagas and Kompoti9, Reference Mathison29). Additionally, excess adiposity may reduce tissue perfusion and affect wound healing(Reference Mathison29). Taken together, it is clear that obesity predisposes individuals to nosocomial infections, and that careful consideration of infection prevention and treatment is required.
Rodent models of obesity and infection
A limited number of studies have demonstrated the negative impact of excess adiposity on immune cell function in rodent models. The implications of these studies, in terms of obesity-related immunity impairments, are often complicated by the use of genetic models of obesity. The most commonly used genetically altered rodents for this purpose are the ob/ob and db/db mice and the rat fa/fa counterpart. These rodent models lacking leptin or the leptin receptor are very useful for the study of obesity-related comorbidities, as they display metabolic abnormalities characteristic of obesity such as hyperglycaemia, dyslipidaemia, glucocorticoid excess and hyperinsulinaemia(Reference Nishina, Lowe and Wang52, Reference Pelleymounter, Cullen and Baker53) (all of which could potentially alter immune cell homoeostasis and function). However, given the vast amount of research highlighting the importance of leptin in immunity(Reference La Cava and Matarese54), a global deficiency in leptin signalling makes it difficult to tease apart the mechanisms contributing to impaired immunity and greater susceptibility to infections in these genetic models of obesity. Nonetheless, these models still provide insight into how excess adiposity may directly or indirectly alter immune cell function and host defence against infectious agents.
In general, a deficiency of leptin (ob/ob) or the leptin receptor (db/db) in mice increases susceptibility to bacterial infections and pneumonia(Reference Mancuso38). Using ob/ob mice, Mancuso et al. demonstrated that a complete deficiency of leptin resulted in impaired pulmonary clearance upon Klebsiella challenge, likely due to defective alveolar macrophage and neutrophil phagocytosis(Reference Mancuso, Gottschalk and Phare55). Similarly, an investigation by Hsu et al. reported that ob/ob mice exhibited enhanced lethality and delayed clearance of Streptococcus pneumoniae following a pulmonary challenge(Reference Hsu, Aronoff and Phipps56). Interestingly, intraperitoneal injections of leptin prior to Streptococcus infection improved survival after the bacterial challenge, but not to the level of wild-type mice. This discrepancy in survival percentages may, in fact, be caused by the increased adiposity of the ob/ob mice. Other studies have reported that ob/ob mice exhibit greater pulmonary Mycobacterium tuberculosis load(Reference Wieland, Florquin and Chan57) and delayed clearance of the Mycobacterium abcessus (Reference Ordway, Henao-Tamayo and Smith58) upon challenge.
In addition to these pulmonary infection models, mice lacking the leptin receptor were shown to be more susceptible to hind paw staphylococcal infection and exhibited a greater inflammatory response compared with wild-type mice(Reference Park, Rich and Hanses59). Furthermore, db/db and ob/ob mice displayed impaired resistance to hepatic Listeria monocytogenes infection(Reference Ikejima, Sasaki and Sashinami60). Obese Zucker rats show decreased ability to clear yeast infection upon challenge with Candida albicans (Reference Plotkin, Paulson and Chelich61).
It is clear that evidence highlighting the importance of leptin for host defence is rapidly accumulating. However, these studies do not offer insight into the mechanisms by which excess body fat (and related metabolic abnormalities) may actually hinder host defence. Adding exogenous leptin to ob/ob mice is helpful in understanding the impact of other metabolic abnormalities on immune dysfunction, but exogenous administration of leptin in mice still differs from studying animals with intact leptin production and signalling. Some key considerations include indirect effects of leptin on immune responses and the fact that leptin has been shown to have autocrine signalling capabilities on select immune cells(Reference De Rosa, Procaccini and Calì62). Although infection models in ob/ob or db/db mice provide important information on the role of leptin in host defence and immunity, these mice do not properly model non-genetically induced obesity, which constitutes the vast majority of human obesity.
Diet-induced obesity (DIO) in rodents more closely mimics human obesity. DIO mice, similar to their human counterparts, develop the typical comorbidities associated with obesity including elevated leptin, insulin resistance and elevated liver TAG. Although the diet models of obesity are often utilised to study metabolic problems associated with obesity, fewer studies have utilised these models in the context of an infection.
Compared with lean control mice, DIO mice have greater morbidity and mortality during either a primary or secondary influenza infection(Reference Smith, Sheridan and Harp63, Reference Karlsson, Sheridan and Beck64). Several forms of immunity impairment were observed in the DIO mice, including reduced natural killer cell activity, poor dendritic cell processing and presentation and impaired CD8+ T-cell function(Reference Karlsson, Sheridan and Beck64, Reference Smith, Sheridan and Tseng65). The mechanism(s) for the immune alterations in the DIO mice remains unclear.
An interesting study by Shamshiev et al. reported apoE−/− mice fed a high fat and cholesterol diet displayed impaired resistance to Leishmania major infection due to impaired dendritic cell function and T-helper type 1 cell immunity(Reference Shamshiev, Ampenberger and Ernst66). Impaired T-cell activity was also reported in DIO mice transgenic for a T-cell receptor specific to a peptide derived from ovalbumuin(Reference Verwaerde, Delanoye and Macia67). One complication associated with using DIO is elucidating whether the observed outcome of infection can be attributed to the abundance of adipose tissue, the influence of the high-fat diet or both. In this case, utilising both genetic obesity models with intact leptin signalling and DIO models in conjunction may be beneficial in advancing our understanding of the impact of the diet v. the state of excess adiposity on immunity(Reference Huszar, Lynch and Fairchild-Huntress68, Reference Kennedy, Ellacott and King69). Another important aspect of diet studies to consider is use of a proper control diet. A defined high-fat diet is commonly used for DIO models, but rarely do investigators include the matched control diet that only differs in fat and carbohydrate content(Reference Warden and Fisler70). In addition to major differences in macro- and micronutrient content, phytoestrogens are nearly absent in defined high-fat diets, whereas chow has high but variable levels(Reference Thigpen, Setchell and Saunders71). Phytoestrogens can have marked effects on rodent physiology including hormone levels, metabolism and locomotor activity(Reference Lephart, Porter and Lund72–Reference Torre-Villalvazo, Tovar and Ramos-Barragán74). Thus, usage of a chow diet can potentially confound the effects of a high-fat diet(Reference Warden and Fisler70). Careful consideration of diet and experimental design is important in assessing the impact of obesity or diet on immunity.
Mechanisms of altered cellular immune function in the obese
It is well known that obesity is associated with a state of chronic, low-grade inflammation both in white adipose tissue and systemically(Reference Bulló, García-Lorda and Megias75–Reference Fenton, Nunez and Yakar78). Additionally, obesity is characterised by altered levels of circulating hormones and nutrients such as glucose and lipids. Circulating immune cells and those resident in peripheral tissues are thus exposed to an energy-rich environment in the context of altered concentrations of metabolic hormones. Understanding how this pro-inflammatory, excess energy milieu impacts immune cell function is key in understanding the immunodeficient state associated with obesity. Although these metabolic abnormalities can undoubtedly have indirect effects on immune cells, this review will focus on the direct impact of these abnormalities on immune cells.
Immunomodulatory adipokines and hormones in obesity
The primary adipose derived immunomodulatory adipokines include leptin, adiponectin and the pro-inflammatory cytokines: TNFα, IL-6 and IL-1β(Reference Fantuzzi76, Reference Tilg and Moschen77, Reference Koerner79). Adiponectin, levels of which are decreased during obesity, has been shown to alter natural killer cell cytotoxicity and cytokine production by human myeloid cells(Reference Wolf, Wolf and Rumpold80, Reference Kim, Kim and Han81). Conversely, there is excess production of TNFα, IL-6 and IL-1β in white adipose tissue of the obese(Reference Tilg and Moschen77). These cytokines can be secreted into the blood and potentially have distal effects; however, exactly how chronic production of these cytokines impacts cellular immunity remains to be elucidated. It is possible that chronic exposure to pro-inflammatory cytokines may desensitise immune cells to inflammatory responses during an actual infection(Reference Ziegler-Heitbrock, Wedel and Schraut82).
The pleiotropic effects of leptin on immune cell activity are highly diverse and complicated(Reference La Cava and Matarese54). Nearly all cells of the innate immune system express the isoform of the leptin receptor, obRb, required for leptin signalling(Reference Lord, Matarese and Howard83–Reference Caldefie-Chezet, Poulin and Tridon87). In monocytes, leptin up-regulates pro-inflammatory cytokine production of IL-6, IL-12 and TNFα, as well as phagocytic activity(Reference Mancuso, Gottschalk and Phare55, Reference Loffreda, Yang and Lin88, Reference Gainsford, Willson and Metcalf89). In polymorphonuclear neutrophils of healthy individuals, leptin signalling induced chemotaxis, reactive oxygen species generation and influenced oxidative capacity(Reference Caldefie-Chezet, Poulin and Tridon87, Reference Caldefie-Chezet, Poulin and Vasson90, Reference Montecucco, Bianchi and Gnerre91). Natural killer cells are highly influenced by leptin signalling, including aspects of differentiation, proliferation, activation and activity(Reference Zhao, Sun and You85, Reference Tian, Sun and Wei92). Given the importance of leptin to innate immune cell function, it follows that nearly all innate immune cells are impaired in mice lacking intact leptin signalling.
The adaptive arm of the immune response is equally affected by leptin signalling(Reference Lord, Matarese and Howard83, Reference Papathanassoglou, El-Haschimi and Li86). Leptin is an important source of pro-survival signals to double-positive and single-positive thymocytes during the maturation of T-cells(Reference Howard, Lord and Matarese93). Leptin has been shown to play a key role in lymphopoieses and myelopoieses given that ob/ob mice had only 60% as many nucleated cells in bone marrow as compared with wild-type controls(Reference Claycombe, King and Fraker94). In the presence of a polyclonal stimulator, leptin can increase T-cell proliferation and can modulate expression of activation markers on both CD4+ and CD8+ T-cells(Reference Martín-Romero, Santos-Alvarez and Goberna95). Leptin can also have profound effects on cellular activity by functioning as a regulator of immune cell metabolism(Reference De Rosa, Procaccini and Calì62, Reference MacIver, Jacobs and Wieman96).
Although several papers have discussed how leptin may be required for or may enhance immune cell function, few have taken into consideration the fact that obese individuals are hyperleptinaemic(Reference Matarese, Moschos and Mantzoros97). Therefore, in obese models, we should ask what are the potential impacts of excess leptin signalling on immune cells? Indeed, studies have demonstrated that T-cells(Reference Papathanassoglou, El-Haschimi and Li86) and natural killer cells(Reference Nave, Mueller and Siegmund98) can become resistant to leptin in rodent models of obesity. Leptin signals through a JAK/STAT (Janus kinase/signal transducer and activator of transcription) signalling pathway, resulting in translocation of the transcription factor, STAT3 (signal transducer and activator of transcription 3), into the nucleus and subsequent transcription of leptin-induced genes, including suppressor of cytokine signalling-3(Reference Bjørbæk, El-Haschimi and Frantz99). Suppressor of cytokine signalling 3 functions as a negative feedback mediator of JAK/STAT signalling, and thus may play an important role in impairing leptin signalling and contributing to central and peripheral leptin resistance(Reference Bjørbæk, Elmquist and Frantz100). Leptin resistance could very well explain obesity-related impaired immunity, as this would mimic a state of leptin deficiency. Leptin resistance, induced by hyperleptinaemia, would obviously not occur in ob/ob mice, which is another reason these mice are not the best model for studying obesity-related immune dysfunction. Although it is widely accepted that leptin resistance occurs centrally in the hypothalamus(Reference Bjørbæk, Elmquist and Frantz100–Reference Munzberg and Myers102), peripheral leptin resistance requires further investigation.
An additional and somewhat novel consideration is how hyperleptinaemia may impact the function and distribution of regulatory T-cells (Treg). An elegant study by De Rosa et al. demonstrated a role for leptin signalling in Treg proliferation and function(Reference De Rosa, Procaccini and Calì62). Abrogation of leptin signalling alters the anergic state of Treg, and allows for enhanced proliferation. Although highly proliferating Treg tend to lose some of their suppressive activity(Reference De Rosa, Procaccini and Calì62), resistance to leptin signalling might contribute to greater Treg number. Treg have the capacity to suppress nearly all aspects of the immune response(Reference Miyara and Sakaguchi103). Thus, this hypothesis fits with the immunosuppressive phenotype associated with infections in the obese. In fact, a recent investigation demonstrated a greater percentage of Treg in the spleen of DIO mice despite lower levels in adipose tissue(Reference Deiuliis, Shah and Shah104). It is clear that obesity can alter Treg number and function(Reference Deiuliis, Shah and Shah104–Reference Ilan, Maron and Tukpah106), but the extent to which this population of immune cells affects infection outcomes in the obese remains unknown.
Hyperinsulinaemia and insulin resistance are common features of obesity; however, there is little known regarding the immunomodulatory effects of excess insulin or impaired insulin signalling in the context of obesity. How the effects of insulin on cellular immunity are only partially understood. Monocytes have been shown to express insulin receptors and are insulin sensitive immune cells(Reference Defronzo, Soman and Sherwin107–Reference Liang, Han and Okamoto110). Interestingly, resting T-cells are insulin insensitive in that the insulin receptor is absent from the plasma membrane. However, once T-cells are activated by a polyclonal stimulator, such as phytohaemagglutinin or by specific antigen, effector T-cells up-regulate de novo emergence of insulin receptors(Reference Stentz and Kitabchi111, Reference Viardot, Grey and Mackay112). Insulin signalling induces glucose uptake, amino acid transport, lipid metabolism and can modulate T-cell activation and function(Reference Stentz and Kitabchi111, Reference Helderman113). Furthermore, insulin promotes an anti-inflammatory T-helper type 2 cell phenotype(Reference Viardot, Grey and Mackay112), but MacIver et al. speculate that insulin resistance in obesity may actually enhance T-helper type 1 cell development(Reference MacIver, Jacobs and Wieman96). It is thus clear that insulin can have potent effects on immune cell metabolism and function, but the effects of excess insulin on immunity remain relatively unresearched.
Altered immune cell metabolism in an abnormal metabolic environment
Immune cells from both innate and adaptive defences require nutrients such as glucose, amino acids and fatty acids to meet energy needs(Reference Delacre, Pot and Grangette114). However, energetic demands and nutrient preference depend on cell type and cellular activity. For example, once T-cells are activated, they become highly proliferative and secretory, and thus require an abundant source of energy that will rapidly yield large quantities of ATP(Reference Frauwirth and Thompson115). Conversely, macrophages and neutrophils are generally considered to be non-proliferative and thus have a different metabolic profile and nutrient requirements(Reference Delacre, Pot and Grangette114, Reference Newsholme, Rosa and Newsholme116). Although glucose and fatty acids are important sources of energy for host defence and immune function(Reference Calder117), elevated levels of these nutrients, as in the obese, may have consequences for immune cell activity.
Glucose uptake by immune cells is facilitated by the family of glucose transport proteins, GLUT. A variety of GLUT are expressed on immune cells. For example, increased expression of GLUT3 and GLUT5 occurs during the differentiation of monocytes to macrophages(Reference Fu, Maianu and Melbert118). GLUT1 appears to be the primary GLUT on T-cells, and functions to maintain glucose uptake for basic metabolic requirements(Reference MacIver, Jacobs and Wieman96, Reference Frauwirth and Thompson115). Upon stimulation, GLUT1 and GLUT3 levels were shown to increase on T-cells and monocytes(Reference Fu, Maianu and Melbert118). Glucose is required for proper T-cell proliferation and survival(Reference MacIver, Jacobs and Wieman96). However, it has also been shown that exposing T-cells to high concentrations of glucose can result in reactive oxygen species generation and lipid peroxidation(Reference Stentz and Kitabchi119). Although little is known of the in vivo effects of hyperglycaemia on immune cell function, Jacobs et al. demonstrated that overexpression of GLUT1 in mouse T-cells resulted in altered T-cell metabolism and cytokine production(Reference Jacobs, Herman and MacIver120). The mechanisms by which elevated glucose influence immune cell function are not entirely clear, but glucose plays a crucial role in activity of immune cells, and thus excessive levels are likely to have a significant impact on cellular function.
Similar to glucose, fatty acids are important in fuelling an immune response, as they are a readily available source of abundant energy. However, the impact of excess circulating NEFA, a hallmark of obesity(Reference Bergman and Ader121), on immune cells has not been well studied. Interestingly, SFA, such as palmitate, share similarities in chemical structure to lipopolysaccharide. This observation sparked studies indicating that SFA can induce an inflammatory response by initiating Toll-like receptor (TLR) signalling pathways(Reference Lee, Sohn and Rhee122–Reference Weatherill, Lee and Zhao126). TLR are critical in inducing innate immune responses as they recognise conserved molecular patterns on microbial pathogens(Reference Kawai and Akira127). SFA, but not unsaturated, have been shown to activate both TLR2 and TLR4 resulting in TIR (Toll/IL-1 receptor) domain-containing adaptor-inducing interferon-β-dependent and myeloid differentiation factor 88-dependent signalling pathways and a subsequent inflammatory response(Reference Lee, Sohn and Rhee122–Reference Shi, Kokoeva and Inouye128). NEFA have been shown to trigger inflammatory responses in both macrophages and dendritic cells indicating that both innate and adaptive immune responses can be affected(Reference Weatherill, Lee and Zhao126, Reference Nguyen, Favelyukis and Nguyen129). The effect of elevated NEFA on insulin resistance and type II diabetes has been widely examined(Reference Shi, Kokoeva and Inouye128). Cells of both innate and adaptive immunity express TLR2 and TLR4, and other than a small number of studies in macrophages(Reference Odegaard and Chawla3,129–Reference Laine, Schwartz and Wang131), there is very little known of the impact of NEFA on TLR signalling in other immune cells, such as T-cells. However, a study by Stentz and Kitabchi reported that increasing concentrations of palmitate but not unsaturated fatty acids resulted in activation of T-cells and a dose-dependent increase in cytokine production as well as reactive oxygen species generation and lipid peroxidation in vitro (Reference Stentz and Kitabchi132).
An additional consideration in which excess fatty acids, as well as glucose and metabolic hormones, may affect immunity is highlighted in several recent studies demonstrating that T-cell populations can have distinct metabolic programmes that are critical to cell fate and function(Reference Michalek, Gerriets and Jacobs133). Michalek et al. show that CD4+ T-cell metabolism is fundamental in regulating differentiation to an effector or regulatory subtype. The CD4+ T effector subset requires glycolytic metabolism, and Treg require lipolytic oxidation(Reference Michalek, Gerriets and Jacobs133). Interestingly, recent studies have shown that CD8+ effector T-cells displayed a glycolytic phenotype, whereas a CD8+ memory T-cell population was associated with a lipid oxidation metabolic profile(Reference Pearce, Walsh and Cejas134–Reference Rao, Li and Odunsi136). What remains to be studied is how nutrition may alter these distinct metabolic programmes. In the context of obesity, how do elevated levels of glucose, fatty acids and metabolic hormones, such as leptin and insulin, impact the metabolic fate of immune cells during an infection?
The best solution to improving health of obese individuals is significant weight loss. However, the aetiology of this highly complex disease is multifactorial, and thus no solution to obesity will be an easy fix. The burden of obesity is shared by adolescents and adults alike, and of the numerous comorbidities associated with obesity, host defence and immune cell dysfunction are less studied compared with type II diabetes or cardiovascular complications. Obesity clearly interferes with protection against infectious agents, and therefore increased research for a better understanding of the interactions between excess adipose-related metabolic abnormalities and immune cell activity is needed. Strong epidemiological evidence highlighting an association between obesity and infection is accumulating, and there are rodent models offering insight into potential mechanisms. An additional, yet key, consideration is how best to prevent and manage infections in this at risk population. Antimicrobial drugs and vaccines may not function as intended in obese individuals. This is cause for major concern in the context of outbreaks of infection, as for the 2009 influenza pandemic. Further consideration and investigation on the impact of obesity on immunity could potentially save millions of lives, especially during the current obesity epidemic dilemma.
J. J. M. wrote the review and M. A. B. provided expert advice in the drafting of the paper. The authors declare no conflicts of interest. The work was supported by NIH grants R01AI078090 and P30DK056350.