The integration of metabolism and immunity (or of nutrient- and pathogen-sensing pathways) can be traced back to an evolutionary need for survival, which resulted in the co-development of the organ systems and signalling pathways that mediate these two processes1
. The pressure to survive would have favoured energy efficiency and storage to prepare for times of food deprivation and for mounting a potent immune response to defend the host against infectious agents. However, the initiation and maintenance of immunity is a metabolically costly endeavour and cannot operate efficiently under conditions of energy deficit2,3
. For example, fever is associated with a 7–13% increase in caloric energy consumption per 1°C increase in body temperature, the energy expenditure of which is estimated to equate to 9.4×106
joules; this is approximately the energy cost of a 70 kg person walking 45 km4,5
. Sepsis can increase the human metabolic rate by 30–60%6
. Furthermore, the production and maintenance of phagocytes during infection is thought to result in an energy consumption of approximately 7.9×105
It is also clear that starvation and malnutrition can impair immune function; a total reduction in body fat has been shown to result in a decrease in the energy that is available for immune responses in rodents7
. In addition, conditions that trigger an immune response during starvation can severely reduce the survival of insects8
. Therefore, immune defence is subject to a trade-off between other energy-demanding processes, such as reproduction, thermoregulation and lactation. Interestingly, energy surplus (which is typical of individuals who are obese or suffer from metabolic syndrome) can also impair immune responses and induce chronic inflammation (see later). Therefore, a balanced energy flux and maintainance of favourable metabolic homeostasis are required for the proper functioning of the immune system.
These processes may have been optimized through the close coordination and co-evolution of metabolic and immune responses, and of the organs that are involved in these processes. Evidence supporting such a developmental history can be found in lower organisms, such as Drosophila melanogaster
, in which immune and metabolic responses are controlled by the same organ, the fat body9
. In addition, tissues that are important in metabolism are thought to have an evolutionary potential to mediate inflammatory responses. The association between metabolism and inflammation is also evident in tissues of higher organisms, for example the liver and adipose tissue, where immune effector cells, such as Kupffer cells and macrophages, are found alongside hepatocytes and adipocytes, respectively1
. Interestingly, lymph nodes are also embedded in adipose tissue, perhaps to have a competitive advantage over other tissues in meeting excessive energy demands at times of immune stress10
. In addition, the perinodal adipose tissue, which is located around the lymph nodes, might influence local immune responses owing to its high polyunsaturated fatty-acid content, which could provide nutrients and soluble mediators that are needed for the responses, and the presence of dendritic cells11
. Remodelling of the adipose tissue can also accompany certain inflammatory processes, for example, the development of panniculitis during inflammatory bowel disease12
Despite the evidence suggesting that the immune and metabolic systems need to colocalize to maintain metabolic homeostasis during an immune response, energy can be transported efficiently throughout the body by the circulatory system, which questions a requirement for local energy supplies. However, most infections can suppress the host’s appetite, possibly by inducing the synthesis of leptin (an adipocyte-derived hormone and cytokine), which suggests that local sources of energy and nutrients are more important during an immune response13
. Nevertheless, many of these observations have not been supported by experimental evidence and therefore their physiological significance is still unclear.
Cells that are involved in metabolic and immune responses also show evidence of coordination and co-evolution. More specifically, macrophages and adipocytes are closely related and share many functions; for example, they both secrete cytokines and can be activated by pathogen-associated components, such as lipopolysaccharide (LPS)14
. In addition, phagocytosis and the expression of membrane-bound NADPH oxidases, which are characteristics of macrophages, are traits that have also been attributed to adipocytes15
. Indeed, pre-adipocytes have been shown to transdifferentiate into macrophages, and transcriptional profiling has suggested that macrophages and pre-adipocytes are genetically related15,16
. Moreover, there is an extensive genetic and functional overlap between fully differentiated adipocytes and macrophages that have transformed into atherogenic foam cells, particularly in terms of metabolic genes ().
molecular characteristics shared between adipocytes and macrophages in physiological conditions and metabolic disease states
It can be envisioned that a threat to the delicate balance between immune and metabolic responses, such as can be induced by chronic nutrient deficiency or a continuous energy surplus, can transform this intimate, long-lasting and productive interaction into a pathological relationship (in this Review, we focus on overnutrition and not on malnutrition). Exposure to excess amounts of nutrients and energy is a modern phenomenon that has been caused by changes in dietary patterns and lifestyle worldwide. These changes are associated with an increase in the incidence of chronic metabolic diseases, such as obesity, type 2 diabetes, fatty liver disease and atherosclerosis, as well as asthma and some cancers1
. Under these energy-rich conditions, the ancient inflammatory potential of metabolically important tissues can be reactivated; the adipose tissue of obese individuals has in fact been shown to produce higher levels of the pro-inflammatory cytokine tumour-necrosis factor (TNF) and other pro-inflammatory factors17,18
Chronic inflammation, particularly when it occurs in metabolically important organs such as the liver and adipose tissue, has a crucial role in the development of many chronic metabolic diseases, such as diabetes, fatty liver disease and cardiovascular disease17
. It is important to recognize that this response does not resemble classic inflammation and perhaps could be considered as an aberrant form of immunity that is triggered by nutrients or other intrinsic cues, and has been referred to as meta-inflammation or para-inflammation1,19
. In fact, many branches of the immune response are defective in obese individuals, including the activity of neutrophils, natural killer cells and T cells13,20
. Nevertheless, it is important to explore the general mechanisms that integrate the immune response with systemic metabolic homeostasis and to identify ways to exploit these pathways for the treatment of chronic metabolic diseases.