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At the Obesity-Immunity Crossroads
Mar 1, 2016

The worldwide prevalence and incidence of obesity has increased dramatically in recent decades. Oversized food portions, inactive lifestyles, genetic heritage, and food company practices are just a few of the factors contributing to the global obesity epidemic. The data shows that 43% of adults in US are obese, and the costs of caring for obesity will grow to $344 billion by 2018. 

The word “obesity” originates from the Latin obesus, which literally means, “having eaten until fat.” Obesity is a disorder involving excessive body fat that damages our well-being and increases the risk of health problems. For example, an obese individual is ten times more likely to have heart disease and five times more likely to have diabetes as opposed to a person of normal weight. Some other symptoms of obesity are high blood lipids (e.g. triglycerides), high blood pressure, and low good cholesterol, which helps remove bad cholesterol from your arteries. Besides leading to a number of diseases, the large waistline formed due to the fat buildup also triggers our immune system, which plays a critical role in the initiation and progression of obesity-associated diseases. Before going into the details of the altered immune response due the increased storage of fat, let’s first explore the perfect order in our immune system, especially in a subset of immune cells called macrophages.

The amazing immune system

Our astounding immune system is in charge of defending our body by clearing out thousands of germs that can make us sick. Our immune cells serve in the context of cleansing the human body from invading germs. The immune system has two branches: the innate and adaptive branches, as defined with respect to the characteristics of their responses. The cross-talk and mutual communication between the two arms constitutes the integral immune response. 
The adaptive immune system operates slowly, by developing for specific pathogens. In addition, it has a memory of previous exposures. The innate immune system provides a first line of defense against the invasion of disease-causing microorganisms (pathogens). It has three defense layers: anatomical barriers, humoral barriers, and cellular barriers. The skin is an example of the physical barriers, which prevent pathogens from getting access to our body. The chemicals found in tears, saliva, and mucus impair bacterial growth, and they represent the humoral barriers. Once an invading bacterium somehow evades these barriers, or a tissue injury occurs, various types of immune cells are recruited to the site of infection for the protection of the host. These cells constitute the third barrier of the innate immune system. As an initial defense system, innate immune cells and their components exhibit a fast, non-specific response with minimal memory of past exposures.

Macrophages: the big eaters

Macrophages, a subgroup of such innate immune cells, form a front-line component of our bodies’ defense. The term "macrophage" is derived from a combination of two Greek words - "macro," meaning big, and "phage," meaning eater. As the early combatants of our immune system, they are armored with perfectly-tuned ingestion capabilities. Macrophages function like the policemen of our body because they are charged with patrolling nearly all of our body’s tissues, except the heart. They are intensely positioned in tissues where infections are likely to arise, such as the gut and lungs.  

There are approximately 200 cell types in our splendid body. Each specialized type of cell is charged to operate like a government or an army. Macrophages are organized to be combative and to secure the body. They possess flawless intelligence, coordination, communication, and movement traits. They are created from differentiating monocytes. Monocytes are produced in the bone marrow and then released into blood circulation. In case of an infection or dangerous threat, they migrate into tissues as early combatants.
To collect intelligence, macrophages are equipped with a large repertoire of sensors or receptors, which are positioned in the cellular membrane and intracellular part of the cellular architecture. These receptors are called pattern recognition receptors (PRRs), whose function is to detect certain structural patterns of pathogens such as bacteria, viruses, parasites, and fungi. Such specific patterns are named pathogen-associated molecular patterns (PAMPs). On the other hand, molecules generated by host cells under extraordinary stress are called danger-associated molecular patterns (DAMPs) which are detected by other specific PRRs. Additionally, macrophages are ornamented with other types of receptors that help recognize and eat extracellular material, including pathogenic microorganisms by a membrane-bound vesicle. This process is phagocytosis, where the pathogen-containing vesicle is ultimately fused with the degradation machinery of the cell (i.e. lysosomes) to eliminate the pathogen.

Once the intelligence is collected by sensors, macrophages become “activated,” meaning that they are mobilized by transmitting and processing the information into the interior of the cell via – from a biologist’s perspective – downstream signaling pathways that initiate the program in the cell nucleus to secrete “alarm” molecules. Such molecules are named cytokines, whose duty is to adjust immune response by aiding cell-to-cell communication and stimulating the movement of macrophages towards the combat zone – in other words, the sites of inflammation.

Metaflammation: a chronic disease caused by obesity

The areas possessing redness, heat, pain, and swelling represent the combat zones of classical inflammation. Such wars are usually short-term and area-specific, with respect to infection and injury; they end with the elimination of the infection and the repair of the damaged tissue, respectively. Unfortunately, chronic inflammation is a different type of prolonged and disorganized immune response. Such a chronic state manifests, a) a low grade increase in immune system markers (inflammation-inducing cytokines); b) a persistent stress response; c) inflammatory effects covering the whole body rather than localized symptoms; and d) a sustained state of the disease. In other words, chronic inflammation corresponds to a lasting state of low-level war all over our body that gradually escalates and leads to various chronic diseases. Interestingly, intense research on the obesity epidemic demonstrated the presence of such low-grade chronic inflammation as the main driver of obesity-associated diseases such as insulin resistance, diabetes, atherosclerosis, pulmonary hypertension, and chronic liver disease. Such an inflammatory state is also termed metabolic inflammation or metaflammation.

The molecular details underlying metaflammation are increasingly better understood. From a scientific standpoint, obesity is characterized by the increased storage of lipid molecules in an expanded fat tissue mass. The macrophages residing in such fat tissues of obese individuals are likely the major source of inflammation-inducing (pro-inflammatory) cytokines, as they seem mobilized mainly due to two reasons. First, the excessive presence of lipid molecules accumulated by overeating are sensed as danger-associated molecular patterns (DAMPs) by various macrophage sensors. Second, macrophages residing in fat tissues have significantly higher level of threat sensors, leading to their easy mobilization. Therefore, the level of such sensors in obese individuals was found to be directly correlated with the severity of obesity-related diseases, such as diabetes and insulin resistance. Moreover, fat tissue macrophage populations are directly associated with the accumulation of fatty tissues in different experimental mouse models. The studies performed in obese and diabetic mice models and patients demonstrated high levels of pro-inflammatory cytokines in blood circulation and fat tissues, contributing to metaflammation.  
To simplify metaflammation, excessive fat buildup is sensed as a threat by the big-eating patrollers of our amazing immune system, leading to their abrupt mobilization and continuous secretion of cytokines as “alarm” molecules. The intensity and locality of cytokines simply determines the state of war (i.e. the category of inflammation). In obese individuals, the low concentration of cytokines in blood circulation and fat tissues represents an ongoing low-level war found all over the body, which is metaflammation. Paradoxically, the degree of the war escalates by the enhanced sensitivity of macrophages to cytokines and the gradual increase of cytokines as a result of additional fat accumulation, hence throwing the body out of order and making it vulnerable to numerous diseases.

Apart from excessive food intake, there are other nutritional, environmental, and behavioral factors that give rise to similar chronic inflammation in our bodies. Things such as processed food, traffic-related air pollution, inactivity, inadequate sleep, and stress, can have similar effects as obesity. To protect our splendid bodies from the harmful effects of chronic inflammation resulting from overeating and other factors, we need to carefully think about our external and internal responsibilities. We may need to make intensive, external lifestyle changes, including restricted energy intake, more exercise/physical activity, and a diet high in healthy, unprocessed foods.
As for the internal responsibilities, the most essential part is strengthening our self-control. By doing so, we may improve our willpower, which is needed to resist the temptation to overeat. Otherwise, disrupting the balance of our wonderful body by overeating is an offense and disrespect to its perfect order. Such an imbalanced state pushes our body further toward a biological cliff, to such an extent that the delicately and perfectly organized immune system declares war against the harmful lipid molecules and leads to the emergence of various inflammation-associated diseases. Therefore, to eliminate the risk of imbalances in our superbly designed bodies, we have many internal and external responsibilities to fulfill.