Every morning, I step out, coffee in hand, into my beloved garden. Before long, however, I begin to notice unwelcome guests poking their heads up here and there, having emerged over the past few days. In the end, I cannot bring myself to ignore them. I squat down and start pulling out the weeds with my bare hands. More often than not, I end up bumping into a nearby rose bush, getting a thorn lodged in my finger or suffering a small cut. There is bleeding, redness, swelling, and a stinging pain. Still, it is fine. My body immediately initiates the healing process. An inflammatory response is triggered. Thanks to this, within a few days I recover completely, and just as a freed goldfish returns to the bait as if nothing happened after three seconds, I am able to return once again to my struggle with the weeds.
Inflammation is a vital response for survival. At some point, however, “inflammation” itself began to be perceived as an unwelcome presence, and in severe cases it has almost been demonized. When considered carefully, the reason an inflammatory response—something my body initiates to keep me alive—has acquired such a bad reputation is clearly related to what is known as “chronic inflammation.” As another major topic of the 21st century, let us take a closer look at inflammation.
Let us begin by defining inflammation.
Inflammation is a normal physiological response to injury or infection. It begins when the body secretes various chemical substances that trigger immune responses in order to fight off infection or repair damaged tissue. In principle, once the injury or infection is resolved, the inflammatory process comes to an end. “Chronic inflammation,” on the other hand, is an abnormal immune response in which inflammation does not resolve—or may even begin—in the absence of infection or injury. [1] Over time, chronic inflammation can damage healthy cells, tissues, and organs, and may lead to diseases such as cancer, heart disease, asthma, Alzheimer’s disease, and autoimmune disorders.
Inflammation can be triggered by external factors. Although invisible to the naked eye, pathogens such as viruses, bacteria, and fungi, direct foreign bodies like thorns, as well as chemicals or radiation, can all initiate inflammation. When these enemies invade the body, our immune system mobilizes allied forces—immune cells—to begin an immune response. The human body is always prepared to launch a time-staggered attack through both innate and adaptive immunity. The inflammatory response lies at the core of the immune system and can be regarded as its integrated, comprehensive reaction. Immune cells involved in innate immunity are the first to be deployed in large numbers and take the lead in driving the inflammatory response.
Hemostasis and blood coagulation
Let us imagine a situation in which a finger is lightly cut by a thorn. A small amount of blood appears. This indicates damage to the skin’s epithelial cells and the vascular endothelial cells. Bleeding means that the endothelial lining of blood vessels has been disrupted, and the processes, discussed previously in the articles on hemostasis and blood coagulation, are set in motion. As endothelial cells are damaged, negatively charged surfaces on the inner side of the cell membrane are exposed, activating the human contact system. This leads to the generation of bradykinin, a powerful inflammatory mediator, simultaneously initiating both the inflammatory response and the coagulation cascade.
Background reading for Blood coagulation
Complement system
Meanwhile, a wound on the finger means that the skin barrier has been breached, allowing external bacteria to invade. Soil undoubtedly contains a wide variety of microorganisms, and these pathogens activate the complement system in the bloodstream. When the immune system recognizes unique carbohydrate structures that do not exist in the human body but are characteristic of pathogens, either the alternative pathway or the lectin pathway of the complement system is triggered. Complement proteins are sequentially cleaved and activated. Among the resulting fragments, the potent inflammatory mediators C3a and C5a initiate inflammatory activity. The C3b fragments, like breadcrumbs clinging to a breaded cutlet, densely coat the pathogen, causing opsonization and enabling macrophages to engulf and eliminate it more efficiently. The remaining fragments assemble to form the membrane attack complex (MAC), which punctures holes in the pathogen’s cell membrane and can ultimately lyse the invading organism.
Backround reading for Complemet system
Pattern Recognition: TLR
Immune cells such as dendritic cells and macrophages identify and recognize the molecular structures of pathogens attached to the thorn or substances released from damaged skin tissue. They do so through receptors capable of recognizing specific patterns, known as pattern recognition receptors (PRRs). These receptors detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). PAMPs are molecular structures that never exist in the human body and are uniquely found in pathogens, allowing the immune system to distinguish invaders. For example, lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, which possess a double membrane to protect themselves from antibiotics and bile acids, serves as a clear smoking gun indicating bacterial infection. DAMPs, in contrast, are molecules released by damaged, stressed, or dying cells and function as danger signals that alert surrounding tissues to potential harm.
Release of cytokines, chemokines, and histamines
Once these molecular patterns are recognized, nearby immune cells are immediately alerted to their presence. When immune cells are presented with molecular fragments from the invading thorn as evidence, they begin secreting various cytokines and chemokines, summoning reinforcements and enabling large numbers of immune soldiers(white blood cells) to rapidly mobilize to the site. Pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 orchestrate this process from the front lines. Neutrophils are among the very first responders. One defining characteristic of neutrophils is their sheer abundance. Cytokines facilitate the convergence of large numbers of neutrophils to the injured site by increasing blood flow and vascular permeability, making it easier for these soldiers to exit the bloodstream and reach the wound. Chemokines, acting as chemical guidance signals, are also released to ensure that the immune cells do not wander aimlessly but arrive precisely at the battlefield. Mast cells further amplify this process by releasing histamine. This entire cascade of events is what we commonly refer to as the inflammatory response.
Lipid Mediators (Eicosanoids)
Vascular endothelial cells do not remain idle either. In situations like this, they release arachidonic acid from their cell membranes and use it to produce and secrete important lipid-derived bioactive mediators known as eicosanoids. Among the various eicosanoids, prostaglandins cause vasodilation, while leukotrienes act as potent chemotactic factors that attract white blood cell soldiers to the site. Thromboxane A₂, on the other hand, promotes blood coagulation. Another class of eicosanoids, lipoxins, later plays a role in bringing the inflammatory process to an end. Although all of these mediators are derived from arachidonic acid, they are generated dynamically through different pathways depending on the tissue involved and the specific circumstances.
Among immune cells, the soldier that arrives first and in the greatest numbers on the battlefield is the neutrophil. The inflammatory responses described above are, in essence, strategies designed to mobilize massive numbers of neutrophils from the bloodstream to the site of injury. To kill bacteria, neutrophils release toxic enzymes and reactive oxygen species (ROS), engulf and digest pathogens through phagocytosis, and then secrete inflammatory cytokines to amplify the inflammatory response and recruit even more immune reinforcements. After their short lives, neutrophils that have fought valiantly against pathogens leave behind pus—evidence of their sacrifice and the time they bought for the host. As the inflammatory process enters its resolution phase, the cytokines that had led and commanded the inflammatory front begin to retreat, while cytokines that suppress and organize inflammation take center stage. After several days, the swelling of the finger subsides and the pain diminishes. Healing has begun. At this stage, bioactive lipids secreted by endothelial cells, such as the aforementioned lipoxins and resolvins, become particularly prominent. It is worth remembering that these molecules are generated through pathways similar to those that produce prostaglandins. Anti-inflammatory cytokines such as IL-10 and TGF-β are now secreted, actively suppressing and clearing the inflammation. Further neutrophil infiltration is blocked, and macrophages thoroughly clean up the battlefield.
After several days of sustained immune activity, the wound gradually heals. As the rampage of pathogens is brought under control, various growth factors involved in tissue repair are mobilized to regenerate the skin. These include factors that promote angiogenesis, stimulate collagen synthesis, and drive epithelial cell proliferation. Collagen and extracellular matrix components are synthesized at the site of injury to form a scaffold for new tissue, allowing epithelial cells and vascular cells to proliferate normally and restore the skin surface. To support this process, angiogenic factors generate new capillaries that supply oxygen and nutrients. In this way, inflammation is an immune response that eliminates pathogens and supports the healing and regeneration of damaged cells and tissues.
Because cytokines, chemokines, bradykinin, and lipid mediators such as prostaglandins, leukotrienes, thromboxanes, and lipoxins are secreted in diverse combinations and play commanding roles throughout the inflammatory process, they are collectively referred to as inflammation mediators.
Naive T Cells: CD4⁺ and CD8⁺ Cells
If immunity is broadly divided into innate immunity and adaptive (acquired) immunity, then the immune responses examined so far represent innate immune responses that occur immediately following injury. Initially, dendritic cells or macrophages recognize bacteria or damage-associated molecules released from injured cells via their Toll-like receptors (TLRs), secrete inflammatory cytokines, and initiate inflammation. With the help of circulating white blood cells such as neutrophils, the wound may heal successfully and inflammation may resolve at this stage. However, if bacterial invasion is severe or infection persists and inflammation continues, the heightened “danger signals” necessitate the activation of adaptive immunity in addition to innate immunity. The principal players in adaptive immunity are T cells and B cells.
Dendritic cells or macrophages that have engulfed pathogens near the wound collect antigen samples and transport them to lymph nodes, where a small elite group of T cells—having survived a rigorous and demanding training process—stand by. These T cells have never encountered antigens before and therefore still bear provisional labels such as CD4⁺ or CD8⁺, earning them the name “naive” T cells. Dendritic cells or macrophages present the antigen samples to these naive T cells, which is why they are literally called antigen-presenting cells(APC). However, antigen recognition alone is insufficient. T-cell differentiation can only begin when the T cell simultaneously binds to co-stimulatory molecules expressed by the APC. This serves as yet another safety mechanism to prevent indiscriminate T-cell activation.
T-Cell Differentiation
Once both the antigen and the co-stimulatory signals presented by the APC are engaged, CD4⁺ and CD8⁺ cells are finally ready to be activated as true T cells. CD8⁺ cells are destined to become powerful, precise offensive weapons that fight directly on the front lines, whereas CD4⁺ cells are fated to differentiate into commanders or generals of the immune war. Accordingly, CD8⁺ cells become cytotoxic T lymphocytes (CTLs), while CD4⁺ cells become helper T cells, and each follows a distinct path. CTLs are formidable killer immune cells that accurately recognize virus-infected cells or cancer cells and destroy them by perforating their cell membranes or inducing programmed cell death. In contrast, helper T cells do not directly attack infected cells but instead orchestrate and direct immune responses through the secretion of various cytokines. Helper T cells further differentiate into multiple subtypes, including Th1, Th2, Th17, and regulatory T cells (Treg).
What determines which subtype naive T cells will become? One major factor is the nature of the pathogen recognized by APCs, including its size, type, and biological characteristics. Although the process is highly complex, it can be simplified by considering a few representative scenarios. If the APC recognizes intracellular bacteria such as bacteria (tuberculosis) or viruses, it secretes cytokines like IL-12 and IFN-γ, driving CD4⁺ cells to differentiate into Th1 cells. Th1 cells then activate macrophages to eliminate intracellular bacteria or, if the infection is too severe for macrophages to handle, induce infected cells to undergo apoptosis. If the APC recognizes a large parasite such as a roundworm, it secretes IL-4 and strongly promotes differentiation into Th2 cells. Th2 cells mobilize eosinophils, basophils, mast cells, and B cells to carry out immune responses. Because these pathogens are enormous, a single immune cell is insufficient, and immune responses often occur in a massive, flood-like manner. Incidentally, mast cells bound to antibodies release histamine, increase mucus secretion, and induce hypersensitive reactions such as sneezing, driven by strong contractions of smooth muscle. These appear to be instinctive efforts to expel pathogens from the body.
Meanwhile, the differentiation of T cells into regulatory T cells (Treg), which act as brakes to prevent excessive inflammation, is promoted by the cytokine TGF-β. This topic was discussed previously in the article on oligosaccharides in the carbohydrate series. As you may recall, short-chain fatty acids produced by gut microbiota through the breakdown of oligosaccharides increase the expression of the transcription factor FOXP3. This transcription factor drives T cells to differentiate into Treg cells, which suppress excessive immune responses and help maintain immune balance. Although the relationship between FOXP3 and Treg cells was proposed more than 20 years ago, it has since been medically validated over decades, culminating in the awarding of the Nobel Prize in Physiology or Medicine in 2025.
It is well known that CTLs, which directly kill infected or cancerous cells, can also attack and destroy normal tissues when inflammation persists chronically. After being produced in the bone marrow, naive T cells migrate to the thymus, where they undergo two rounds of rigorous testing to determine whether they can clearly distinguish self from non-self. Cells that fail these tests are mercilessly eliminated through apoptosis, and only a small number of safe T cells that pass are allowed to migrate to lymph nodes and remain on standby. Through this process, the human body establishes so-called immune tolerance, ensuring that immune cells do not attack the body’s own tissues. Nevertheless, some T cells may still escape this tight surveillance, or regulatory T cells may fail to properly suppress them even when self-antigens are recognized. Furthermore, if antigens persist or repeatedly reappear, CTLs may repeatedly attack them, leading to tissue destruction, fibrosis, or loss of target specificity, ultimately damaging normal tissues. Autoimmune diseases, in which the immune system recognizes components of the body as antigens and attacks them, are truly devastating. Examples include type 1 diabetes, in which pancreatic β cells are destroyed as self-antigens, eliminating insulin secretion; multiple sclerosis, in which myelin—the fatty insulating material surrounding axons—is mistakenly targeted and destroyed; and rheumatoid arthritis, which damages cartilage and bone within joints. Repeated secretion of inflammatory cytokines leads to tissue damage, which in turn exposes more self-antigens, creating a vicious cycle of ongoing inflammation. Although many theories exist to explain autoimmune diseases, no single definitive cause has been identified. What is clear, however, is that long-standing chronic inflammation is closely associated with autoimmune disease, and autoimmune disorders are often regarded as one form of chronic inflammatory disease.
Finally, although not discussed here in detail, B cells also produce antibodies specific to the antigens presented by APCs. This ensures that if the same antigen invades again in the future, the immune system can rapidly produce the appropriate antibodies and mount a swift attack. Exposure to a wide variety of antigens from early life thus serves as immune training, resulting in a diverse antibody repertoire. I hope to have an opportunity to address antibodies and B cells in a separate article.
Are Cytokines Exclusive to Immune Cells?
We have briefly reviewed the roles of immune cells. Within the immune system that protects our bodies, cytokines can be regarded as a means of communication that enables smooth signal transmission among immune cells. However, even cytokines—key components of our defense mechanisms—can become a double-edged sword and harm the body when secreted in excessive amounts for any reason. These small signaling proteins are not produced solely by immune cells such as T cells, B cells, macrophages, neutrophils, mast cells, and dendritic cells. Endothelial cells lining blood vessels, fibroblasts, muscle cells, and skin cells also secrete cytokines when needed to defend the body and expel harmful threats. There is, however, one rather unexpected tissue that produces cytokines: adipose tissue. In particular, inflammatory cytokines secreted by adipose tissue in a state of chronic obesity—not normal adipose tissue—can lead to pathological consequences. Having taken a broad overview of inflammation, we can now begin to examine the central theme of this article: the relationship between inflammation and fat.
Fat: A Survival Strategy
The white polar bear roaming between glaciers, leisurely swimming through icy waters despite the harsh climate, is wrapped in a thick layer of fat known as blubber. By consuming enormous amounts of food during the relatively abundant summer months and converting it into stored fat, the bear prepares for the food-scarce winter. Moreover, this fat layer functions as insulation, preventing body heat from escaping and maintaining core temperature—an excellent two-for-one survival strategy. Modern humans, who have evolved far beyond their hunter-gatherer ancestors and no longer worry about prolonged periods of food scarcity, have little reason to accumulate fat for the same purposes, nor do they require bodies like those of polar bears. That said, it is entirely natural that newborns, who have spent a long time in the warm, stable environment of the womb at 37°C and are suddenly thrust into an external world of around 20°C, possess brown fat tissue throughout their bodies to regulate body temperature. This brown fat, rich in mitochondria and therefore brown in color, has a unique mechanism that converts energy directly into heat. For our ancestors, who lived with chronic food shortages and faced famine whenever natural disasters struck, adipose tissue must have been crucial for survival. However, beyond its well-known roles in efficient energy storage and thermoregulation—functions directly tied to survival—adipose tissue actually performs far more diverse activities than is commonly appreciated and secretes a wide range of biologically active substances to do so.
Adipocytes as Endocrine Organs
When we think of fat cells, we tend to picture sites of fat storage or soft, cushioned abdominal fat packed with visceral fat. Yet the role of adipocytes extends far beyond simply storing fat. Much like endocrine organs, adipocytes secrete a wide variety of substances, including hormones and cytokines, and play a central role in regulating energy balance and insulin sensitivity. As with most things, excess leads to problems. If obesity persists over a long period, a warning signal is triggered, and the normal, beneficial functions of adipose tissue begin to break down.
Adipose Remodeling: The Adipose Tissue Expandability Hypothesis and the Spillover Hypothesis
Obesity refers to a state of excessive fat accumulation. However, fat does not accumulate overnight, nor does obesity develop suddenly in a single day. When there is an imbalance between energy intake and energy expenditure—resulting in excess energy that must be stored—the surplus fat is first deposited as subcutaneous fat beneath the skin, which accounts for the largest storage capacity. When additional storage space is required, pre-adipocytes differentiate into mature adipocytes, allowing for further fat storage. In a metabolically healthy state, excess fat can be accommodated by both increasing the number of adipocytes (hyperplasia) and enlarging existing adipocytes (hypertrophy). This concept is explained by the adipose tissue expandability hypothesis. The problem is that even this healthy and normal expansion has its limits. Once the storage capacity of adipose tissue is exceeded, fat begins to seek alternative storage sites and accumulates in visceral tissues. Fat deposition in tissues that are not designed for fat storage—such as the liver, skeletal muscle, heart, and pancreas—is referred to as ectopic fat. The spillover hypothesis describes the idea that when all appropriate fat storage sites are saturated, excess lipids overflow and accumulate ectopically in abnormal tissues. Both hypotheses converge on the same conclusion: unhealthy fat accumulation begins once adipose tissue exceeds its capacity to safely store fat. Commonly, fat accumulation within subcutaneous tissue is considered relatively “healthy obesity,” whereas fat that spills over into visceral and ectopic depots is referred to as inflammatory obesity. Just as obesity does not develop overnight, it is a slow and prolonged process. Chronic obesity is closely linked to chronic disease. Unlike acute inflammatory responses to foreign bodies or pathogens lodged in a finger—which are immediate, resolve within a defined period, and then terminate—chronic inflammation persists at a very low level but for an exceptionally long time. It is akin to a light drizzle that eventually soaks one’s clothes completely. We must closely examine the uneasy relationship between obesity and chronic inflammation, and clarify how obesity-related inflammation connects to chronic and metabolic diseases.
Adipokines: Substances Secreted by Adipocytes
It is difficult to label substances secreted by adipocytes as inherently harmful or beneficial. Just as a knife cannot be morally judged in isolation—the outcome depends on who holds it and where it's used—the substances secreted by fat cells can produce vastly different results depending on context. Adipocytes may faithfully carry out their assigned role of cellular defense, yet unintentionally cause adverse outcomes under altered conditions. Before exploring the background factors that lead to such outcomes in chronic obesity, let us first examine the substances secreted by adipocytes. Fat cells can be more formally referred to as adipocytes, a term derived from the Latin word adipis meaning fat, combined with “-cyte,” meaning cell. All substances secreted by adipocytes that stimulate or regulate physiological processes are collectively referred to as adipokines. Let us begin with two key hormones that are almost exclusively secreted by adipocytes: leptin and adiponectin.
Leptin
From both a logical and a humane perspective, it is fortunate that adipocytes secrete the hormone leptin. It is particularly intriguing that leptin is produced exclusively by fat cells. Perhaps this reflects a finely tuned cellular strategy to prevent excessive fat accumulation. When leptin signals to the hypothalamus in the brain, “I’ve had enough.”, we experience satiety and stop eating. The more we eat—and the more obese we become—the more leptin is secreted. After meals, rising blood glucose levels stimulate insulin secretion from the pancreas, and insulin likewise sends a satiety signal to the hypothalamus while also increasing leptin secretion. Under normal conditions, both hormones function properly. The problem arises when obesity persists for a long time and both leptin and insulin are chronically overproduced. In this state, the brain becomes unable to interpret these signals. No matter how insistently leptin signals that eating should stop and fat storage should cease, the brain becomes unresponsive, leading to what is known as leptin resistance. Unaware of this malfunction, the brain continues to drive fat accumulation in an effort to store more energy, creating a vicious cycle. In this scenario, insulin sensitivity also declines, further exacerbating leptin resistance. It becomes a compounded and chaotic situation.
Adiponectin
Adiponectin is a protein hormone secreted by adipose tissue, particularly subcutaneous fat, and is highly abundant in the bloodstream. It is remarkably beneficial to the body, exerting positive effects on metabolism and inflammation. Adiponectin suppresses inflammatory cytokines such as TNF-α and IL-6 while inducing anti-inflammatory cytokines like IL-10, thereby inhibiting inflammation. It reduces glucose production in the liver, suppresses fat accumulation, and promotes fatty acid oxidation (β-oxidation, the use of fat as energy) in skeletal muscle. Meta-analyses integrating multiple prior studies have shown that adiponectin improves insulin sensitivity, suggesting its potential as an effective therapeutic target for various metabolic disorders associated with insulin resistance.[2] However, paradoxically, although adiponectin is synthesized by adipocytes, its levels decrease as body fat mass increases, adipocyte size enlarges, and obesity worsens. This occurs because inflammatory cytokines secreted in greater amounts by obese adipose tissue—particularly TNF-α—suppress adiponectin expression, leading to reduced secretion. For this reason, adiponectin levels are often used as a useful biomarker. Low adiponectin levels indicate inflamed and metabolically unhealthy adipose tissue and are considered suggestive of increased risk for metabolic syndrome, diabetes, fatty liver disease, and cardiovascular disease.
Pro-Inflammatory Cytokines
Adipocytes secrete not only anti-inflammatory hormones such as adiponectin but also a variety of pro-inflammatory cytokines, including TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1). In obese states, inflammatory cytokines secreted by adipocytes stimulate the production of additional inflammatory cytokines both within the same cells and in neighboring tissues, amplifying and intensifying inflammation. Let us examine the mechanisms underlying this amplification.
Hypoxia and Hypoxia-Inducible Factors
As obesity becomes more severe, adipocytes undergo hypertrophy, enlarging to store increasing amounts of excess fat. Imagine balloon-like adipocytes swelling and becoming tightly packed, pressing against one another with little space in between. As discussed in earlier articles on carbohydrates, the extracellular matrix (ECM) supports cells from the outside. In hypertrophic adipose tissue, however, the rapid enlargement of adipocytes leads to a relative deficiency of surrounding ECM, compromising structural support and nutrient delivery. Capillaries running between adipocytes may also become compressed, impairing oxygen and nutrient supply and subjecting adipocytes to severe hypoxic stress. Under such conditions, cells are prone to necrosis. To survive oxygen deprivation, adipocytes express a transcription factor known as hypoxia-inducible factor-1α (HIF-1α). This factor represents an intelligent survival strategy: it promotes angiogenesis to increase oxygen supply and enhances glucose uptake and anaerobic glycolysis to sustain energy production. The problem, however, is that hypoxia also signals cellular damage, triggering the recruitment of inflammatory immune cells. As a result, the pro-inflammatory cytokine TNF-α is secreted, and large numbers of macrophages infiltrate the tissue to clear necrotic cells. Inflammation within adipose tissue begins to intensify.
Moreover, angiogenesis driven by HIF-1α requires tissue remodeling to create space for new blood vessels. During this process, matrix metalloproteinases (MMPs), which degrade ECM proteins, are produced in large quantities to break down and reorganize existing extracellular matrix. Inevitably, this degradation releases fragments of hyaluronic acid and collagen. These fragments act as damage-associated molecular patterns (DAMPs). When they bind to receptors on immune cells and are recognized as danger signals, they activate the nuclear factor kappa B (NF-κB) signaling pathway. This activation leads to the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
Macrophages
At this point, let us pause briefly to examine macrophages in greater detail. Macrophages are originally generated in the bone marrow and circulate throughout the body in the form of monocytes. When needed, they differentiate into macrophages and are deployed for immune defense. However, some macrophages abandon this free-roaming lifestyle altogether and instead settle permanently in specific tissues, taking up long-term residence much like long-standing inhabitants. These resident macrophages often have specialized names depending on their tissue of residence. Examples include microglia in the central nervous system, Kupffer cells in the liver, alveolar macrophages in the lungs, and Langerhans cells in the skin. All of these are tissue-resident macrophages.
Functional Phenotypes of Macrophages: M1 vs. M2
More important than classification by anatomical location is the functional phenotype of macrophages. Macrophages exhibit two primary phenotypes: the pro-inflammatory M1 type and the anti-inflammatory M2 type. Polarization toward either phenotype depends on the surrounding environment and the cytokines that stimulate the cells; this polarization is not fixed and can shift flexibly in response to changing conditions. During the early phase of infection, M1 macrophages predominate, whereas during the later phase of tissue repair and wound healing, macrophages transition toward the M2 phenotype. The macrophages that appear during the resolution phase of inflammation—such as when a finger wound heals—are representative of this M2 type.
Anti-inflammatory adiponectin also promotes macrophage polarization toward the M2 phenotype, as do cytokines such as IL-4, IL-10, and IL-13. In contrast, cytokines such as interferon-γ (IFN-γ), produced in response to antigen recognition, drive macrophages toward the M1 phenotype. Activation of the NF-κB signaling pathway likewise promotes polarization toward the inflammatory M1 state.
Adipose Tissue Macrophages (ATMs)
Macrophages residing within adipose tissue—referred to as adipose tissue macrophages (ATMs)—deserve particular attention. In lean, metabolically healthy individuals, macrophages comprise only about 10% of the cellular population within adipose tissue. In contrast, in obese individuals, this proportion can increase dramatically, reaching as high as 50%. [3] Under normal conditions, ATMs tend to exhibit an anti-inflammatory, M2-like phenotype. However, in the obese environment, inflammatory cytokines recruit additional macrophages into adipose tissue and drive them toward the M1 phenotype. At the same time, macrophages that were already resident in the tissue may also undergo phenotypic switching. As a result, the overall macrophage population within obese adipose tissue becomes dominated by the pro-inflammatory M1 phenotype. Hypertrophied adipocytes that rupture or undergo necrosis attract macrophages tasked with clearing cellular debris, and these macrophages are activated toward the M1 phenotype. Furthermore, stressed adipocytes secrete chemokines such as monocyte chemoattractant protein-1 (MCP-1), which recruit circulating monocytes from the bloodstream into adipose tissue. Upon entry, these monocytes are exposed to the inflammatory environment and differentiate into M1 macrophages. Hypoxia-inducible factor-1α (HIF-1α) is also known to promote differentiation toward the M1 phenotype. These inflammatory macrophages secrete a range of pro-inflammatory mediators, including IL-6, TNF-α, IL-1β, MCP-1, and plasminogen activator inhibitor-1 (PAI-1). These inflammatory signals, in turn, recruit even more macrophages, creating a self-perpetuating vicious cycle in which the M1 inflammatory state is continuously reinforced. Histological examination of obese adipose tissue reveals macrophages encircling enlarged, necrotic adipocytes in a crown-like arrangement. This structure is referred to as a crown-like structure (CLS) and serves as a representative marker of chronic inflammation within adipose tissue. The effects of M1 macrophages on insulin resistance will be discussed in detail later.
Returning now to inflammatory mediators secreted by adipocytes themselves, the cytokines most worth remembering in the context of inflammation are TNF-α (tumor necrosis factor-alpha), IL-6, and IL-1β. All of these cytokines are produced by adipocytes.
Mitochondrial Stress and Endoplasmic Reticulum (ER) Stress
To be honest, when I picture adipocytes, I tend to imagine cells almost entirely filled with lipid droplets, with the nucleus flattened and pushed to one side. In doing so, I often forget that adipocytes, like all other cells, contain mitochondria, endoplasmic reticulum (ER), Golgi apparatus, and other organelles although we have just discussed the many substances these cells actively secrete. Indeed, the vast majority of cytoplasmic space in adipocytes is occupied by lipids, forcing other organelles into a cramped corner, almost like tenants living in a tiny rented room.
The problem arises when obesity develops. Under obese conditions, these organelles are subjected to stress, which in turn promotes inflammation. Mitochondria tirelessly generate energy from glucose and fatty acids, but when fatty acid supply becomes excessive, mitochondria enter a state of overload. During oxidative phosphorylation, electrons are transferred through the electron transport chain and ultimately passed to oxygen. Protons accumulate across the inner mitochondrial membrane, creating a steep electrochemical gradient that drives ATP synthesis as protons flow back into the matrix. Because reactive oxygen species (ROS) are inevitably generated as byproducts of this process, cells are already equipped with antioxidant networks to neutralize them.
Under normal circumstances, ROS production is well controlled and poses no problem. However, when mitochondria are chronically overloaded, antioxidant defenses become depleted or insufficient, and mitochondria enter a state of oxidative stress. Mitochondria-derived ROS negatively affect the ER, which is responsible for proper protein folding and maturation. When proteins fail to fold correctly, the ER activates stress responses, which may include the induction of apoptosis. This process further fuels inflammation.
When mitochondrial overload occurs, free fatty acids (FFAs) cannot be fully oxidized, leading to the accumulation of partially oxidized lipid intermediates such as diacylglycerol (DAG) and ceramides. These lipid intermediates are not inert waste products; rather, they function as toxic signaling molecules that disrupt cellular homeostasis. DAG, in particular, excessively activates protein kinase C (PKC), which in turn activates NADPH oxidase. NADPH oxidase is a key enzyme in the respiratory burst used by macrophages to kill pathogens, producing potent ROS such as superoxide anions (O₂⁻). Thus, a ROS-generating system intended for immune defense becomes aberrantly activated within normal cells due to lipid metabolic dysfunction. Excessive intracellular ROS induces oxidative stress, interferes with insulin signaling, and contributes to chronic inflammation and metabolic disease.
Ceramides: Lipotoxic Metabolites
Ceramides are biologically active lipids that normally serve as components of cell membranes and regulators of cellular growth, differentiation, aging, and apoptosis. In obesity, however, ceramides act as pro-inflammatory, lipotoxic molecules. Considering the bidirectional relationship between obesity and insulin resistance, it is important to remember that insulin resistance increases circulating free fatty acids (FFAs) by impairing their storage in cells. Elevated FFAs, particularly saturated fatty acids such as palmitate, markedly stimulate ceramide biosynthesis.
Ceramides exert toxicity through multiple mechanisms. In adipose tissue, they insert into the outer mitochondrial membrane, compromising membrane integrity and stability. This promotes caspase activation and mitochondrial apoptosis. Ceramides also disrupt electron transport chain complexes, reducing ATP production while increasing ROS generation. Elevated ROS activates inflammatory pathways such as NF-κB and JNK, leading to excessive secretion of inflammatory cytokines. Ceramides further exacerbate insulin resistance and increase the risk of type 2 diabetes.
Ceramides also impair ER function. The ER membrane contains the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), which pumps calcium ions into the ER lumen. Calcium homeostasis is essential for proper protein folding and chaperone activity. Ceramides inhibit SERCA activity, reducing ER calcium stores and inducing ER stress. Persistent ER stress suppresses protein translation, promotes inflammation, and induces expression of pro-apoptotic genes, ultimately worsening tissue damage and inflammation.
Adipose Tissue as a Reservoir for Lipophilic Toxins
Various toxins accumulate in the human body, including components of cigarette smoke, air pollutants, persistent organic pollutants (POPs), heavy metals (such as cadmium, lead, and mercury), and pesticides. These toxins are largely lipophilic and therefore accumulate in adipose tissue. This represents another critical dimension of fat-related risk. Cell membranes consist of lipid bilayers that restrict the entry of water-soluble substances, whereas lipophilic toxins readily cross membranes and accumulate intracellularly. Unlike water-soluble toxins, which can be filtered by the kidneys and excreted in urine, lipophilic toxins persist in circulation and accumulate in vital organs. To mitigate this risk, the body appears to have evolved a protective mechanism by sequestering such toxins in adipose tissue, thereby reducing their concentration in the bloodstream and limiting their harmful effects on other tissues. Notably, these toxins tend to accumulate at higher concentrations in visceral fat compared to subcutaneous fat. [3]
Toxins stored in adipose tissue remain sequestered until fat breakdown occurs through weight loss, dieting, or exercise. The most desirable detoxification strategy is the gradual release of these toxins, allowing hepatic metabolism and excretion. Rapid and excessive fat loss, however, can abruptly release large quantities of toxins into circulation, potentially overwhelming detoxification pathways and causing symptoms such as fatigue, headaches, and nausea.
As discussed previously in the article about sugar acid in carbohydrates series, hepatic detoxification fundamentally involves conjugation reactions—such as the attachment of glucuronic acid (GlcA), a representative sugar acid—to lipophilic compounds, converting them into water-soluble forms that can be excreted via the kidneys or bile. This process requires adequate intake of nutrients including B vitamins, vitamin C, selenium, zinc, copper, magnesium, and sulfur. Therefore, gradual weight loss with sufficient nutritional intake is far wiser than extreme fasting, allowing fat loss while supporting detoxification and overall health.
What Are POPs?
POPs, or persistent organic pollutants, are toxic organic compounds that resist degradation and persist in the environment and in living organisms for decades or even centuries. Because they bioaccumulate, top predators in the food chain—including humans—harbor the highest concentrations. POPs originate from sources such as plastic additives, charcoal grilling and cigarette smoke, dioxins, pesticides, polychlorinated biphenyls (PCBs) found in old electronics and building materials, Per- and Polyfluoroalkyl Substances(PFAS) used in non-stick cookware coatings(teflon), food packaging, and insecticides such as DDT.
Endocrine Disruption: Xenoestrogens
One of the most serious problems posed by environmental toxins is endocrine disruption. Xenoestrogens are estrogen-like compounds that mimic endogenous estrogen, bind to estrogen receptors, and send false signals that interfere with normal hormonal regulation. Prominent examples include bisphenol A (BPA), used in plastics and thermal receipt paper; phthalates, which act as plasticizers; and dioxins, byproducts of waste incineration.
Importantly, POPs do not disrupt estrogen alone. Androgens (such as testosterone), thyroid hormones, insulin, cortisol, and gonadotropins may also be affected. Extensive research is underway to investigate links between these disruptions and the rising incidence of hormone-related cancers (such as breast and prostate cancer), precocious puberty, and infertility.
Beyond accumulating in adipose tissue, these toxins may actively promote obesity. [4] Certain organochlorine pesticides increase fatty acid uptake, BPA has been shown to enhance lipid accumulation, and some toxins cause weight gain and cellular hypertrophy in animal models. Although POP is certainly a fascinating topic to cover with in-depth details, this article limits discussion to highlighting their unfavorable relationship with obesity. Accumulation of these toxins damages mitochondria, increases ROS production, stimulates inflammatory cytokine release, and recruits macrophages into adipose tissue—repeating the inflammatory cycles described earlier. Ultimately, these processes may culminate in insulin resistance and diabetes.
Conclusion
The purpose of this lengthy discussion has been to explain why obesity should be avoided—and why, if obesity is present, it is important to escape from it. To that end, we briefly reviewed fundamental aspects of immunity, examined how adipose tissue contributes to inflammation, and explored how obesity extends beyond inflammation to induce endocrine disruption and even cancer. This is not an argument for eliminating all body fat indiscriminately, nor is it related to appearance-oriented ideals that harm mental health. Rather, it is an appeal to one of life’s most difficult principles: striving for moderation and balance.
[References]
[1] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/inflammation
[2] Meta-Analysis of Adiponectin as a Biomarker for the Detection of Metabolic Syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC6176651/
[3] https://pmc.ncbi.nlm.nih.gov/articles/PMC6101675/
[4] Persistent organic pollutants in adipose tissue should be considered in obesity research
https://doi.org/10.1111/obr.12481
