Obesity-Associated Chronic Inflammation: A Protective Mechanism against Type 2 Diabetes

1.1. Early Observations The link between obesity and inflammation was initially observed in the early 1990s when researchers began to unravel the complex interactions within adipose tissue. One pivotal moment came with the study by Hotamisligil et al., who identified the increased expression of tumor necrosis factor-alpha (TNF-α) by adipocytes in adipose tissues of obese mice and humans; moreover, the increased TNF-α expression was associated with insulin resistance in the obese mice; injection of TNF-α antibody into the mice to neutralize the TNF-α was found to improve the insulin sensitivity [1]. In another early study, infusion of TNF-α into rats was found to reduce insulin sensitivity by induction of hepatic glucose production and inhibition of muscle glucose uptake in rats [2]. These findings set up the foundation for a couple of popular concepts, including obesity-associated inflammation, immunometabolism, and adipose tissue inflammation in systemic insulin resistance. However, another activity of TNF-α has been ignored for a long time. TNF-α was reported to stimulate glucose uptake in the liver, muscle, and many other tissues in the rats [2], which may be responsible for the reduction in insulin-stimulated glucose uptake and insulin-trigged inhibition of hepatic glucose production. In support, TNF-α was found to inhibit the signaling activity of insulin receptors, which provided a molecular mechanism for insulin resistance [3]. Therefore, as an inflammatory cytokine, TNF-α is a representative model for the concept of inflammation in insulin resistance (Figure 1). These early studies, together with many subsequent studies, consistently suggest that TNF-α may serve as a signal of immune cells in the regulation of energy metabolism. Glucose, fatty acids, and amino acids are the major energy substrates that are used to generate ATP and synthesize biomaterials. Immune cells are the most active cells in the secretion of TNF-α, especially macrophages. In the adipose tissue, mouse adipocytes may express TNF-α protein, but human adipocytes do not express TNF-α protein. Later studies found that in obese mice, TNF-α protein came from macrophages instead of adipocytes in the year 2003 [4,5], which has been well-accepted in the field since then (Figure 1). Macrophages are immune cells that play an important role in the organization of immune responses through the cytokine secretion to manage energy supply to the immune cells. TNF-α induces glucose uptake in target cells and, at the same time, inhibits insulin action in the cells, which are examples of cytokine activities in the regulation of energy metabolism. In the traditional view, adipose tissue was considered an inert energy storage depot. Now, adipose tissue is generally accepted as an active endocrine organ for its secretion of adipokines, such as leptin, adiponectin, etc. [6]. The finding that TNF-α levels were elevated in adipose tissue of obese individuals and correlated with insulin resistance provided the first direct evidence linking obesity-associated inflammation to metabolic disorders, which is the basis of the concept of immunometabolism. In this subfield of immunology, energy metabolism in immune cells and its impact on other types of cells have been the focus [7]. TNF-α from macrophages regulates energy metabolism in immune cells as well as in non-immune cells, including hepatocytes and muscle cells [3]. These effects of TNF-α were observed in vivo with TNF-α infusion and in vitro with TNF-α treatment at concentrations above nM, as reported by many groups, including us [8,9]. However, TNF-α concentration only reaches this level locally in the fat tissue under obesity. This may explain why TNF-α antibody treatment could not improve insulin sensitivity in obese patients. In obese patients, TNF-α concentration cannot reach the level in the circulation, which may explain why the anti-TNF therapy could not improve insulin sensitivity in T2DM patients. In addition to TNF-α, other pro-inflammatory cytokines are elevated in obesity. Elevations in other pro-inflammatory cytokines are extensively reported, such as interleukin-6 (IL-6), IL-1β, and C-reactive protein (CRP) in the circulation of obese individuals [10]. These markers of inflammation were persistently higher in the blood of obese patients compared to lean counterparts, suggesting a chronic and systemic low-grade inflammatory state associated with excess body fat. The association of these inflammatory mediators and metabolic disorders sparked interest in exploring the causes and impact of inflammation on human health. 1.2. Key Concepts Systemic low-grade inflammation in obesity represents a mild and chronic inflammatory state, which is commonly characterized by elevated blood levels of C– reactive protein ranging approximately from 2–10 mg/L [11]. Distinct from acute inflammation, it entails a subtle yet persistent activation of the immune system with a strong elevation of pro-inflammatory cytokines. Despite often being symptomless, chronic inflammation can play a significant role in the development and progression of various diseases and aging, such as autoimmune diseases, cancers, and cardiovascular diseases. Adipose tissue inflammation represents a part of systemic low-grade inflammation. The initiation of adipose inflammation is related to several factors, including local hypoxia response from adipose tissue expansion [12,13], an imbalanced extracellular matrix and fibrosis [14], as well as the overloading of cells by intermediate metabolites that disrupts cellular homeostasis [15]. This type of inflammation is marked by an elevation in M1-like macrophage phenotype, more production of reactive oxygen species, endoplasmic reticulum stress, endothelial dysfunction, cell death, and senescence. The adipose inflammation is induced to repair the stress-induced damages from tissue expansion in favor of maintenance of tissue homeostasis. It may contribute to the systemic low-grade inflammation in obesity. The inflammation was considered a target in the treatment of type 2 diabetes, but the possibility has been challenged by the results of most clinical trials in the past 30 years [16]. The resolution of inflammation is an actively regulated physiological process that commences at the peak of inflammation [17]. Its purpose is to re-establish homoeostasis and clear cellular debris. The effectors of this resolution are specialized pro-resolving mediators synthesized through transcellular processes by immune, epithelial, and endothelial cells. The NLRP3 inflammasome is a multiprotein complex that participates in the innate immune response through inflammation. It consists of three main components: NLRP3 (NOD-, LRR- and pyrin domain- containing 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase 1. The NLRP3 sensor can detect signals of endogenous danger-associated molecular patterns (DAMPs) released during cellular stress and tissue damage, as well as signals of pathogen-associated molecular patterns (PAMPs) released during infection. The ASC adapter protein connects NLRP3 to pro-caspase 1, facilitating the cleavage of the inactive enzyme into active caspase 1. Subsequently, active caspase 1 activates cytokine precursors such as IL-1β and IL-18. In this way, the NLRP3 inflammasome initiates a cascade of inflammatory responses, leading to the production and release of pro-inflammatory cytokines, recruitment of immune cells, and amplification of the inflammatory process. The pathway was considered to contribute to obesity-associated chronic inflammation through bacteria-derived endotoxin from gut microbiota. While blood levels of IL-1β and IL-18 in obese patients do not support the possibility. 1.3. Subsequent Key Findings Building on the early observations, subsequent research has been conducted to understand the impact of inflammation in T2DM patients. Those subsequent studies led to several key findings that have reshaped our understanding of the metabolic effects of obesity-induced inflammation. In this line, TNF-α was a dominant model and extensively investigated in both animals and humans as being reviewed [18]. In the clinical studies, Bernstein et al. reported that anti-TNF drugs like Etanercept were effective in improving inflammation parameters in T2DM patients, but the drug could not improve insulin sensitivity [19]. For IL-1, Larsen et al., demonstrated that IL-1 receptor antagonist (IL-1Ra) was able to improve glycemic control in T2DM patients but could not improve insulin sensitivity [20]. In the CANTOS trial, IL-1β inhibition with Canakinumab for 3.5 years did not reduce the incidence of new-onset T2DM [21]. These clinical studies challenged the expectations derived from the classical inflammation concept. Meta-analysis of numerous studies leads to a conclusion that inhibition of IL-1β activity by the receptor antagonist reduced HbA1c effectively in T2DM patients with shorter duration but not in patients with longer duration (>3 years) [22]. However, the therapeutic effect was not a result of the improvement of insulin sensitivity. Those anti-inflammatory studies consistently suggest that inhibition of TNF-α or IL-1β could not improve insulin sensitivity in the treatment of T2DM patients. IL-1 secretion is increased in macrophages by activation of NLRP3 inflammasome. Colchicine is considered a safe and affordable NLRP3 inflammasome inhibitor [23]. Its main activity involves disrupting microtubule dynamics inhibiting immune cell recruitment/division [24]. Colchicine also blocks oligomerization of NLRP3 inflammasome and prevents active IL-1β processing/release. Colchicine decreased cardiovascular event risk (cardiovascular-related death, myocardial infarction, stroke, and urgent coronary revascularizations) in a study [23], but there is no evidence for its activity in the prevention of T2DM by reducing the disease incidence. In addition to these clinical trials, laboratory research has elucidated the cellular and molecular mechanisms of obesity-related inflammation. It was demonstrated that induction of chronic inflammation in adipose tissue by NF-κB p65 overexpression could enhance energy expenditure, uncoupling inflammation from insulin resistance, offering new insights into the relationship between inflammation and metabolism [25]. A later study of the effect of NF-κB inhibition in adipocytes by Sherer’s group suggests that NF-κB inhibition led to adipocyte dysfunction in lipid storage and made the transgenic mice more susceptible to insulin resistance [26]. Consistently, Zhu et al. reported that suppressing adipocyte inflammation using adenoviral protein RIDα/β paradoxically led to insulin resistance, further highlighting the beneficial effect of inflammatory response in the adipose tissues [27]. In a review article, adipose tissue inflammation in obesity is proposed as a protective mechanism in the maintenance of energy balance [10]. Recently, type 2 diabetes has been considered a “sacrifice program” that handles energy surplus through adaptive mechanisms, including insulin resistance and inflammation [28]. Inflammatory cytokines are able to induce mobilization of energy like triglycerides and glycogens. The cytokines promote lipolysis of triglycerides in adipocytes to release free fatty acids and glycerol into the blood. They may induce hydrolysis of glycogen in liver and muscle cells to induce cell consumption of glucose. At the same time, the cytokines may promote energy expenditure to reduce energy surplus in obesity. When the cytokine level is returned to normal after inflammation, the cells should exhibit a higher insulin sensitivity due to the reduction in energy storage. The primary activity of insulin is to stimulate energy storage in the form of glycogen and triglycerides by consumption of blood glucose, which results in blood glucose reduction as a secondary effect. Energy surplus in cells is an important trigger of insulin resistance in both physiological and pathological conditions [28].