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Characterization and Treatment of Inflammation and Insulin Resistance in Obese Adipose Tissue
Received 9 July 2020
Accepted for publication 1 September 2020
Published 1 October 2020 Volume 2020:13 Pages 3449—3460
DOI https://doi.org/10.2147/DMSO.S271509
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Ming-Hui Zou
Zhenhua Lu, Yao Li, Jinghai Song
Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
Correspondence: Jinghai Song
Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, People’s Republic of China
Tel +8619800315020
Email [email protected]
Abstract: Adipose tissue is the largest energy storage and protection organ. It is distributed subcutaneously and around the internal organs. It regulates metabolism by storing and releasing fatty acids and secreting adipokines. Excessive nutritional intake results in adipocyte hypertrophy and proliferation, leading to local hypoxia in adipose tissue and changes in the release of adipokines. These lead to recruit of more immune cells into adipose tissue and release of inflammatory signaling factors. Excess free fatty acids and inflammatory factors interfere with intracellular insulin signaling. In this review, we summarize the characteristics of obese adipose tissue and analyze how its inflammation causes insulin resistance. We further discuss the latest clinical research progress on the control of insulin resistance and inflammation resulting from obesity through anti-inflammatory therapy and bariatric surgery. Our review shows that targeted anti-inflammatory therapy is of great significance for obese patients with insulin resistance.
Keywords: obesity, adipose tissue, inflammation, insulin resistance, anti-inflammatory therapy
Introduction
Over the past 40 years, the incidence of overweight and obesity has risen in both developed and developing countries due to unbalanced diets, inadequate physical activity, chronic stress, certain drug intake, and environmental pollutants.1–4 There are over 1.9 billion overweight adults worldwide, and more than 650 million were classified as obese in 2016. The world’s obesity rate has almost tripled since 1975.5,6 Obesity may cause many chronic diseases, including cardiovascular and cerebrovascular diseases, diabetes, and some cancers.7–12 In particular, non-insulin-dependent diabetes (type 2 diabetes) is closely related to obesity.13,14 Obesity is defined as “abnormal or excessive fat accumulation that may impair health” by the World Health Organization.5 Adipose tissue (AT) remodeling occurs during obesity, resulting in hypertrophy, hypoxic necrosis, immune cell infiltration, release of adipokines, and changes in inflammatory signaling.15 All these factors lead to AT dysfunction and chronic sterile inflammation. By discussing the inflammatory changes in obese AT, we will further review the effects of anti-inflammatory treatments and bariatric surgery on insulin resistance.
Adipose Tissue Classification
In humans, multiple types of AT are distributed throughout the body. White AT (WAT) includes subcutaneous AT (SAT) and visceral AT (VAT). Both types have an important role in regulating metabolism.16 During energy supplementation, excess non-esterified fatty acids (NEFA) become esterified into triacylglycerols (TAGs). White adipocytes store TAGs in cytosolic lipid droplets (LDs). During exercise and fasting, TAGs are mobilized by hormones, releasing fatty acids via lipolysis.17 Compared with SAT, VAT is less sensitive to fatty acid synthesis by insulin, but has a higher sensitivity to catecholamines, which promote lipolysis.18 Higher lipolysis in VAT can lead to metabolic complications related to visceral obesity. Klein et al found that omental AT removal can significantly reduce insulin resistance, but subcutaneous liposuction has no such effect.19 Hocking et al found that SAT transplantation can improve insulin sensitivity in mice, especially when transplanting them into VAT.20 In obesity, these regulatory functions are impaired, mainly due to the decrease in esterification and the increase of lipolysis.
Brown AT may be present in the clavicle, perirenal, paravertebral, and other parts of the human body.21 It is characterized by more lipid droplets and mitochondria, giving it a brown appearance.22 Muscle cells and brown adipocytes are derived from Myf5+ cells and they uniquely express uncoupling protein 1 (UCP-1) which can regulate the conversion of energy to heat by uncoupling ATP in mitochondrial respiration.23 Brown adipocytes maintain body temperature through non-shivering heat production. They are abundant in human neonates, gradually decreasing in adults, and decreasing further in obese people.21 Specialized white adipocytes called beige adipocytes have the shape and high metabolic activity of brown fat cells.24 Because of their high metabolic functions, increasing the number of beige or brown adipocytes may be an effective strategy to reduce obesity and insulin resistance. More characteristics of different adipose tissues and adipocytes are summarized in Table 1.
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Table 1 The Characteristics of Different Adipose Tissues |
Immune Cells in Obese Adipose Tissue Inflammation
Adipocytes account for about 90% of human AT by volume. However, in terms of cell diversity, approximately 4 million other types of cells exist in one gram of AT compared to 1–2 million adipocytes per gram.18 Other cells include various immune cells, endothelial cells, pre-adipocytes, and pericytes. Immune cells are roughly divided into lymphocytes and bone marrow cells. Lymphocytes include T and B cells, while myeloid cells include eosinophils, basophils, dendritic cells (DCs), macrophages, neutrophils, mast cells, and so on.25 During the development of obesity, adipocytes secrete adipokines, gradually changing the balance of immune cells from anti-inflammatory to pro-inflammatory. This process leads to chronic inflammation of AT and insulin resistance.
Macrophages have different functions depending on environmental stimuli. In acute inflammation and injury, macrophages kill infected cells by phagocytosis. In chronic inflammation caused by obesity, the production of anti-inflammatory macrophages can be insufficient, leading to extracellular matrix (ECM) fibrosis.26 In healthy AT, M2 macrophages are widely distributed and have anti-inflammatory effects. They express IL-4, IL-10, TGF-β, and other anti-inflammatory factors.27 IL-10 can antagonize the effect of TNF-α and promote insulin sensitivity.28 Additionally, M2 macrophages and eosinophils can assist in the production of beige adipocytes.29 In obesity, more adipokines like MCP-1 are secreted from hypertrophic adipocytes, inducing monocytes to infiltrate AT and differentiate into macrophages.30,44 Macrophages account for only 5% of healthy AT but can account for 50% of obese AT.31 In obese AT, type I interferon, LPS, TLR4, saturated FFA, and ceramide activation can induce M1 macrophages to gather around necrotic adipocytes to form “crown-like structures” (CLS)28,32 (Figure 1). Unlike M2 macrophages, activated M1 type macrophages express CD11c and produce proinflammatory mediators such as resistin, IL-6, IL −1β,TNF-α, and NO.33 These mediators further induce adipocyte death and downregulate the expression of peroxisome proliferator-activated receptor (PPAR-γ), which normally promotes adipose synthesis.34 A decrease in PPAR-γ activity contributes to insulin resistance.35
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Figure 1 Changes of immune cells in obese adipose tissue. In healthy adipose tissue, Eosinophils and Th2 cells secrete IL-4,13 promote the activation of M2-type macrophages to produce anti-inflammatory factors such as IL-10 and IL-4. With continuous dietary intake, adipocytes gradually proliferate and hypertrophy, releasing more adipokines to regulate body balance, and local hypoxia due to limited capillaries releases hypoxia inducible factor-1 (HIF-1). All these factors will cause more pro-inflammatory immune cells to infiltrate the adipose tissue. Pro-inflammatory immune cells secreted inflammatory signals and free fatty acid (FFA) will further lead to insulin resistance. |
In obese AT, the ratio of CD4 + and CD8 + type T cells changes.36 Inflammatory factors such as IL-4, and IL-6 can stimulate CD4 + T cells to differentiate into Th1, Th2, Treg, and Th17 cells. These types of cells participate in the inflammatory response. In healthy AT, Th2 cells secrete anti-inflammatory cytokines such as IL-4 and IL-13 that can activate M2 macrophages to secrete IL-10 and promote insulin sensitivity.37 As body weight increases, Th2 cells and Tregs are gradually polarized into Th1, Th17, and CD8 + T cells. These cells produce pro-inflammatory cytokines.38–40 In mice with a high-fat diet, Treg decreased by 50% and CD8 + T cells doubled. After a normal diet, body weight and adipocyte size normalized, but the content of CD8 cells and Treg cells in AT did not. Insulin resistance did not improve, which indicates that immune cell memory may be the main cause of insulin resistance.41 By transferring Th2 cells to diet-induced obese mice with immunodeficiency, weight gain and insulin resistance can be reversed. Short-term treatment with CD3 specific antibodies or F(ab’)2 fragments can reduce Th1 cells, and It can reduce insulin resistance caused by high-fat diet.37 In recent years, it has been discovered that mucosal-associated invariant T cells (MAIT) induce polarization of M1 macrophages in obese AT, which promotes inflammation and intestinal microbiota disorders, leading to insulin resistance.42
A relative low number of B cells in healthy visceral fat resist bacterial infections from the peritoneal cavity.43 However, B cells increase in obese AT, promoting the activation of other immune cells such as T cells and M1 macrophages, which affect the metabolic state.40,44 B cells produce cytokines and the antibody IgG2c, which may also directly interact with adipocytes and affect insulin sensitivity.45 Treatment with CD20 antibody depletes B cells and can reduce insulin resistance and inflammation.38
Eosinophils are related to helminth immunity and allergy. They are reduced in obese AT and recover during intermittent fasting.46 Eosinophils can express IL-4 and IL-5, activate alternatively activated macrophages (AAMs) and exert anti-inflammatory effects.47 In worm-infected mice, eosinophils increased, while AT and blood sugar decreased.47 Additionally, eosinophils can activate beige fat cells by secreting certain factors such as KLF3, thereby reducing obesity-related disease.48
Neutrophils are often the first immune cells to reach the site of inflamed tissue. The production of leukotriene B 4 (LTB 4) in AT promotes the accumulation of neutrophils which express IL-1β through the NF-κB pathway to cause chronic inflammation.49 Other studies have also shown that, when exposed to saturated fatty acids, macrophages release nucleotides through pannexin-1. This may promote the recruitment of neutrophils into obese AT.50 These results indicate that in diet-induced obesity, neutrophils quickly infiltrate the abdominal AT and cause chronic inflammation.
Dendritic cells are the most effective antigen presenting cells (APC) in the immune system, they can play an important role in the transition from innate immunity to adaptive immunity by initiating differentiation of CD4 + helper T cells into Th1 and Th17. The increase of DCs in the AT of obese patients promotes the differentiation of Th17, which in turn leads to insulin resistance.51 In diet-induced obesity, DCs increase significantly in both the liver and in AT which promotes macrophage infiltration.52
Mast cells (MCs) can secrete many immune factors that are closely related to human allergic diseases. These cells induce obesity and insulin resistance by producing IL-6 and interferon-γ (IFN-γ).54 In diet-induced obese humans and mice, the number of mast cells increases and knocking out mast cells can reduce body weight and inflammation.53
We summarize the above immune cell changes in Figure 1. During the development of obesity, the immune cells in AT are transformed from anti-inflammatory immune cells (eosinophils, Th2 cells, and Tregs) to pro-inflammatory immune cells (neutrophils, B cells, CD8 T cells, DC, Th1 cells, and mast cells), leading to the occurrence of chronic sterile inflammation of AT, which in turn leads to insulin resistance.
Adipokine Dynamics in Obese Adipose Tissue
In addition to their role in energy regulation, adipocytes and AT immune cells secrete adipokines, biologically active peptides and proteins that regulate metabolism. Various proteomics methods have been used to study adipokines, and more than 600 potential adipokines have been identified.55 Cells secrete different types of adipokines depending on AT type and BMI levels. Adipokines can be roughly divided into two types: anti-inflammatory and pro-inflammatory. Unregulated expression of adipokines may be related to obesity, which further causes adipocyte dysfunction, chronic inflammation, and systemic insulin resistance. This review summarizes well-studied adipokines and the dysfunctions resulting from obesity.
Leptin is a peptide hormone that is produced by differentiated adipocytes in subcutaneous WAT.56,57 Leptin-deficient mice will progress to obesity with an unrestricted diet, which shows that leptin may suppress the appetite via the central nervous system.58 Related studies have shown that leptin binds to the leptin receptor (LepR or LRb)(Figure 2), and directly inhibits the feeding center by activating signal transducers and transcription activators (STAT).59,60 Leptin can also increase fatty acid oxidation and insulin sensitivity by activating AMP protein kinase (AMPK).61 As body weight increases, the level of leptin in the body also increases. In obese patients, increased leptin does not suppress appetite, which may be due to leptin resistance. This may be due to down-regulation of leptin signaling by stimulating tyrosine phosphorylation on leptin receptor and suppression of cytokine signaling 3(SOCS3).62
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Figure 2 Intracellular signal transduction of adipokines and insulin resistance. In obese adipose tissue, inflammatory factors IL-1 and TNF-α can enter cells through the JNK/AP-1 and IKK/NF-κB signaling pathways, which increases the transcription of adipokines MCP-1, recruits more pro-inflammatory immune cells, and produces more inflammatory factors IL-1 and TNF-α; they can also directly inhibit the phosphorylation of IRS-1, leading to insulin resistance. Leptin and IL-6 can increase the expression of suppressor of cytokine signaling 3(SOCS3) through the JAK-STAT3 signaling pathway, and also inhibit the phosphorylation of IRS-1. Adiponectin and leptin can directly activate glucose transporters through the AMPK pathway and increase insulin sensitivity. Arrows express promotion, T-bar represent inhibition. |
Adiponectin is an insulin-sensitive adipokine that is highly expressed in AT. It exists in the blood in three main forms: high molecular weight, hexamer, and trimer.63 Adiponectin mRNA expression level is inversely proportional to BMI and is lower in VAT than in SAT.64,65 Adiponectin promotes insulin sensitivity by activating AMPK and peroxisome proliferator-activated receptor (PPAR)-α pathways (Figure 2). These pathways inhibit hepatic gluconeogenesis and increase the oxidation of FFA.28 Adiponectin can also inhibit the adhesion of monocytes and vascular endothelial cells and alleviate inflammation in AT.29
Resistin is so named because it can induce insulin resistance by reducing the expression of insulin receptor substrate (IRS) and AMPK (Figure 2).66 Resistin increases significantly in obese and diabetic people.67 Resistin can also directly damage endothelial cells by inducing the expression of MCP-1 and vascular cell adhesion molecules (VCAM-1).66 Mouse resistin is mainly expressed in AT, but in humans it is mainly secreted by monocytes and macrophages.68 Resistin also increases the expression of inflammatory factors such as IL-6 and TNF-α in AT.69
Omentin is a novel adipokine synthesized mainly in visceral stromal vascular cells. In adipocytes, omentum enhances the phosphorylation of Akt in insulin signaling and improves insulin sensitivity.70 In obese and diabetic patients, omentum decreases.71 Omentin can also inhibit the expression of endothelial cell adhesion molecules, and thus play a protective role in cardiovascular diseases.72,73
Tumor necrosis factor-α (TNF-α) is an adipokine that can be secreted by both adipocytes and immune cells.74 Adipose tissue TNF-α increases in overweight individuals. Compared with lean humans adipose tissue, TNF-α expression is 2.5 times higher in obesity. There is a strong positive correlation with hyperinsulinemia.75 TNF-α can increase lipolysis by increasing the level of cAMP.76 TNFα can also increase FFA release by directly activating hormone-sensitive lipase (HSL), which in turn promotes insulin resistance in the liver and skeletal muscle. TNFα inhibits the phosphorylation of insulin receptor substrate 1 (IRS-1) by activating c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), thereby preventing insulin signal transduction (Figure 2).17 In human obesity, TNF-α can also accelerate atherosclerosis by inducing vascular cell adhesion molecule 1 (VCAM1).77
IL-6 directly stimulates lipolysis.78 IL-6 in AT can stimulate the liver to produce C-reactive protein (CRP), which is an important cardiovascular risk factor.79 Omentum AT releases 2–3 times IL-6 than subcutaneous AT. IL-6, like leptin, can suppress appetite via STAT3 signaling in the central nervous system. In addition, IL-6 can inhibit the phosphorylation of IRS-1 in adipocytes and liver cells by increasing the expression of suppressor of cytokine signaling 3 (SOCS3) (Figure 2). This inhibits insulin conduction and leads to insulin resistance.80,81
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a CC chemokine family member.82 During the development of obesity, macrophages and adipocytes secrete MCP-1. It binds to monocytes in the blood, causing them to accumulate in AT. These monocytes differentiate into M1 macrophages that secrete proinflammatory factors, accelerating AT inflammation and systemic Insulin resistance.83,84 Palmitate (PA) induces MCP-1 secretion of macrophages through the MAPK/TLR4 signaling pathway.85 BMI and obesity are positively correlated with the expression level of MCP-1. Weight loss causes a decrease in MCP-1 expression.86
In recent years, many other adipokines have been found which may be related to obesity metabolism. They are summarized in Table 2. In obese patients, the levels of these adipokines and inflammatory signals undergo changes. These changes are closely related to obesity-related conditions such as insulin resistance, cardiovascular disease, and cancer.
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Table 2 Some Other Adipokines Related to Obesity Metabolism |
Anti-Inflammatory Therapeutic Effect of Some Drugs
We already know that chronic sterile inflammation of obese AT leads to insulin resistance. Can it be targeted to prevent the transmission of inflammation signals and improve insulin sensitivity? Many studies have confirmed that this is feasible. Anti-inflammatory treatment has visible potential. Biological inhibitors of classical inflammatory molecules (including TNF-α, IL-6 and IL-1) are being used in the clinical treatment of rheumatoid arthritis (RA), and there are several prospective clinical trials for RA patients with insulin resistance. The results have shown that the use of anti-TNF drugs such as infliximab, etanercept, and other treatments can increase AKT phosphorylation and can significantly improve insulin sensitivity.87 After 3–6 months of anti-TNF treatment in patients with rheumatoid arthritis and insulin resistance, insulin sensitivity and β-cell function were significantly improved.88 Additionally, the non-steroidal anti-inflammatory drug aspirin can also inhibit TNF-α levels and NF-κB activation to improve insulin sensitivity, with 8 weeks of aspirin treatment in diabetic rats, insulin resistance and inflammatory factors reduced.89 However, some related studies indicate of TNF-α inhibitors that have not replicated these findings.90 The latest systematic analysis of retrospective studies concluded that anti-TNF therapy can improve insulin sensitivity.91 Other studies also provided promising evidence that anakinra, an IL-1 receptor antagonist, can significantly improve insulin resistance and related inflammation in RA and T2D participants.92 The IL-6 inhibitor, tocilizumab, produces a rapid beneficial effect on insulin sensitivity.93 The JAK inhibitor, tofacitinib, can reduce insulin resistance and hyperglycemia in T2D patients.94 Erythropoietin (EPO) has been found in recent years to not only promote erythropoiesis, but also activate phosphatidylinositol 3-kinase (PI3K)/AKT pathway and promote PPAR-γ transcription. EPO can promote fat synthesis and glucose transport, so it is a potential drug for the treatment of insulin resistance.95,96 At present, these targeted therapies to inhibit inflammatory signaling have achieved limited success for insulin-resistant patients without other complications, and further studies are needed. The harmful immunosuppressive effects and possible harmful side effects of any anti-inflammatory treatment must be carefully examined.
Anti-Inflammatory Therapeutic Effect of Bariatric Surgery
In 1991, the National Institutes of Health established the initial surgical intervention standard for obesity. Patients with a BMI ≥ 35 kg/m2 with comorbidities, such as cardiovascular disease, diabetes, arthritis, respiratory barriers, reproductive disorders, etc., or those with BMI ≥40 kg/m2 are suitable candidates for bariatric surgery.97,98 Compared with lifestyle changes and medication management, bariatric surgery can lead to sustained weight loss (20% to 30%). Type 2 diabetes remission rates range from 23% to 60%, and the risk of surgery is as low as ordinary appendectomy and cholecystectomy.99 Bariatric surgery aims to physically limit the intake or absorption of food. It can produce lasting weight loss and health benefits by changing metabolism and reducing appetite.100 In 2018, the number of bariatric surgeries in the United States reached 250,000. Sleeve gastrectomy (SG) was the most common operation at 61.4%, followed by Roux-en-Y gastric bypass (RYGB) at 17.0%, laparoscopic adjustable gastric banding (LAGB) at 1.1%; biliopancreatic diversion at 0.8%, and a modified surgery, bioenterics intragastric balloon and vagal blockade.101 Sjostrom’s study showed that the adjusted mortality rate of bariatric surgery was 30.7% lower than that of non-surgical group.102 Jouan et al found that chemerin may play a key role in inflammation caused by obesity. In addition, there was a significant correlation between weight loss and improvement of inflammatory parameters. After surgery, weight loss reached (39.5±13.8 kg), and pro-inflammatory markers (IL-6, CRP, leptin, and resistin) were significantly reduced. The anti-inflammatory markers (IL-10 and adiponectin) increased.103 In another prospective observational study, the levels of inflammation markers like high-sensitivity CRP and soluble urokinase gradually decreased, and the secretion of pro-inflammatory interleukins (1, 6, and 8) decreased within one year after RYGB surgery.104 Many clinical studies have also shown that inflammatory factors and TLR receptors are significantly reduced after surgery, but adipokines like leptin and adiponectin have not shown consistent results.105–107 Some bariatric surgery patients regained weight after weight loss, but the inflammatory factors continued to decrease, indicating that bariatric surgery may have a long-term effect on inflammation control.108
Conclusion
In conclusion, AT is a multifunctional organ with complex energy regulation and immune functions throughout the body. White AT regulates metabolism through esterification and lipolysis, while brown and beige AT utilize fatty acids for heat production and energy consumption via UCP-1. In healthy individuals, adipocytes can resist the lipotoxicity of non-esterified fatty acids through hyperplasia and hypertrophy. They also secrete adipokines such as leptin and resistin to regulate appetite and fatty acid oxidation. However, in obese individuals, with excessive energy intake, adipocytes proliferate and hypertrophy, blood supply decreased, AT secretes more hypoxia factors and adipokines such as HIF-1, MCP-1, leptin, resistin, etc. These dysregulated adipokines attract more pro-inflammatory cells such as M1 macrophages, neutrophils, Th1, and Th17 cells, into the AT. These pro-inflammatory cells will secrete more inflammatory signals such as TNF-α, IL- 6, which will increase lipolysis and decrease synthesis. AT releases more FFA and proinflammatory adipokines will interfere with the insulin-glucose transport pathway, which will lead to the occurrence of insulin resistance. Therefore, for obese people with insulin resistance, anti-inflammatory therapy has great potential.
Future Perspectives
In recent years, there have been more and more clinical studies on drugs and surgery for obese individuals. We also summarized the effects of anti-inflammatory and surgical treatments on inflammation and insulin resistance. The results show that both anti-inflammatory treatments and surgical treatments benefit insulin resistance and reduce inflammatory factors in circulation. Therefore, controlling AT inflammation may be an effective approach to treat obesity and insulin resistance. However, these studies are still in the early stages. In the future, researchers may focus on finding inhibitors of specific inflammatory signals without the immunosuppressive side effects of existing anti-inflammatory drugs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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