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Santillana, N.; Astudillo-Guerrero, C.; D’espessailles, A.; Cruz, G. White Adipose Tissue Dysfunction. Encyclopedia. Available online: https://encyclopedia.pub/entry/43303 (accessed on 07 May 2024).
Santillana N, Astudillo-Guerrero C, D’espessailles A, Cruz G. White Adipose Tissue Dysfunction. Encyclopedia. Available at: https://encyclopedia.pub/entry/43303. Accessed May 07, 2024.
Santillana, Natalia, Camila Astudillo-Guerrero, Amanda D’espessailles, Gonzalo Cruz. "White Adipose Tissue Dysfunction" Encyclopedia, https://encyclopedia.pub/entry/43303 (accessed May 07, 2024).
Santillana, N., Astudillo-Guerrero, C., D’espessailles, A., & Cruz, G. (2023, April 20). White Adipose Tissue Dysfunction. In Encyclopedia. https://encyclopedia.pub/entry/43303
Santillana, Natalia, et al. "White Adipose Tissue Dysfunction." Encyclopedia. Web. 20 April, 2023.
White Adipose Tissue Dysfunction
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This entry is adapted from the peer-reviewed paper 10.3390/nu15071722

White adipose tissue (AT) dysfunction plays an important role in the development of cardiometabolic alterations associated with obesity. AT dysfunction is characterized by the loss of the expansion capacity of the AT, an increment in adipocyte hypertrophy, and changes in the secretion profile of adipose cells, associated with accumulation of macrophages and inflammation. 

adipose tissue dysfunction inflammation obesity visceral fat fibrosis

1. Introduction

The study of adipose tissue (AT) has substantially changed in the last decades. Until the late 1940s, AT was considered merely a lipid-containing tissue with no link to metabolism. In the late 1980s and mid-1990s, serum fat-derived factors such as adipsin, tumor-necrosis factor (TNF)-α, and leptin were discovered [1]. In consequence, the original role of AT as an organ that only stores energy was changed by a new concept in which AT is considered an endocrine organ with key roles in energy homeostasis. Since then, studies on the development, function, and pathophysiology of AT have increased substantially. In recent years, the loss of AT functionality has been strongly associated with obesity-induced metabolic alterations [2][3].
Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health [4]. Under a positive energy balance, AT stores the excess of energy as triglycerides, leading to an expansion of AT. Although this expansion of AT is a physiological mechanism to store energy, an unhealthy expansion of AT is associated with metabolic dysfunctions [5][6].

2. Adipose Tissue Composition and Function

Understanding AT structure and function is key to understanding better how it becomes dysfunctional. White AT can typically be organized into two categories: subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). SAT includes the gluteus femoral and abdominal or upper-body area, whereas VAT includes both omental and mesenteric depots (also known as intra-abdominal fat) [7][8], but also the fat surrounding the heart [9], and kidneys [10], among others [11].
Within AT, the adipocyte is the cell specializing in the synthesis, storage, and hydrolysis of triglycerides [1]. Adipocytes are surrounded by an extracellular matrix (ECM) and other types of cells such as stem cells, immune cells, endothelial cells, fibroblasts, and preadipocytes, known as the stromal–vascular fraction. Preadipocytes are stem cells that can be recruited to proliferate and differentiate to new adipocytes [12]. Indeed, AT expansion can be the result of either pre-adipocyte proliferation or adipocyte hypertrophy [13]. A healthy AT expansion is characterized by AT enlargement due more to adipocyte proliferation than to adipocyte hypertrophy [14][15], an increased angiogenic response that is proportional to adipose tissue enlargement [16], an adequate extracellular matrix (ECM) remodeling [17], and minimal inflammation.
Adipocytes also secrete specialized molecules called adipokines that have autocrine, paracrine, and endocrine functions [18]. The adipokines include hormones, cytokines, chemokines, growth factors, and the complement system [19]. Intriguingly, the AT also secretes extracellular vesicles that can transport proteins, lipids, and nucleic acids (i.e., microRNAs) that participate in endocrine regulation [20][21].
Each gram of AT contains 1–2 million adipocytes and 4–6 million stromal cells, of which more than half are immune cells [1]. Among the immune cells found in the AT are the macrophages. Macrophages that secrete cytokines such as TNF-α, interleukin (IL)-6, and IL-1β, among others, are described to have an “M1” phenotype, while the anti-inflammatory “M2” macrophages produce immunomodulatory cytokines such as IL-4, IL-10, and IL-13 [22][23]. A healthy expansion of adipose tissue is associated with M2 macrophages instead of M1 ones, which are proinflammatory [24].
The ECM is a network consisting of proteins and proteoglycans that provide structural support and can mediate differentiation, migration, repair, survival, and development of different cells. Importantly, ECM remodeling is required for healthy AT expansion [17]. ECM remodeling is a rearrangement of the ECM due the breakdown of its components by proteases such as metalloproteinases (MMPs). This process permits adipocytes to grow harmonically with adequate ECM replacement and vascularization. During unhealthy AT expansion, ECM remodeling occurs, with an excess in the synthesis of ECM components, leading to fibrosis.

3. Adipose Tissue Dysfunction

Fat percentage is highly variable among people, ranging between 5 and 60% of total body weight [25]. In overfeeding, a compensatory increase in total energy expenditure occurs but is usually not enough to equilibrate the intake of energy, leading to AT expansion [26][27][28]. Currently, the AT expansion hypothesis holds that a decreased capacity for SAT expansion favors visceral fat deposition [29][30][31]. This suggests that there is a limit of SAT expandability, which also determinates a genetic susceptibility to develop disorders such as type 2 diabetes [28]. 
The term “unhealthy expansion” of AT refers to the expansion of dysfunctional AT, in which there is a hypersecretion of pro-inflammatory adipokines, a decreased secretion of anti-inflammatory adipokines [6][32], a loss of the AT capacity to store energy, and a lack of coordination between adipocyte expansion and extracellular matrix (ECM) remodeling. Unhealthy AT expansion and, consequently, metaflammation leads to an impairment in insulin signaling pathways in the adipocyte, thus decreasing its capacity to store energy [33]. Consequently, a chronic increase in circulating free fatty acids occurs, thus promoting a deposit of lipids in ectopic tissues and, hence, lipotoxicity [34]. Therefore, the current paradigm positions the loss of functionality of AT as a link between obesity and the associated disorders. Remarkably, the AT buffering capacity of the excess of energy is highly variable among individuals [35], and those who that have a low threshold of healthy AT expansion have a phenotype that is metabolically unhealthy, while those who have a high capacity of healthy AT expansion are metabolically healthy, even if they are classified as obese, depending on their BMI.
In adults, fat mass expansion occurs mainly through adipocyte hypertrophy, since just around 8% of adipocytes are renewed each year from preadipocytes [36]. Interestingly, AT expansion in the femoral area is mainly through hyperplasia in adult men and women after 8 weeks in response to overfeeding [7][36][37]. A healthy expansion of AT requires precise coordination between adipocyte hypertrophy/hyperplasia, with adequate vascularization and remodeling of ECM [38][39]. In this sense, when the vasculature does not supply enough irrigation to a zone containing hypertrophic adipocytes, the latter could be exposed to hypoxia.
Healthy AT expansion occurs during an entire lifetime, and studies to clarify the mechanisms by which this expansion occurs are scarce [40]. How excess weight during early life can contribute to the susceptibility to develop unhealthy expansion in adulthood is still unknown. Apparently, there is a genetic susceptibility that determines the threshold to develop unhealthy AT expansion with overfeeding, but this is also influenced by nutritional factors, physical activity, gender, and hormonal status [28]. Omitting the genetic background, all factors preventing inflammation appear to avoid or at least delay unhealthy AT expansion, inflammation being a key marker of AT dysfunction.

3.1. Role of ECM Remodeling in Adipose Tissue Dysfunction

Energy availability is variable, and AT needs adequate flexibility to permit its reduction and expansion with changes in energy balance. The flexibility of the ECM permits an adequate adaptation of the adipose tissue to these changes of energy storing, permitting a reorganization of its components (ECM remodeling) when the number and size of adipocytes is modified. Therefore, an altered ECM remodeling during adipose tissue expansion is a feature of AT dysfunction. In this context, an excessive accumulation of ECM components (fibrosis) results from an imbalance between the excessive synthesis of fibrillar components and a slow degradation of these proteins. Chronic overnutrition and AT expansion triggers an excessive synthesis of ECM components due different mechanisms. For example, hypertrophy of adipocytes usually does not allow adequate irrigation of the tissue, thus leading to hypoxia [41][42][43]. Therefore, low oxygen levels lead to molecular adaptations in the cell, such as a high expression of hypoxia inducible factor-1 (HIF-1), which is a transcription factor that increases expression of inflammatory cytokines and ECM components [43][44][45][46]. In addition, the recruitment of inflammatory macrophages leads to an increased inflammatory environment, with several cytokines acting on adipocytes and other cells in the AT [47][48][49]. These cytokines stimulate adipocytes and fibroblasts to produce ECM components [50][51]. The increased expression of ECM proteins, such as collagen, leads to a decreased flexibility of ECM [39]. In fact, collagen VI (an ECM protein) knockout mice consuming a high-fat diet showed larger adipocytes and a better metabolic profile than their wild-type counterparts [52], suggesting that a less rigid ECM would facilitate a functional AT expansion during periods of positive energy balance.
In conclusion, how ECM remodeling occurs is essential as a mechanism leading to AT dysfunction. In this sense, a higher flexibility of the ECM to reorganize its components and adapt to changes in the size and number of adipocytes is a feature of healthy AT expansion while a rigid ECM with an excessive production of its components (e.g., fibrosis) is a feature of unhealthy AT expansion.

3.2. Inflammation as a Key Component of AT Dysfunction and Metabolic Impairments

Chronic low-grade inflammation is a key feature of hypertrophied AT in the context of obesity. VAT expansion is associated with an inflammatory environment and immune cell recruitment [21][32]. This local inflammatory environment promotes macrophage infiltration towards the AT, which exacerbates the secretion of proinflammatory cytokines, thus contributing to a systemic inflammatory state [32][48]. In this sense, macrophage infiltration is a key event in the genesis of inflammation and AT dysfunction [53][54][55]. In a proinflammatory context, the M2 macrophages switch to the M1 phenotype, accentuating the imbalance between pro- and anti-inflammatory factors [56]. M1–M2 polarization is a tightly controlled process that responds to environmental changes. Toll-like receptors (TLR) and inflammasomes are key modulators of macrophage polarization. TLR and inflammasomes activate NF-kB and STAT 1 signaling, triggering the inflammatory response in those cells. Wang, Liang and Zen [57], and Castoldi et al. [58] have detailed reviews on the molecular mechanisms subjacent to macrophage polarization and the role of M1 macrophages in metabolic alterations.
In VAT, M1 macrophages infiltrate AT and surround dead hypertrophic adipocytes, forming “crown-like” structures [59][60]. M1 macrophages secrete chemoattractant proteins such as monocyte chemoattractant protein (MCP)-1 (also known as chemokine (C-C motif) ligand 2, CCL2), thus generating a feedforward and exacerbating inflammation [32][61][62]. In addition, immune cell paracrine interaction with adipocytes results in the loss of AT functionality [63] by inhibiting the differentiation of preadipocytes [64][65][66], reducing insulin sensitivity [32][67][68], and decreasing anti-inflammatory adipokine secretion [66][69][70]. The exact molecular pathways initiating macrophage infiltration are unknown. However, adipocyte death and hypoxia can initiate an inflammatory response [71]. Signaling pathways activated by these events are JNK and NF-κB, which control several inflammatory and oxidative cascades [72]. JNK and NF-κB activation increase the production of pro-inflammatory cytokines, endothelial adhesion molecules, and chemotactic proteins, thus promoting monocyte infiltration in VAT and their subsequent differentiation into M1 macrophages [73]. More detailed mechanisms about the relative relevance of local versus infiltrated macrophages in AT dysfunction have previously been described [73][74][75].
Another relevant molecular mechanism involved in AT dysfunction is the activation of the NLRP3 inflammasome. Inflammasomes are protein-signaling platforms that are assembled after the recognition of danger signals. After assembly, pro-caspase 1 is activated, which controls the maturation and secretion of interleukins such as IL-1β and IL-18, which are pro-inflammatory cytokines [76]. Several metabolic stressors such as saturated fatty acids [77], oxidative stress [78], and ceramides [79] activate the inflammasome [80], increasing IL-1β secretion in adipocytes and immune cells. In this context, the expression levels of NLRP3 and IL-1β are increased in the VAT of obese patients with metabolic alterations when compared with obese patients without these alterations [81], suggesting that the NLRP3 inflammasome has an important role in metabolic alterations associated with obesity [82]. In this sense, NLRP3 inflammasome promotes the M1 phenotype in macrophages from the VAT of obese mice [82][83], enhancing the inflammatory status of the AT and contributing to its dysfunction. Interestingly, the blockade of NLRP3 inflammasome activation in human adipocytes decreases the expression of ECM proteins, thus potentially decreasing AT fibrosis [84].
Inflammation also impairs adipogenesis (new adipocyte formation) [85]. In in vitro interaction models, inflammatory factors secreted by macrophages decrease human preadipocyte differentiation into adipocytes but increase proliferation of fibroblasts and promote a profibrotic phenotype [86][87][88]. Thus, an inflammatory environment inhibits adipogenesis, leading to an exacerbated and pathological enlargement of existing adipocytes, thus affecting the healthy expansibility of AT.
In addition to inflammation and ECM remodeling, oxidative stress plays a crucial role in the pathogenesis of metabolic alterations. Oxidative stress is the imbalance between the production of ROS (reactive oxygen species) and antioxidant mechanisms. The mitochondrion is the most important sources of ROS [89]. In this sense, it has been proposed that mitochondrial dysfunction may be a primary cause of AT inflammation [90]. Mitochondria dysfunction is characterized by a decrease in mitochondrial biogenesis, altered membrane potential, a decrease in mitochondrial numbers, and altered activities of oxidative proteins [91]. Recently, Long Xu et al. [92] proposed that mitochondrial dysfunction triggers macrophage polarization, inducing AT inflammation in obesity. These data show the relevance of oxidative stress and mitochondrial function, which have been widely reviewed [91][93][94].

3.3. Adipose Tissue Dysfunction and Metabolic Disturbances

The relationship between obesity and insulin resistance (IR) has been widely described, and involves numerous signaling pathways, proteins, adipokines, reactive oxygen species, and inflammation [95]. Insulin signaling disruption is characterized by a decrease in the ability of cells or tissues to respond to physiological levels of insulin [96][97]. The paracrine interaction between M1 macrophage secretion and adipocytes compromises adipose cells’ functionality and promotes insulin signaling disruption [48][98][99]. In this inflammatory context, there is an activation of several proteins, such as c-Jun N-terminal kinase (JNK) and protein kinase C (PKC), as well as transcription factors like nuclear factor (NF)-κB. These signaling pathways are associated with inhibition of insulin-receptor substrates (IRSs) phosphorylation, a decrease in Akt phosphorylation, and an increase in insulin receptor–serine phosphorylation, contributing to the disruption of insulin signaling [100].
Insulin resistance leads to increased lipolysis in AT. Disorders associated with elevated levels of free fatty acids (FFA) in blood and metabolic disturbances of these fatty acids along with intracellular signaling pathways in non-adipose body organs have been termed lipotoxicity [101][102]. Hypertrophic adipocytes release FFA, which activate macrophages, triggering a positive inflammatory loop leading to IR in adipocytes and to fatty acid spillover [34]. In addition, FFA produced by lipolysis in VAT insulin-resistant adipocytes are drained via the portal vein into the liver, contributing to the hepatic deposit of fatty acids [103][104][105]. FFA also are released into the circulation, reaching the pancreas and skeletal muscle, affecting insulin secretion and signaling, and hence glucose uptake [104][105][106][107]. Likewise, the deposition of fatty acids in the heart and kidneys has also been described in an obesity context [105][108]. Thereby, under conditions of chronic overnutrition and loss of healthy AT expandability, surplus energy could be detrimental for the whole organism.
A typical consequence of AT dysfunction is presenting high levels of plasma triglycerides, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) [109], and low levels of high-density lipoprotein (HDL) [110][111]. In this sense, the increase in FFA disposal into the liver favors hepatic synthesis of triglycerides and their subsequent increase in plasma. Additionally, hepatic VLDL synthesis is also increased [112]. Furthermore, with the increasing triglycerides in plasma, there is a raised exchange of triglycerides for cholesterol esters in HDL and LDL. Subsequently, the HDL particles become highly enriched in TG and are more susceptible to degradation [113][114][115], leading to low HDL levels in plasma. These low HDL levels are a strong predictor for cardiovascular diseases and mortality [116].

References

  1. Rosen, E.D.; Spiegelman, B.M. What we talk about when we talk about fat. Cell 2014, 156, 20–44.
  2. Esser, N.; Legrand-Poels, S.; Piette, J.; Scheen, A.J.; Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 2014, 105, 141–150.
  3. Engin, A.B. Adipocyte-Macrophage Cross-Talk in Obesity. Adv. Exp. Med. Biol. 2017, 960, 327–343.
  4. The GBD 2015 Obesity Collaborators. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med. 2017, 377, 13–27.
  5. Bluher, M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract. Res. Clin. Endocrinol. Metab. 2013, 27, 163–177.
  6. Longo, M.; Zatterale, F.; Naderi, J.; Parrillo, L.; Formisano, P.; Raciti, G.A.; Beguinot, F.; Miele, C. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int. J. Mol. Sci. 2019, 20, 2358.
  7. Tchkonia, T.; Thomou, T.; Zhu, Y.; Karagiannides, I.; Pothoulakis, C.; Jensen, M.D.; Kirkland, J.L. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 2013, 17, 644–656.
  8. Arner, P.; Ryden, M. Human white adipose tissue: A highly dynamic metabolic organ. J. Intern. Med. 2022, 291, 611–621.
  9. Gaborit, B.; Sengenes, C.; Ancel, P.; Jacquier, A.; Dutour, A. Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat? Compr. Physiol. 2017, 7, 1051–1082.
  10. Grigoras, A.; Balan, R.A.; Caruntu, I.D.; Giusca, S.E.; Lozneanu, L.; Avadanei, R.E.; Rusu, A.; Riscanu, L.A.; Amalinei, C. Perirenal Adipose Tissue-Current Knowledge and Future Opportunities. J. Clin. Med. 2021, 10, 1291.
  11. Schafer, K.; Drosos, I.; Konstantinides, S. Perivascular adipose tissue: Epiphenomenon or local risk factor? Int. J. Obes. 2017, 41, 1311–1323.
  12. Berry, R.; Rodeheffer, M.S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 2013, 15, 302–308.
  13. Wang, Q.A.; Tao, C.; Gupta, R.K.; Scherer, P.E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 2013, 19, 1338–1344.
  14. McLaughlin, T.; Craig, C.; Liu, L.F.; Perelman, D.; Allister, C.; Spielman, D.; Cushman, S.W. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans. Diabetes 2016, 65, 1245–1254.
  15. Kim, S.M.; Lun, M.; Wang, M.; Senyo, S.E.; Guillermier, C.; Patwari, P.; Steinhauser, M.L. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 2014, 20, 1049–1058.
  16. Cao, Y. Angiogenesis modulates adipogenesis and obesity. J. Clin. Investig. 2007, 117, 2362–2368.
  17. Ruiz-Ojeda, F.J.; Mendez-Gutierrez, A.; Aguilera, C.M.; Plaza-Diaz, J. Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases. Int. J. Mol. Sci. 2019, 20, 4888.
  18. Fasshauer, M.; Bluher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 2015, 36, 461–470.
  19. Kirichenko, T.V.; Markina, Y.V.; Bogatyreva, A.I.; Tolstik, T.V.; Varaeva, Y.R.; Starodubova, A.V. The Role of Adipokines in Inflammatory Mechanisms of Obesity. Int. J. Mol. Sci. 2022, 23, 14982.
  20. Arner, E.; Mejhert, N.; Kulyte, A.; Balwierz, P.J.; Pachkov, M.; Cormont, M.; Lorente-Cebrian, S.; Ehrlund, A.; Laurencikiene, J.; Heden, P.; et al. Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 2012, 61, 1986–1993.
  21. Kappeler, L. Role of Adipose Tissue microRNAs in the Onset of Metabolic Diseases and Implications in the Context of the DOHaD. Cells 2022, 11, 3711.
  22. Yao, J.; Wu, D.; Qiu, Y. Adipose tissue macrophage in obesity-associated metabolic diseases. Front. Immunol. 2022, 13, 977485.
  23. Li, C.; Xu, M.M.; Wang, K.; Adler, A.J.; Vella, A.T.; Zhou, B. Macrophage polarization and meta-inflammation. Transl. Res. 2018, 191, 29–44.
  24. Ruggiero, A.D.; Key, C.C.; Kavanagh, K. Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity. Front. Nutr. 2021, 8, 625331.
  25. Lee, M.J.; Wu, Y.; Fried, S.K. Adipose tissue heterogeneity: Implication of depot differences in adipose tissue for obesity complications. Mol. Asp. Med. 2013, 34, 1–11.
  26. Leibel, R.L.; Rosenbaum, M.; Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 1995, 332, 621–628.
  27. Schlogl, M.; Piaggi, P.; Pannacciuli, N.; Bonfiglio, S.M.; Krakoff, J.; Thearle, M.S. Energy Expenditure Responses to Fasting and Overfeeding Identify Phenotypes Associated with Weight Change. Diabetes 2015, 64, 3680–3689.
  28. Cuthbertson, D.J.; Steele, T.; Wilding, J.P.; Halford, J.C.; Harrold, J.A.; Hamer, M.; Karpe, F. What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications? Int. J. Obes. 2017, 41, 853–865.
  29. Iacobini, C.; Pugliese, G.; Blasetti Fantauzzi, C.; Federici, M.; Menini, S. Metabolically healthy versus metabolically unhealthy obesity. Metabolism 2019, 92, 51–60.
  30. Ryden, M.; Andersson, D.P.; Bergstrom, I.B.; Arner, P. Adipose tissue and metabolic alterations: Regional differences in fat cell size and number matter, but differently: A cross-sectional study. J. Clin. Endocrinol. Metab. 2014, 99, E1870–E1876.
  31. White, U.; Beyl, R.A.; Ravussin, E. A higher proportion of small adipocytes is associated with increased visceral and ectopic lipid accumulation during weight gain in response to overfeeding in men. Int. J. Obes. 2022, 46, 1560–1563.
  32. Kawai, T.; Autieri, M.V.; Scalia, R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol.-Cell Physiol. 2021, 320, C375–C391.
  33. Hotamisligil, G.S. Inflammation, metaflammation and immunometabolic disorders. Nature 2017, 542, 177–185.
  34. Carobbio, S.; Pellegrinelli, V.; Vidal-Puig, A. Adipose Tissue Function and Expandability as Determinants of Lipotoxicity and the Metabolic Syndrome. Adv. Exp. Med. Biol. 2017, 960, 161–196.
  35. Taylor, R.; Holman, R.R. Normal weight individuals who develop type 2 diabetes: The personal fat threshold. Clin. Sci. 2015, 128, 405–410.
  36. Johannsen, D.L.; Tchoukalova, Y.; Tam, C.S.; Covington, J.D.; Xie, W.; Schwarz, J.M.; Bajpeyi, S.; Ravussin, E. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: Testing the “adipose tissue expandability” hypothesis. Diabetes Care 2014, 37, 2789–2797.
  37. Tchoukalova, Y.D.; Votruba, S.B.; Tchkonia, T.; Giorgadze, N.; Kirkland, J.L.; Jensen, M.D. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc. Natl. Acad. Sci. USA 2010, 107, 18226–18231.
  38. Corvera, S.; Solivan-Rivera, J.; Yang Loureiro, Z. Angiogenesis in adipose tissue and obesity. Angiogenesis 2022, 25, 439–453.
  39. Crewe, C.; An, Y.A.; Scherer, P.E. The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis and impaired angiogenesis. J. Clin. Investig. 2017, 127, 74–82.
  40. Orsso, C.E.; Colin-Ramirez, E.; Field, C.J.; Madsen, K.L.; Prado, C.M.; Haqq, A.M. Adipose Tissue Development and Expansion from the Womb to Adolescence: An Overview. Nutrients 2020, 12, 2735.
  41. Blaak, E.E.; van Baak, M.A.; Kemerink, G.J.; Pakbiers, M.T.; Heidendal, G.A.; Saris, W.H. Beta-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects. Metabolism 1995, 44, 183–187.
  42. Goossens, G.H.; Bizzarri, A.; Venteclef, N.; Essers, Y.; Cleutjens, J.P.; Konings, E.; Jocken, J.W.; Cajlakovic, M.; Ribitsch, V.; Clement, K.; et al. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization and inflammation. Circulation 2011, 124, 67–76.
  43. Trayhurn, P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 2013, 93, 1–21.
  44. Fujisaka, S.; Usui, I.; Ikutani, M.; Aminuddin, A.; Takikawa, A.; Tsuneyama, K.; Mahmood, A.; Goda, N.; Nagai, Y.; Takatsu, K.; et al. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia 2013, 56, 1403–1412.
  45. Babapoor-Farrokhran, S.; Gill, D.; Alzubi, J.; Mainigi, S.K. Atrial fibrillation: The role of hypoxia-inducible factor-1-regulated cytokines. Mol. Cell. Biochem. 2021, 476, 2283–2293.
  46. Darby, I.A.; Hewitson, T.D. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016, 365, 553–562.
  47. Weisberg, S.P.; McCann, D.; Desai, M.; Rosenbaum, M.; Leibel, R.L.; Ferrante, A.W., Jr. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003, 112, 1796–1808.
  48. Lee, B.C.; Lee, J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim. Biophys. Acta 2014, 1842, 446–462.
  49. Rausch, M.E.; Weisberg, S.; Vardhana, P.; Tortoriello, D.V. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int. J. Obes. 2008, 32, 451–463.
  50. Henegar, C.; Tordjman, J.; Achard, V.; Lacasa, D.; Cremer, I.; Guerre-Millo, M.; Poitou, C.; Basdevant, A.; Stich, V.; Viguerie, N.; et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol. 2008, 9, R14.
  51. Johnston, E.K.; Abbott, R.D. Adipose Tissue Paracrine-, Autocrine-, and Matrix-Dependent Signaling during the Development and Progression of Obesity. Cells 2023, 12, 407.
  52. Khan, T.; Muise, E.S.; Iyengar, P.; Wang, Z.V.; Chandalia, M.; Abate, N.; Zhang, B.B.; Bonaldo, P.; Chua, S.; Scherer, P.E. Metabolic dysregulation and adipose tissue fibrosis: Role of collagen VI. Mol. Cell. Biol. 2009, 29, 1575–1591.
  53. Martinez-Santibanez, G.; Lumeng, C.N. Macrophages and the regulation of adipose tissue remodeling. Annu. Rev. Nutr. 2014, 34, 57–76.
  54. Boutens, L.; Stienstra, R. Adipose tissue macrophages: Going off track during obesity. Diabetologia 2016, 59, 879–894.
  55. Liang, W.; Qi, Y.; Yi, H.; Mao, C.; Meng, Q.; Wang, H.; Zheng, C. The Roles of Adipose Tissue Macrophages in Human Disease. Front. Immunol. 2022, 13, 908749.
  56. Hammarstedt, A.; Gogg, S.; Hedjazifar, S.; Nerstedt, A.; Smith, U. Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity. Physiol. Rev. 2018, 98, 1911–1941.
  57. Wang, N.; Liang, H.; Zen, K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front. Immunol. 2014, 5, 614.
  58. Castoldi, A.; Naffah de Souza, C.; Camara, N.O.; Moraes-Vieira, P.M. The Macrophage Switch in Obesity Development. Front. Immunol. 2015, 6, 637.
  59. Cinti, S.; Mitchell, G.; Barbatelli, G.; Murano, I.; Ceresi, E.; Faloia, E.; Wang, S.; Fortier, M.; Greenberg, A.S.; Obin, M.S. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 2005, 46, 2347–2355.
  60. Murano, I.; Barbatelli, G.; Parisani, V.; Latini, C.; Muzzonigro, G.; Castellucci, M.; Cinti, S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 2008, 49, 1562–1568.
  61. Kanda, H.; Tateya, S.; Tamori, Y.; Kotani, K.; Hiasa, K.; Kitazawa, R.; Kitazawa, S.; Miyachi, H.; Maeda, S.; Egashira, K.; et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 2006, 116, 1494–1505.
  62. Weisberg, S.P.; Hunter, D.; Huber, R.; Lemieux, J.; Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel, R.L.; Ferrante, A.W., Jr. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Investig. 2006, 116, 115–124.
  63. Lu, J.; Zhao, J.; Meng, H.; Zhang, X. Adipose Tissue-Resident Immune Cells in Obesity and Type 2 Diabetes. Front. Immunol. 2019, 10, 1173.
  64. Keophiphath, M.; Achard, V.; Henegar, C.; Rouault, C.; Clement, K.; Lacasa, D. Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol. Endocrinol. 2009, 23, 11–24.
  65. Sorisky, A.; Molgat, A.S.; Gagnon, A. Macrophage-induced adipose tissue dysfunction and the preadipocyte: Should I stay (and differentiate) or should I go? Adv. Nutr. 2013, 4, 67–75.
  66. Liu, F.; He, J.; Wang, H.; Zhu, D.; Bi, Y. Adipose Morphology: A Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction. Obes. Surg. 2020, 30, 5086–5100.
  67. Chung, S.; Lapoint, K.; Martinez, K.; Kennedy, A.; Boysen Sandberg, M.; McIntosh, M.K. Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 2006, 147, 5340–5351.
  68. Lee, Y.S.; Li, P.; Huh, J.Y.; Hwang, I.J.; Lu, M.; Kim, J.I.; Ham, M.; Talukdar, S.; Chen, A.; Lu, W.J.; et al. Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 2011, 60, 2474–2483.
  69. Kern, P.A.; Di Gregorio, G.B.; Lu, T.; Rassouli, N.; Ranganathan, G. Adiponectin expression from human adipose tissue: Relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003, 52, 1779–1785.
  70. Gariballa, S.; Alkaabi, J.; Yasin, J.; Al Essa, A. Total adiponectin in overweight and obese subjects and its response to visceral fat loss. BMC Endocr. Disord. 2019, 19, 55.
  71. Reilly, S.M.; Saltiel, A.R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 2017, 13, 633–643.
  72. Hernandez, E.D.; Lee, S.J.; Kim, J.Y.; Duran, A.; Linares, J.F.; Yajima, T.; Muller, T.D.; Tschop, M.H.; Smith, S.R.; Diaz-Meco, M.T.; et al. A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. Cell Metab. 2014, 20, 499–511.
  73. Zatterale, F.; Longo, M.; Naderi, J.; Raciti, G.A.; Desiderio, A.; Miele, C.; Beguinot, F. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front. Physiol. 2019, 10, 1607.
  74. Burhans, M.S.; Hagman, D.K.; Kuzma, J.N.; Schmidt, K.A.; Kratz, M. Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus. Compr. Physiol. 2018, 9, 1–58.
  75. Bai, Y.; Sun, Q. Macrophage recruitment in obese adipose tissue. Obes. Rev. 2015, 16, 127–136.
  76. Broz, P.; Dixit, V.M. Inflammasomes: Mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 2016, 16, 407–420.
  77. Reynolds, C.M.; McGillicuddy, F.C.; Harford, K.A.; Finucane, O.M.; Mills, K.H.; Roche, H.M. Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance. Mol. Nutr. Food Res. 2012, 56, 1212–1222.
  78. Sharma, A.; Tate, M.; Mathew, G.; Vince, J.E.; Ritchie, R.H.; de Haan, J.B. Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications. Front. Physiol. 2018, 9, 114.
  79. Legrand-Poels, S.; Esser, N.; L’Homme, L.; Scheen, A.; Paquot, N.; Piette, J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 2014, 92, 131–141.
  80. Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci. 2019, 20, 3328.
  81. Esser, N.; L’Homme, L.; De Roover, A.; Kohnen, L.; Scheen, A.J.; Moutschen, M.; Piette, J.; Legrand-Poels, S.; Paquot, N. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue. Diabetologia 2013, 56, 2487–2497.
  82. Wu, K.K.; Cheung, S.W.; Cheng, K.K. NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases. Int. J. Mol. Sci. 2020, 21, 4184.
  83. Vandanmagsar, B.; Youm, Y.H.; Ravussin, A.; Galgani, J.E.; Stadler, K.; Mynatt, R.L.; Ravussin, E.; Stephens, J.M.; Dixit, V.D. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 2011, 17, 179–188.
  84. Unamuno, X.; Gomez-Ambrosi, J.; Ramirez, B.; Rodriguez, A.; Becerril, S.; Valenti, V.; Moncada, R.; Silva, C.; Salvador, J.; Fruhbeck, G.; et al. NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling. Cell. Mol. Immunol. 2021, 18, 1045–1057.
  85. Jiang, N.; Li, Y.; Shu, T.; Wang, J. Cytokines and inflammation in adipogenesis: An updated review. Front. Med. 2019, 13, 314–329.
  86. Bourlier, V.; Sengenes, C.; Zakaroff-Girard, A.; Decaunes, P.; Wdziekonski, B.; Galitzky, J.; Villageois, P.; Esteve, D.; Chiotasso, P.; Dani, C.; et al. TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS ONE 2012, 7, e31274.
  87. Tanaka, M.; Ikeda, K.; Suganami, T.; Komiya, C.; Ochi, K.; Shirakawa, I.; Hamaguchi, M.; Nishimura, S.; Manabe, I.; Matsuda, T.; et al. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat. Commun. 2014, 5, 4982.
  88. Rabhi, N.; Desevin, K.; Belkina, A.C.; Tilston-Lunel, A.; Varelas, X.; Layne, M.D.; Farmer, S.R. Obesity-induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors. Life Sci. Alliance 2022, 5, e202101286.
  89. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1–13.
  90. Woo, C.Y.; Jang, J.E.; Lee, S.E.; Koh, E.H.; Lee, K.U. Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation. Diabetes Metab. J. 2019, 43, 247–256.
  91. Ruiz-Ojeda, F.J.; Ozla, J.; Gil, Á.; Concepción, M.A. Chapter 1—Oxidative Stress and Inflammation in Obesity and Metabolic Syndrome. In Obesity; del Moral, A.M., María, C., Eds.; Academic Press: Cambridge, MA, USA, 2018; pp. 1–15.
  92. Xu, L.; Yan, X.; Zhao, Y.; Wang, J.; Liu, B.; Yu, S.; Fu, J.; Liu, Y.; Su, J. Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity. Int. J. Mol. Sci. 2022, 23, 9252.
  93. Masschelin, P.M.; Cox, A.R.; Chernis, N.; Hartig, S.M. The Impact of Oxidative Stress on Adipose Tissue Energy Balance. Front. Physiol. 2019, 10, 1638.
  94. Manna, P.; Jain, S.K. Obesity, Oxidative Stress, Adipose Tissue Dysfunction and the Associated Health Risks: Causes and Therapeutic Strategies. Metab. Syndr. Relat. Disord. 2015, 13, 423–444.
  95. Petersen, M.C.; Shulman, G.I. Mechanisms of Insulin Action and Insulin Resistance. Physiol. Rev. 2018, 98, 2133–2223.
  96. Lee, S.H.; Park, S.Y.; Choi, C.S. Insulin Resistance: From Mechanisms to Therapeutic Strategies. Diabetes Metab. J. 2022, 46, 15–37.
  97. Khalid, M.; Alkaabi, J.; Khan, M.A.B.; Adem, A. Insulin Signal Transduction Perturbations in Insulin Resistance. Int. J. Mol. Sci. 2021, 22, 8590.
  98. Glass, C.K.; Olefsky, J.M. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012, 15, 635–645.
  99. Lauterbach, M.A.; Wunderlich, F.T. Macrophage function in obesity-induced inflammation and insulin resistance. Pflügers Arch.-Eur. J. Physiol. 2017, 469, 385–396.
  100. Boucher, J.; Kleinridders, A.; Kahn, C.R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 2014, 6, a009191.
  101. Yazici, D.; Sezer, H. Insulin Resistance, Obesity and Lipotoxicity. Adv. Exp. Med. Biol. 2017, 960, 277–304.
  102. Engin, A.B. What Is Lipotoxicity? Adv. Exp. Med. Biol. 2017, 960, 197–220.
  103. Nielsen, S.; Guo, Z.; Johnson, C.M.; Hensrud, D.D.; Jensen, M.D. Splanchnic lipolysis in human obesity. J. Clin. Investig. 2004, 113, 1582–1588.
  104. Sears, B.; Perry, M. The role of fatty acids in insulin resistance. Lipids Health Dis. 2015, 14, 121.
  105. Sobczak, A.I.S.; Blindauer, C.A.; Stewart, A.J. Changes in Plasma Free Fatty Acids Associated with Type-2 Diabetes. Nutrients 2019, 11, 2022.
  106. Oh, Y.S.; Bae, G.D.; Baek, D.J.; Park, E.Y.; Jun, H.S. Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes. Front. Endocrinol. 2018, 9, 384.
  107. Tumova, J.; Andel, M.; Trnka, J. Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle. Physiol. Res. 2016, 65, 193–207.
  108. Nishi, H.; Higashihara, T.; Inagi, R. Lipotoxicity in Kidney, Heart, and Skeletal Muscle Dysfunction. Nutrients 2019, 11, 1664.
  109. Lessard, J.; Laforest, S.; Pelletier, M.; Leboeuf, M.; Blackburn, L.; Tchernof, A. Low abdominal subcutaneous preadipocyte adipogenesis is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state. Adipocyte 2014, 3, 197–205.
  110. Veilleux, A.; Caron-Jobin, M.; Noel, S.; Laberge, P.Y.; Tchernof, A. Visceral adipocyte hypertrophy is associated with dyslipidemia independent of body composition and fat distribution in women. Diabetes 2011, 60, 1504–1511.
  111. Su, X.; Peng, D. The exchangeable apolipoproteins in lipid metabolism and obesity. Clin. Chim. Acta 2020, 503, 128–135.
  112. Jung, U.J.; Choi, M.S. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int. J. Mol. Sci. 2014, 15, 6184–6223.
  113. Rashid, S.; Barrett, P.H.; Uffelman, K.D.; Watanabe, T.; Adeli, K.; Lewis, G.F. Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 483–487.
  114. Rashid, S.; Trinh, D.K.; Uffelman, K.D.; Cohn, J.S.; Rader, D.J.; Lewis, G.F. Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Circulation 2003, 107, 3066–3072.
  115. Stadler, J.T.; Marsche, G. Obesity-Related Changes in High-Density Lipoprotein Metabolism and Function. Int. J. Mol. Sci. 2020, 21, 8985.
  116. Zhong, G.C.; Huang, S.Q.; Peng, Y.; Wan, L.; Wu, Y.Q.; Hu, T.Y.; Hu, J.J.; Hao, F.B. HDL-C is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: A pooled analysis of 37 prospective cohort studies. Eur. J. Prev. Cardiol. 2020, 27, 1187–1203.
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Subjects: Nutrition & Dietetics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Natalia Santillana
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Camila Astudillo-Guerrero
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Amanda D’Espessailles
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Gonzalo Cruz
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Update Date: 21 Apr 2023
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