Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 + 1486 word(s) 1486 2021-08-31 06:00:17 |
2 format correct Meta information modification 1486 2021-09-07 10:13:20 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Petelin, A. Serum Bilirubin in Obese Individuals. Encyclopedia. Available online: (accessed on 05 December 2023).
Petelin A. Serum Bilirubin in Obese Individuals. Encyclopedia. Available at: Accessed December 05, 2023.
Petelin, Ana. "Serum Bilirubin in Obese Individuals" Encyclopedia, (accessed December 05, 2023).
Petelin, A.(2021, September 07). Serum Bilirubin in Obese Individuals. In Encyclopedia.
Petelin, Ana. "Serum Bilirubin in Obese Individuals." Encyclopedia. Web. 07 September, 2021.
Serum Bilirubin in Obese Individuals

Bilirubin, the end product of heme metabolism, is a potent endogenous antioxidant with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. Serum bilirubin concentrations depend on the complex interactions between bilirubin production, consumption (depending on oxidative stress and inflammation), metabolism, and elimination. Importantly, numerous studies have shown that serum bilirubin levels are inversely associated with obesity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and other oxidative-stress-mediated diseases, including atherosclerosis. Moreover, serum bilirubin levels were recently proposed as a potential pre-disease biomarker for developing metabolic syndrome in asymptomatic middle-aged individuals. 

adipokines antioxidant anti-inflammatory bilirubin obesity overweight

1. Overview

Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties.

Bilirubin, the end product of heme metabolism, is a potent endogenous antioxidant with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties [1][2][3]. Serum bilirubin concentrations depend on the complex interactions between bilirubin production, consumption (depending on oxidative stress and inflammation), metabolism, and elimination. Importantly, numerous studies have shown that serum bilirubin levels are inversely associated with obesity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and other oxidative-stress-mediated diseases, including atherosclerosis [2][4][5]. Moreover, serum bilirubin levels were recently proposed as a potential pre-disease biomarker for developing metabolic syndrome in asymptomatic middle-aged individuals [6].
Obesity and overweight are considered pathological states of chronic low-grade inflammation with increased oxidative stress and altered endocrine signaling; therefore, these conditions result in lowered serum bilirubin levels [6]; on the other hand, reducing body weight leads to increased serum bilirubin levels [7][8]. Importantly, mild hyperbilirubinemia is associated with health benefits in overweight and obese individuals, as well as with lower adiposity [9][10]. This review addresses the current knowledge on how overweight and obesity affect bilirubin levels, along with the potential intervention strategies to modulate systemic bilirubin levels to alleviate the obesity-related negative effects on health.

2. Obesity

Obesity is the accumulation of excessive fat that harms health. Indeed, obesity and overweight are associated with several dysmetabolic conditions, including T2DM, non-alcoholic fatty liver diseases, cardiovascular diseases (CVDs), cancer, and neurodegenerative disorders, among others. Recently, the understanding of adipose tissue has undergone radical changes. Adipose tissue has been recognized as a heterogeneous tissue; indeed, it is composed of several cell types, including preadipocytes, mature adipocytes, fibroblasts, dendritic cells, mast cells, T-cells, endothelial cells, and macrophages [11]. Importantly, obesity is linked to a state of chronic low-grade inflammation, mainly due to proinflammatory cytokine secretion, macrophage infiltration, and disrupted function of tissue involved in glucose homeostasis [12]. Additionally, obesity is also associated with a significant increase in macrophage number [13][14], which also contributes to the maintenance of the low-grade chronic inflammation state linked to obesity [15]. Macrophages are increased in adipose tissue during obesity due to several factors, free fatty acids, cholesterol, and lipopolysaccharide [16]. Macrophages can be classified, based on their surface expression or their cytokine or chemokine expression, into two main populations. M1 macrophages are associated with a proinflammatory profile and secrete proinflammatory cytokines (tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6)), whereas M2 macrophages are associated with tissue remodeling and inflammation resolution and secrete anti-inflammatory cytokines (IL-10, IL-1) [17][18]. Moreover, treating macrophages with a mix of glucose, palmitate, and insulin generates a unique macrophage proinflammatory phenotype that is different from M1 and secretes proinflammatory cytokines (TNF-α, IL-1ß), while the secretion depends on peroxisome-proliferator-activated receptor gamma (PPAR-γ) and p62 expression [19]. The mechanisms by which inflammation increases during obesity are still not fully understood. First, increased proinflammatory cytokine secretion contributes to insulin resistance and other complications related to obesity. Second, obesity not only promotes the infiltration of macrophages but also induces a shift in macrophage balance toward the M1 phenotype [17]; however, the adipose tissue is not the sole site of inflammation. In contrast, obesity-related inflammation occurs in many other tissues, such as the liver, muscle, hypothalamus, pancreatic islets, and the gut [20].
Adipose tissue was considered as an inert tissue having a primary role in controlling energy homeostasis. Additionally, it is now recognized that adipose tissue exhibits endocrine-regulatory properties and releases a cluster of bioactive substances, among them hormones and adipokines with pleiotropic functions [11][21][22][23]. Adipokines comprise, among others, classical cytokines (TNFα, IL-6) and chemokines (IL-8, monocyte chemoattractant protein 1 (MCP-1), macrophage-inflammatory protein-1α, macrophage-inflammatory protein-2α, stromal-cell-derived factor-1), vasoactive and coagulation factors, regulators of lipoprotein metabolism, and proteins more specifically secreted by the adipocytes, such as leptin and adiponectin [24]. Adipocytes have been recognized as important sources of MCP-1, which was the first discovered human ß-chemokine and is a recognized marker of adipose tissue dysfunction in obesity and T2DM [25]. An early study determined a link between obesity and inflammation and showed that adipose tissue synthesizes and releases the proinflammatory cytokine TNF-α [26]. Based on these findings, it was suggested that adipose tissue plays an important immune role and might be a major source of proinflammatory mediators, which initiate the development of low-grade chronic inflammation. Indeed, excess adipose tissue leads to high levels of proinflammatory cytokines TNF-α and IL-6 and a sensitive marker of inflammation C-reactive protein (CRP) in circulating blood. TNF-α is synthesized as a 26 kDa transmembrane protein. It has been shown that macrophages from the stromal vascular fraction are also the source of adipose-derived TNF-α and that its increased levels in obesity are due to the increased infiltration of adipose tissue with M1 macrophages [13]. Several studies have demonstrated that TNF-α impairs insulin signaling in hepatocytes and adipose tissue [27][28]. Moreover, IL-6 is a cytokine produced by many different cells. Approximately one-third of the IL-6 detected in plasma is attributed to the production from white adipose tissue [29]. In adipocytes and hepatocytes, IL-6 has been demonstrated to impair insulin-induced insulin receptor and insulin receptor substrate 1 phosphorylation [30][31]. Furthermore, it has been shown that IL-6 stimulates hepatocytes to produce and secrete CRP, indicating a state of inflammation [32]. CRP is a sensitive marker of inflammation, which is synthesized and secreted mainly by the liver [32], the serum concentrations of which are higher among obese subjects [33][34]. Adiponectin is one of the most abundant adipokines produced by adipocytes and is involved in glucose and lipid metabolism [35]. In adipose tissue, adiponectin exerts an anti-inflammatory function by reducing macrophage infiltration and inhibiting the local production of numerous proinflammatory cytokines [36]. Leptin, which is almost exclusively secreted from adipocytes, controls food intake and energy expenditure and has atherogenic and growth properties [37]. Since the discovery of leptin, the number of adipokines has notably increased in the last years with new molecules such as omentin-1, chemerin, resistin, visfatin, apelin, adipocyte fatty acid-binding protein (A-FABP), retinol-binding protein 4 (RBP4), among others [38]. Visfatin, originally identified as a pre-B-cell colony-enhancing factor (PBEF), is expressed in many cells and tissues act as a cytokine with immune regulatory action and as nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in the NAD+ salvage pathway [39].

3. Anti-Inflammatory Activity of Bilirubin

Bilirubin has evident anti-inflammatory activity, and indeed several studies have shown an inverse relationship between serum bilirubin levels and CRP in overweight or diabetic subjects [5][8][40][41]. Since low-grade chronic inflammation plays an important role in adipose tissue, the liver, the aorta, the kidneys, and pancreatic cells, the anti-inflammatory and antioxidative effects of bilirubin may likely contribute to the protective effect on vascular damage [1]. Recently, adipokines were studied along with serum bilirubin levels in normal and overweight asymptomatic adults. Importantly, there was an inverse relationship between serum bilirubin levels and proinflammatory cytokines (TNF-α, IL-6, visfatin, and CRP) and a positive relationship between serum bilirubin levels and adiponectin [5][42].
Moreover, recently biliverdin treatment reduced the expression levels of M1 macrophage markers in adipose tissues induced by high-fat diet feeding mice. This indicates that bilirubin may improve high-fat-diet-induced insulin resistance by reducing chronic inflammation in adipose tissue [10].
Additionally, adiponectin exerts anti-inflammatory and antiatherogenic properties via its ability to stimulate vascular endothelial nitric oxide (NO) production [43]. Equivalently, more recent studies have shown the role of bilirubin in the activation of Akt and endothelial nitric oxide synthase leading to the synthesis of NO, which can also improve endothelial cell function and insulin resistance [44].
To address the potency of bilirubin responses, in several animal models of endotoxemia, septicemia, and ischemia–reperfusion injury, bilirubin exhibited significant anti-inflammatory activity via mechanisms such as inhibiting the expression of adhesion molecules, suppressing the infiltration of inflammatory cells and reducing the levels of proinflammatory cytokines [45]. In another study, bilirubin also suppressed T cell proliferation and activation [46]. Overall, bilirubin has complex immunosuppressive effects [47]. A recent study also identified the neutrophil-to-lymphocyte ratio in blood as a variable that is negatively associated with total bilirubin levels [48].

4. Conclusions

Overweight and obese adults have lower serum bilirubin values compared to normal-weight individuals. Since bilirubin is an endogenous molecule with antioxidant, anti-inflammatory, antithrombogenic, endocrine, and many other activities, the modulation of serum bilirubin levels represents a novel therapeutic approach. Mildly increased serum bilirubin levels will protect other organs and directly affect the adipose tissue and its adipokine secretion pattern. In our opinion, the modulation of serum bilirubin levels will be an effective adjunctive therapy for obesity that can improve several obesity-induced pathological conditions.


  1. Inoguchi, T.; Sonoda, N.; Maeda, Y. Bilirubin as an important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes: A new aspect on old molecule. Diabetol. Int. 2016, 7, 338–341.
  2. Vitek, L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front. Pharmacol. 2012, 3, 55.
  3. Vitek, L.; Tiribelli, C. Bilirubin: The yellow hormone? J. Hepatol. 2021.
  4. Nano, J.; Muka, T.; Cepeda, M.; Voortman, T.; Dhana, K.; Brahimaj, A.; Dehghan, A.; Franco, O.H. Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence. Diabetes Metab. 2016, 42, 389–397.
  5. Yoshino, S.; Hamasaki, S.; Ishida, S.; Kataoka, T.; Yoshikawa, A.; Oketani, N.; Saihara, K.; Okui, H.; Shinsato, T.; Ichiki, H.; et al. Relationship between bilirubin concentration, coronary endothelial function, and inflammatory stress in overweight patients. J. Atheroscler. Thromb. 2011, 18, 403–412.
  6. Jenko-Praznikar, Z.; Petelin, A.; Jurdana, M.; Ziberna, L. Serum bilirubin levels are lower in overweight asymptomatic middle-aged adults: An early indicator of metabolic syndrome? Metabolism 2013, 62, 976–985.
  7. Friis, R.; Vaziri, N.D.; Akbarpour, F.; Afrasiabi, A. Effect of rapid weight loss with supplemented fasting on liver tests. J. Clin. Gastroenterol. 1987, 9, 204–207.
  8. Andersson, C.; Weeke, P.; Fosbol, E.L.; Brendorp, B.; Kober, L.; Coutinho, W.; Sharma, A.M.; Van Gaal, L.; Finer, N.; James, W.P.; et al. Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: An analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism 2009, 58, 1109–1115.
  9. DiNicolantonio, J.J.; McCarty, M.F.; O’Keefe, J.H. Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications. Open Heart 2018, 5, e000914.
  10. Takei, R.; Inoue, T.; Sonoda, N.; Kohjima, M.; Okamoto, M.; Sakamoto, R.; Inoguchi, T.; Ogawa, Y. Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines. PLoS ONE 2019, 14, e0223302.
  11. Calder, P.C.; Ahluwalia, N.; Brouns, F.; Buetler, T.; Clement, K.; Cunningham, K.; Esposito, K.; Jonsson, L.S.; Kolb, H.; Lansink, M.; et al. Dietary factors and low-grade inflammation in relation to overweight and obesity. Br. J. Nutr. 2011, 106, S1–S78.
  12. McArdle, M.A.; Finucane, O.M.; Connaughton, R.M.; McMorrow, A.M.; Roche, H.M. Mechanisms of obesity-induced inflammation and insulin resistance: Insights into the emerging role of nutritional strategies. Front. Endocrinol. 2013, 4, 52.
  13. 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.
  14. Xu, H.; Barnes, G.T.; Yang, Q.; Tan, G.; Yang, D.; Chou, C.J.; Sole, J.; Nichols, A.; Ross, J.S.; Tartaglia, L.A.; et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821–1830.
  15. Curat, C.A.; Wegner, V.; Sengenes, C.; Miranville, A.; Tonus, C.; Busse, R.; Bouloumie, A. Macrophages in human visceral adipose tissue: Increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006, 49, 744–747.
  16. Castoldi, A.; Naffah de Souza, C.; Camara, N.O.; Moraes-Vieira, P.M. The Macrophage Switch in Obesity Development. Front. Immunol. 2015, 6, 637.
  17. Lumeng, C.N.; Bodzin, J.L.; Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Investig. 2007, 117, 175–184.
  18. Mantovani, A.; Biswas, S.K.; Galdiero, M.R.; Sica, A.; Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 2013, 229, 176–185.
  19. Kratz, M.; Coats, B.R.; Hisert, K.B.; Hagman, D.; Mutskov, V.; Peris, E.; Schoenfelt, K.Q.; Kuzma, J.N.; Larson, I.; Billing, P.S.; et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 2014, 20, 614–625.
  20. Lumeng, C.N.; Saltiel, A.R. Inflammatory links between obesity and metabolic disease. J. Clin. Investig. 2011, 121, 2111–2117.
  21. Galic, S.; Oakhill, J.S.; Steinberg, G.R. Adipose tissue as an endocrine organ. Mol. Cell. Endocrinol. 2010, 316, 129–139.
  22. Kang, Y.E.; Kim, J.M.; Joung, K.H.; Lee, J.H.; You, B.R.; Choi, M.J.; Ryu, M.J.; Ko, Y.B.; Lee, M.A.; Lee, J.; et al. The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction. PLoS ONE 2016, 11, e0154003.
  23. Kershaw, E.E.; Flier, J.S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 2004, 89, 2548–2556.
  24. Fasshauer, M.; Bluher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 2015, 36, 461–470.
  25. Panee, J. Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. Cytokine 2012, 60, 1–12.
  26. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87–91.
  27. Ruan, H.; Miles, P.D.; Ladd, C.M.; Ross, K.; Golub, T.R.; Olefsky, J.M.; Lodish, H.F. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: Implications for insulin resistance. Diabetes 2002, 51, 3176–3188.
  28. Stephens, J.M.; Lee, J.; Pilch, P.F. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J. Biol. Chem. 1997, 272, 971–976.
  29. Mohamed-Ali, V.; Goodrick, S.; Rawesh, A.; Katz, D.R.; Miles, J.M.; Yudkin, J.S.; Klein, S.; Coppack, S.W. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 1997, 82, 4196–4200.
  30. Rotter, V.; Nagaev, I.; Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J. Biol. Chem. 2003, 278, 45777–45784.
  31. Senn, J.J.; Klover, P.J.; Nowak, I.A.; Zimmers, T.A.; Koniaris, L.G.; Furlanetto, R.W.; Mooney, R.A. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J. Biol. Chem. 2003, 278, 13740–13746.
  32. Volanakis, J.E. Human C-reactive protein: Expression, structure, and function. Mol. Immunol. 2001, 38, 189–197.
  33. Ebrahimi, M.; Heidari-Bakavoli, A.R.; Shoeibi, S.; Mirhafez, S.R.; Moohebati, M.; Esmaily, H.; Ghazavi, H.; Saberi Karimian, M.; Parizadeh, S.M.; Mohammadi, M.; et al. Association of Serum hs-CRP Levels with the Presence of Obesity, Diabetes Mellitus, and Other Cardiovascular Risk Factors. J. Clin. Lab. Anal. 2016, 30, 672–676.
  34. Ellulu, M.S.; Khaza’ai, H.; Rahmat, A.; Patimah, I.; Abed, Y. Obesity can predict and promote systemic inflammation in healthy adults. Int. J. Cardiol. 2016, 215, 318–324.
  35. Yamauchi, T.; Kamon, J.; Minokoshi, Y.; Ito, Y.; Waki, H.; Uchida, S.; Yamashita, S.; Noda, M.; Kita, S.; Ueki, K.; et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 2002, 8, 1288–1295.
  36. Dietze-Schroeder, D.; Sell, H.; Uhlig, M.; Koenen, M.; Eckel, J. Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. Diabetes 2005, 54, 2003–2011.
  37. Ahima, R.S.; Flier, J.S. Leptin. Annu. Rev. Physiol. 2000, 62, 413–437.
  38. Nakamura, K.; Fuster, J.J.; Walsh, K. Adipokines: A link between obesity and cardiovascular disease. J. Cardiol. 2014, 63, 250–259.
  39. Sonoli, S.S.; Shivprasad, S.; Prasad, C.V.; Patil, A.B.; Desai, P.B.; Somannavar, M.S. Visfatin—A review. Eur. Rev. Med. Pharmacol. Sci. 2011, 15, 9–14.
  40. Melissas, J.; Malliaraki, N.; Papadakis, J.A.; Taflampas, P.; Kampa, M.; Castanas, E. Plasma antioxidant capacity in morbidly obese patients before and after weight loss. Obes. Surg. 2006, 16, 314–320.
  41. Ohnaka, K.; Kono, S.; Inoguchi, T.; Yin, G.; Morita, M.; Adachi, M.; Kawate, H.; Takayanagi, R. Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res. Clin. Pract. 2010, 88, 103–110.
  42. Petelin, A.; Jurdana, M.; Jenko Praznikar, Z.; Ziberna, L. Serum Bilirubin Correlates with Serum Adipokines in Normal Weight and Overweight Asymptomatic Adults. Acta Clin. Croat. 2020, 59, 19–29.
  43. Chen, H.; Montagnani, M.; Funahashi, T.; Shimomura, I.; Quon, M.J. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J. Biol. Chem. 2003, 278, 45021–45026.
  44. Ikeda, N.; Inoguchi, T.; Sonoda, N.; Fujii, M.; Takei, R.; Hirata, E.; Yokomizo, H.; Zheng, J.; Maeda, Y.; Kobayashi, K.; et al. Biliverdin protects against the deterioration of glucose tolerance in db/db mice. Diabetologia 2011, 54, 2183–2191.
  45. Zhu, H.; Wang, J.; Jiang, H.; Ma, Y.; Pan, S.; Reddy, S.; Sun, X. Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation. Exp. Mol. Med. 2010, 42, 739–748.
  46. Liu, Y.; Li, P.; Lu, J.; Xiong, W.; Oger, J.; Tetzlaff, W.; Cynader, M. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. J. Immunol. 2008, 181, 1887–1897.
  47. Jangi, S.; Otterbein, L.; Robson, S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int. J. Biochem. Cell Biol. 2013, 45, 2843–2851.
  48. El-Eshmawy, M.M.; Mahsoub, N.; Asar, M.; Elsehely, I. Association between Total Bilirubin Levels and Cardio-metabolic Risk Factors Related to Obesity. Endocr. Metab. Immune Disord. Drug Targets 2021.
Subjects: Others
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 531
Revisions: 2 times (View History)
Update Date: 07 Sep 2021