Role of Adipokines in Obesity and Obesity related Metabolic Disorders
Jayamathi Govindaraj1*, Keerthidaa Govindaraj2, S. Raghavendra Jayesh3,
Kesavaram Padmavathy4, Mathangi Ramalingam5, Vidyarekha U.6
1Professor, Department of Biochemistry, Sree Balaji Dental College and Hospital,
Bharath Institute of Higher Education and Research, Pallikaranai, Chennai, 600100, India.
2MDS Department of Periodontics, Thai Mookambihai Dental College and Hospital,
MGR University, Maduravoyal, Chennai, India.
3Professor, Department of Prosthodontics, Sree Balaji Dental College and Hospital,
Bharath Institute of Higher Education and Research, (BIHER) Pallikaranai, Chennai, 600100, India.
4Associate Professor, Department of Microbiology, Sree Balaji Dental College and Hospital,
Bharath Institute of Higher Education and Research, Pallikaranai, Chennai, 600100, India.
5Professor, Department of Biochemistry, Sree Balaji Dental College and Hospital,
Bharath Institute of Higher Education and Research, (BIHER) Pallikaranai, Chennai, 600100, India.
6Senior Lecturer in Public Health Dentistry, Sree Balaji Dental College and Hospital,
Bharath institute of Higher Education and Research, Pallikaaranai, Chennai, 600100, India.
*Corresponding Author E-mail: gjayamathe@gmail.com, keerthidaagovindaraj@gmail.com
ABSTRACT:
Obesity is defined as an excessive growth of adipose tissue. It is associated with over nutrition, which impairs systemic metabolic homeostasis. Adipokines secreted by adipose tissue could play an vital role in the development of obesity and associated metabolic disorders includes insulin resistance, inflammation, hypertension, cardiovascular risk etc. Adipokines will be of importance in the development of novel therapies for obesity-associated diseases. This review emphasises on obesity and the role of some Adipokines in obesity and related metabolic disorders.
KEYWORDS: Obesity, adipose tissue, Adipokines.
INTRODUCTION:
Its consequences go far beyond adverse metabolic effects on health, causing oxidative stress, which leads to various inflammatory diseases2. The objective of this review is to describe the obesity specific-adipokine in obesity-related metabolic disorders.
Adipose tissue:
Adipose tissue also has a major endocrine function secreting adipokines which includes chemokines, cytokines and hormones etc. In mammals, the adipose tissue is composed of, the white adipose tissue (WAT) and the brown adipose tissue (BAT) which have different morphology, distribution, gene expression, and function. WAT is the main energy reservoir and secretes a huge number of hormones and cytokines that regulate metabolism and insulin resistance. The development of obesity depends not only on the balance between food intake and energy expenditure but also on the balance between white adipose tissue, as the main energy reservoir, and brown adipose tissue, specialized in energy expenditure. WAT has been recognized as an active endocrine organ that secretes a large number of bioactive polypeptides, i.e., adipokines3. Adipokines act centrally to regulate appetite and energy expenditure, and peripherally affect insulin sensitivity, oxidative capacity, and lipid uptake. Thus, in obesity, the release of adipokines leads to metabolic disturbances that could play a central role in the development of insulin resistance, type-2 diabetes and the increased risk of cardiovascular disease.
BAT could affect body metabolism and alter insulin sensitivity as well as modifying the susceptibility to develop obesity. The main role of brown adipose tissue is to convert food energy into heat; physiologically, both the heat produced and utilized during metabolism in a balanced manner reflects the metabolic efficiency4. Adiposity and adipocyte malfunction result in secretion of a wide range of adipose tissue derived secretory factors, referred to as adipokines, which may contribute to the development of various metabolic disorders via altered carbohydrate and lipid homeostasis as well as inflammatory responses.
Adipokines:
The term adipokines is used for any substance released by adipose tissue. In recent years, the number of adipokines has expanded rapidly and these include adiponectin, resistin, visfatin, apelin, retinol binding protein-4, serum amyloid A, plasminogen activator inhibitor-1, angiotensinogen, vaspin, omentin, chemerin etc. Proinflammatory cytokines produced by macrophages infiltrated in WAT, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, are also considered as adipokines5.
Table 1: Role of Adipokines in obesity
|
Adipokines |
Function |
|
Leptin |
Neuronal resistance to its action. Signals to the brain about body fat stores. Energy homeostasis. Wide variety of physiological functions |
|
Adiponectin |
Plays a protective role in the pathogenesis of type 2 diabetes and cardiovascular disease. are related to increase insulin sensitivity through activation of AMP protein kinase (AMPK) |
|
Resistin |
Induce insulin resistance via increased expression of gluconeogenic enzymes in liver and decreased activity of AMPK |
|
Plasminogen activator inhibitor-1(PAL-1) |
Responsible for decreased fibrinolytic system by inhibition of activation of plasminogen. |
|
Angiotensinogen |
Precursor of angiotensin II; A major role in blood pressure regulation through salt reabsorption in renal tubules and vasoconstriction. And electrolyte homeostasis. |
|
Serum amyloid A(SAA) |
SAA is associated with systemic inflammation and atherosclerosis |
|
Visfatin |
Potential glucose-lowering effect |
|
Vaspin |
Upregulates insulin resistance |
|
Omentin |
Anti inflammatory ability |
|
Chimerin |
Chemoattractant for immune cells |
|
TNF –α |
Inflammatory cell activation and recruitment |
|
IL-6 |
IL-6 is a proinflammatory factor produced by monocytes, fibroblasts and the stromal vascular fraction of visceral WAT |
|
SFRP5 |
SFRP5 regulates glucose homeostasis or insulin resistance |
Obesity and Insulin Resistance:
Obesity develops insulin resistance to, characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in fat and muscle6. Insulin resistance is a key etiological factor for type 2 diabetes mellitus (T2DM), which has reached epidemic proportions. The obesity-associated increase in FAs can trigger insulin resistance through intracellular metabolites that activate various signaling pathways that inhibit insulin signaling. FAs and potentially several metabolites including acyl-CoAs, ceramides, and diacyglycerol serve as signaling molecules that activate protein kinases such as Protein Kinase C (PKC), Jun kinase (JNK), and the inhibitor of nuclear factor-κB (NF-κB) kinase-β (IKKβ). These kinases can then impair insulin signaling by increasing the inhibitory serine phosphorylation of insulin receptor substrates (IRS), the key mediators of insulin receptor signaling. Obesity associated changes in secretion of adipokines that modulate insulin signaling. Obesity is characterized by an increase in the accumulation of adipose tissue macrophages, which increase the production of inflammatory cytokines which inturn inhibit insulin signaling. Endocrine and inflammatory mediators Converging on Serine/Threonine kinases that inhibit Insulin Signaling. Obesity- associated activation of NF-κB heightens inflammatory responses that exacerbate insulin resistance. Fatty acids also trigger insulin resistance by direct activation of TLR4 (Toll like receptor-4) and the innate immune response. In the obese person, the adipocyte is integral to the development of obesity-induced inflammation by increasing secretion of various pro-inflammatory chemokines and cytokines. Many of them, including monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, interlukin (IL)-1, IL-6 and IL-8, have been reported to promote insulin resistance. Insulin resistance is an central feature of metabolic dysfunction and is a major predictor of the development of type 2 diabetes7.
Secretion of inflammatory adipokines from adipose tissue in obese state:
In obese state, adipose tissue enlargement leads to dysregulated secretion of pro-inflammatory adipokines and increased release of free fatty acids, which modify inflammatory responses as well as glucose and lipid metabolism in tissues, thereby contributing to metabolic syndrome. In addition, obesity induces a phenotypic switch in adipose tissue from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages. On the other hand, the adipose tissue production of insulin- sensitizing adipokines with anti-inflammatory properties, such as adiponectin, is decreased in obese state. Evidence has suggested that the free fatty acids and various adipokines released from adipose tissue have been involved in abnormal insulin signaling. Obesity-induced insulin resistance is also associated with increased secretion of cytokines and other bioactive substances from adipose tissue as well as the number of adipose macrophages8. In the adipose tissue of obese person, there are a large number of macrophages infiltrations, and this recruitment is linked to the pathogenesis of obesity-induced inflammation and insulin resistance.
In obesity, the dysfunctional adipose tissue influences both carbohydrate and fat metabolism by secreting various adipokines, proinflammatory macrophages and elevated free fatty acids, in such a way, it impairs insulin signaling mechanisms. Adipose tissue in response to insulin, stimulates adipose tissue for storage of triglycerides, promoting the differentiation of preadipocytes to adipocytes, enhancing lipogenesis and inhibiting lipolysis9.
Adipocytes and immune cells (primarily macrophages) in the adipose tissue are the primary sources of many inflammatory proteins10. There are two types of inflammatory proteins: pro-inflammatory and anti-inflammatory. A number of pro-inflammatory proteins, including MCP-1, TNF-α, IL-6, IL-18, leptin, resistin, plasminogen activator inhibitor (PAI)-1, visfatin, retinol binding protein 4 (RBP4) and angiopoietin-like protein 2 (ANGPTL2). SFRP5 (secreted frizzled-related protein) is a new adipokine with insulin sensitizing and anti-inflammatory properties that exhibits beneficial effects on metabolic dysfunction. Several studies demonstrated that plasma levels of SFRP5 were lower in type 2 diabetes compared to normal glucose tolerance subjects, and its levels were negatively correlated with body mass index (BMI), and waist-to-hip ratio. In addition, circulating SFRP5 levels were increased after weight loss11. Tan (2013) reported a positive correlation between serum SFRP5 levels and parameters of glucose homeostasis or insulin resistance in healthy and obese subjects.
Obesity and obesity-related disorders:
Obesity increases the risk of many chronic diseases and contributes to functional disabilities. In obesity, adipose tissue enlargement leads to hypertrophy of adipocytes, characterize a macrophage infiltration, and fibrosis, could lead to regions of hypoxia which could activate an inflammatory response. On the other hand, hypertrophic adipocytes shift the immune balance towards the production of proinflammatory molecules12. In addition, the development of hypoxic conditions in the expanded WAT during obesity results in an increased production of reactive oxygen species and the corresponding development of oxidative stress13. This phenomenon could alter the adipokine profile via reduced adiponectin expression and increased leptin and RBP-4 secretion. Increased TNF-α and IL-6 production by adipose tissue infiltrated-macrophages were associated with insulin resistance, atherogenic effects and dysregulation of other adipokines, mainly ZAG and adiponectin14. Adipocytes are leptin responsive and secrete adipokines to stimulate insulin sensitivity and fatty acid oxidation15. In obesity, adipocytes are hypertrophic and resistant to leptin and insulin action Fat mass expansion is associated with production of adipokines such as RBP-4, SSA, PAI-1, angiotensinogen involved in hypertension, insulin resistance and atherogenesis in obesity, an over expression of angiotensinogen and an increased activity of vasoconstrictor renin-angiotensin system have been demonstrated16. The obesity-related diseases are characterized by inflammatory pathophysiology induced by several risk factors and an onset generally correlated with ageing process.
Therapeutic approach of obesity:
An early indication for the treatment of obesity along with caloric restriction is physical exercise in dosed way appropriate to the physical condition of each patient. There are considerable evidences that caloric restriction increases the life expectancy and reduces the risk of developing diabetes, cardiovascular disease, degenerative disorders, and some types of cancer. In addition to caloric restriction, there are evidences showing that an energy balance maintained for several months, which includes an increase in energy expenditure, tends to be effective in lowering adiposity17. Another aspect that enhances the physical exercise in obese patients is the lipid profile. First, it raises HDL levels and therefore lowers the LDL/HDL ratio and increases the size of the LDL and HDL particles leading to a less atherogenic lipid profile. Moreover, a regular physical exercise also decreases adiposity, through an improvement in insulin sensitivity, produces an increase in oxidative potential and thus promotes the metabolism of more lipids and carbohydrates in the aerobic way. Therefore, the physical exercise will be essential for a more effective treatment of type-2 diabetes and associated diseases18.
CONCLUSION:
Obesity is associated with metabolic dysfunction, such as insulin resistance, dyslipidemia and other disorders. Enlarged adipose tissue results in the infiltration of macrophages and imbalance between pro-inflammatory and anti-inflammatory factors secreted by adipose tissue, which lead to the promotion of inflammation, impairment of insulin sensitivity and dysregulation of lipid metabolism. Thus, obesity-specific adipokine profile could play a central role in obesity-related metabolic derangements. Thus, further elucidation of the functions and mechanisms of adipose tissue-released bioactive substances will lead to a better understanding of the development of obesity-related metabolic syndrome, and it may provide novel therapeutic approaches to prevent or treat obesity and its metabolic complications.
CONFLICT OF INTEREST:
The authors have no issue of conflict of interest.
REFERENCES:
1. Reaven G, Abbasi F, Mc. Laughlin T. Obesity, insulin resistance and cardiovascular disease. Recent Prog Horm Res. 2004; 59: 207-23.
2. Xu H, Barnes G.T, Yang, Q, Tan G, Yang D, Chou C.J, Sole J. Nichols A, Ross JS, Tartaglia LA. 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.
3. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol. 2004; 89: 2548-56.
4. Aldhahi W and Hamdy O. Adipokines, inflammation, and the endothelium in diabetes. Current Diabetes Reports. 2003; 3(4): 293-298.
5. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous adipose tissues of obese humans. Endocrinology. 2004; 14: 52273-82.
6. Saltiel AR., Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414: 799-806.
7. Petersen KF, Shulman GI. Etiology of insulin resistance. Am. J. Med. 2006; 119(Suppl. 1): S10–S16.
8. Chawla A, Nguyen KD, and Goh YPS. Macrophage-mediated inflammation in metabolic disease. Nature Reviews Immunology 2011; 11(11): 738-749
9. Gil A, Aguilera CM, Gil-Campos M, and Cañete R. Altered signalling and gene expression associated with the immune system and the inflammatory response in obesity, British Journal of Nutrition. 2007; 98(1): S121-S126.
10. Fain, J.N. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: A review. Mediat. Inflamm. 2010; 2010: 513948.
11. Tan X, Wang X, Chu H, Liu H, Yi X, Xiao Y. SFRP5 correlates with obesity and metabolic syndrome and increases after weight loss in children. Clin. Endocrinol. (Oxf) 2014; 81(3): 363-9.
12. Bourlier V, Zakaroff-Girard A, Miranville A et al., “Remodeling phenotype of human subcutaneous adipose tissue macrophages,” Circulation 2008; 117(6): 806-815
13. Houstis N, Rosen ED, and Lander ES, “Reactive oxygen species have a causal role in multiple forms of insulin resistance” Nature 2006; 440(7086): 944-948.
14. Lago F, Dieguez C, Gómez-Reino J, and Gualillo O, “Adipokines as emerging mediators of immune response and inflammation,” Nature Clinical Practice Rheumatology 2007; 3(12): 716-724.
15. Wang ZV and Scherer PE, “Adiponectin, cardiovascular function, and hypertension,” Hypertension 2008; (51)1 : 8-14.
16. Engeli S, Schling P, Gorzelniak K et al., “The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome?” International Journal of Biochemistry and Cell Biology, 2003; 35(6): 807-825.
17. Atluri P, Morine KJ, Liao GP et al, “Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression,” Cellular and Molecular Biology Letters 2007; 12(1): 127-138.
18. Bobbert T, Rochlitz H, Wegewitz U et al., “Changes of adiponectin oligomer composition by moderate weight reduction,” Diabetes 2005; 54(9): 2712-2719.
Received on 11.11.2019 Modified on 14.01.2020
Accepted on 23.03.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(8):4261-4264.
DOI: 10.52711/0974-360X.2021.00739