Open access peer-reviewed chapter - ONLINE FIRST

Adipocytokines: Are They the Theory of Cancer Progression?

Written By

Rowyda Nawwaf Al-Harithy

Submitted: March 8th, 2022 Reviewed: March 21st, 2022 Published: April 30th, 2022

DOI: 10.5772/intechopen.104581

Tumor Angiogenesis Edited by Ke Xu

From the Edited Volume

Tumor Angiogenesis [Working Title]

Dr. Ke Xu

Chapter metrics overview

11 Chapter Downloads

View Full Metrics


Adipocytokines have gained significant attention in the scientific community over the past few decades. They are a family of enzymes, hormones, growth factors, proteins, and other bioactive molecules that are important regulators of many processes. Adipocytokines are predominantly produced by preadipocytes and mature adipocytes to act through a network of autocrine, paracrine, and endocrine pathways. Leptin (LEP) is the first adipocytokine discovered that has a role in modulating adiposity and has been shown to exert pleiotropic effects on many metabolic pathways through the leptin receptors (LEPRs). LEP has pro-tumoral roles; it promotes angiogenesis, proliferation, survival of tumor cells, and inhibits apoptosis. To exercise its role in tumorigenesis, LEP-LEPR signaling and epithelial-mesenchymal transitions (EMTs) play a significant role. LEP is an oncogenic factor mainly due to its proinflammatory and proangiogenic effects. In angiogenesis, LEP acts directly as an endothelial growth factor or indirectly through cellular pathways, such as STAT3/ERK1/2, JAK2/STAT3, MAPK/ERK, PI3K/AKT, p38, p53, MAPK, and Wnt/β-catenin.


  • adipocytokines
  • leptin
  • inflammation
  • angiogenesis
  • cancer

1. Introduction

Adipose tissue is a complex, dynamic, and heterogenic endocrine organ with diverse homeostatic processes [1]. During the past few decades, the structural and functional principles of adipose tissue have evolved considerably to get to today’s concept [2]. In the human body, the adipose tissue is restricted in depot sites and varies in cellular composition and character. Adipose tissue can be classified by morphology into white, brown, beige, pink, and yellow [3]. Our understanding of their importance started with identifying a range of adipose tissue products and their functions. Since then, much has been learned about how adipose tissue communicates with other organs of the body. More recently, its functions have been reported to be highly influenced by bioactive molecules with widespread systemic effects contributing to numerous physiological and pathological processes [4]. The white adipose depots are considered a specialized organ representing the largest endocrine tissue in humans. It can be broadly classified by location into subcutaneous and visceral. In its different locations, it shows different metabolic profiles with different functions. In general, they are responsible for storing chemical energy formatted as triglycerides packed in unilocular lipid droplets. The white adipocytes, especially in the visceral area, secrete abundant mediators, including exosomes, miRNA, lipids, inflammatory cytokines, and peptide hormones that participate in the process of interorgan communication via paracrine and endocrine modes [5].

White adipose tissue comprises many different cell types; approximately 40–50% of the cells are adipocytes, with the rest represented by the stromal vascular fraction (SVF) of cells, including preadipocytes, fibroblasts cells, endothelial cells, vascular progenitor cells, mesenchymal stem cells, and a variety of immune cells (macrophages, natural killer cells, B-lymphocytes, and T-lymphocytes) [6]. Adipocytes, specific to white adipose tissue, are plastic and respond to changes in metabolism by altering their size, number, and their exerted functions [7, 8]. The white adipose tissue multifarious composition renders white adipose tissue an important mediator of metabolism and inflammation [9]. White adipose tissue influences metabolism through maintaining energy homeostasis, adipocyte differentiation, and insulin sensitivity. It also affects inflammation through its actions in the immune system as pro- and anti-inflammatory mediators (Figure 1). This function is controlled by numerous adipocytokines, other cytokines, chemokines, and growth factors [10]. While the term adipokine is commonly used to refer to adipose tissue-derived proteins, adipocytokines are mainly, but not solely, produced by adipocytes.

Figure 1.

Adipocytokines and their mechanisms as an anti-inflammatory and proinflammatory.


2. Adipocytokines

The word adipocytokine is derived from the Greek root meaning fat cell movement. Adipocytokines are produced exclusively or substantially by preadipocytes and mature adipocytes, hence their name. They are biologically active molecules that are important regulators for many physiological processes. Adipocytokines are heterogeneous in structure and function, which is mainly affected by the specific anatomical location of the producing adipocytes. Adipocytokines have the ability to act locally or distally as inflammatory, immune, or hormonal signalers. They can be categorized in terms of their function as metabolic factors, proinflammatory factors, proangiogenic factors, and extracellular matrix components. Adipocytokines are secreted in response to different triggers; their involvement has been noted in insulin action, endothelial cell function, blood pressure, appetite, hemostasis, reproduction, angiogenesis, and immunity [11].

The year 2022 marks the 35th anniversary of adipocytokines. The breakthrough discovery of the first adipocytokine, adipsin, followed by tumor necrosis factor (TNF), leptin (LEP), and adiponectin led to the widespread recognition of adipose tissue as an endocrine organ. Adipsin (also known as complement factor D) was identified as an adipokine in 1987 [12]. In 1993, TNF was identified as a proinflammatory adipocytokine in the models of diabetes and obesity, becoming pioneering evidence for a functional link between obesity and inflammation [13]. The identification and cloning of LEP in 1994 followed by that of adiponectin in 1995 were an inflection point into the endocrine era [14, 15]. LEP and adiponectin are the classic adipocytokines of visceral adipose tissue and clearly the two most widely studied adipocyte products. LEP is acknowledged as an adipose tissue-specific secreted protein that regulates food intake and energy. Adiponectin, also known as ACRP30, AdipoQ , and gelatin-binding protein-28, has anti-inflammatory actions on the liver, the heart, the kidneys, muscle cells, and pancreatic β cells, to name a few [16, 17, 18]. It plays roles that are most likely relevant to cognitive dysfunction, namely, synaptic regulation, insulin sensitivity, neuroinflammation, neuroprotection, and neurogenesis [19, 20].

Adiponectin and LEP’s detailed mechanisms of action at the cellular level of their target organs and their mutual effects on each other remain ambiguous. Despite extensive research on the topic, much more regarding LEP and adiponectin, their relationship to each other and to the body remains to be discovered. However, it is important to note that the ratio of adiponectin to LEP has been proposed as a marker of adipose tissue dysfunction [21, 22]. On review of the literature, LEP is found to be the most studied in the context of cancer risk and progression (Figure 1).


3. Leptin

Friedman and his colleagues discovered LEP in 1994 and named it after the word “leptos,” which means thin in Greek reference to its demonstrated effect on the body. In humans, LEP is encoded by the LEP gene that is located on chromosome 7 7q31.3 and consists of three exonic regions with two intronic regions. It is a nonglycosylated adipocytokine consisting of 146 amino acids. LEP is a multifunctional adipocytokine primarily secreted by the white adipocytes. LEP is also produced by other tissues, such as the stomach, placenta, and mammary glands [23, 24, 25, 26]. The past 25 years of research on LEP have provided important insights into the intricate network that links nutrition, metabolism, reproduction, endocrine regulation, inflammation, and immune function [27, 28, 29]. LEP is a key regulator of the adipose organ, and its main task is to regulate energy balance, which is possible by lowering the appetite. The essential characteristics of LEP are listed in Table 1.

Leptin (LEP)Signals through leptin receptor isoform b (LEPRb)
Binds short and soluble leptin receptor isoforms (LEPRa, LEPRc)
Regulates bone mass
Regulates reproduction
Regulates body weight gain
Regulates immune cell functions
Regulates food intake and energy expenditure
Regulates glucose tolerance and insulin sensitivity
Regulates brain sympathetic output to different tissues
May regulate body temperature
May regulate hematopoiesis
Induce epithelial-mesenchymal transition
Promote adipogenesis
Increases adipocyte lipolysis
Increases angiogenesis
Increases brown adipose tissue activity
Increases skeletal muscle cell glucose uptake
Increases adipocyte, hepatocyte, and skeletal muscle cell fatty acid oxidation
May increase adipose tissue stromal cell proliferation
May increase white adipose tissue browning
Decreases adipocyte glucose uptake
Decreases adipocyte, hepatocyte, and skeletal muscle cell lipogenesis

Table 1.

The functions of leptin.

LEP expression in the adipose tissue is influenced by a variety of hormones, including insulin, glucocorticoids, catecholamines, and cortisol, and several other metabolic factors, including TNF-α, fatty acids, and glucose [30, 31, 32, 33]. Recently, a fat-specific long noncoding RNA (lncRNA) has been identified to interact with redundant enhancers and regulate LEP expression [34]. LEP deficiency or resistance is associated with the dysregulation of cytokine production, increased susceptibility to infections, autoimmune disorders, malnutrition, and inflammatory responses. The elevated levels of serum LEP have been unequivocally correlated with an increased risk of developing various tumor forms, including testicular, breast, prostate, colon, and pancreatic cancers [35, 36, 37, 38, 39, 40]. The short-, medium-, and long-term regulatory actions of LEP are supported by its specific LEP receptor (LEPR). The LEPR is a class I cytokine receptor and structurally a transmembrane receptor encoded by the LEPR(OBR) gene on chromosome 1p31.3 [41, 42, 43]. In humans, there are at least four splice variants of the LEPR gene that have been identified and categorized as long (LEPRb), short (LEPRa, and LEPRc), and secretive (LEPRe) isoforms. The isoforms have different lengths of intracellular C-terminal domains. The LEPRb contains the full intracellular domain 303 amino acids, and the short isoforms contain 32–40 amino acids. Although long and short isoforms share a sequence of 29 amino acids proximal to the transmembrane region, the LEPRe isoform lacks both transmembrane and cytoplasmic domains [44, 45]. The long LEPR contains the full intracellular domain to fully induce intracellular signaling necessary for the activation of critical second messenger pathways and normal leptin action. The LEPR isoforms are distributed in almost all peripheral tissues and seem to mediate the transport of LEP. In humans, the effects of LEP can be detected at various sites given that LEPR are found in the brain, heart, placenta, lung, liver, muscle, kidney, pancreas, spleen, thymus, prostate, testes, ovary, small intestine, and colon [46]. Therefore, LEPR locations demonstrate LEP’s importance in human molecular processes. The signaling events that follow the binding of LEP to its LEPRs have been studied extensively and characterized at the biochemical and molecular levels in many systems and, more recently, in relation to immune responses [47].


4. Leptin and cancer

LEP is the most studied adipocytokine, particularly in metabolism and obesity-related cancers. It is well established that LEP has pro-tumoral roles; it promotes angiogenesis, proliferation, survival of tumor cells, and inhibits apoptosis [48]. To exercise its role in tumorigenesis, LEP-LEPR signaling and epithelial-mesenchymal transitions (EMTs) play a significant role in tumor initiation, progression, metastasis, and chemoresistance. The function of the leptin axis in cancer is through LEP-LEPR singling. The binding of LEP to LEPR induces the activation of several signaling pathways, such as JAK/STAT3, PI3K/AKT, and MAPK/ERK. Cumulative research demonstrated high levels of LEP and LEPR expression in cancer cells. LEP and LEPR levels are usually missing in epithelial breast tissue but are found in abundance in breast cancer [49]. Other cancers that show high levels of LEP and LEPR include hepatocellular carcinoma [50], lung cancer [51], prostate cancer [52], colorectal cancer [53], melanoma [54], ovarian cancer [55] renal carcinoma [56], and breast cancer (Figure 2) [57]. It was also demonstrated that the upregulated level of LEP correlates with clinical and prognostic outcomes in multiple cancer types such as the presence of remote metastasis of breast cancer and the short survival of its patients. The level of LEP expression is influenced by numerous physiological mechanisms, which are noted to be associated with fat mass. One of such mechanisms is the ability of inflammatory cytokines, i.e., TNF-α, interleukin-1 (IL-1), and leukemia inhibitory factor, to induce adipocytes to produce LEP and increase the expression of its mRNA synthesis [58]. Another factor is the genetic variations in the LEPgene and/or LEPRgene that modulates LEP level [59, 60]. The genetic variations in these genes have been specifically linked to the progression of prostate, breast, gastric, and lung carcinomas [61, 62, 63]. Since the proposal of LEP as an EMT inducer a decade ago, research has proven it to be very important in driving the cellular process to aggressive cancer phenotypes. EMT is a complex reprogramming cellular process allowing epithelial cells to acquire mesenchymal characteristics, an important role in the tumor microenvironment (TME). This change enhances migratory and invasive capability and has been demonstrated to be essential in the metastatic spread of several cancer types, including prostate, lung, liver, pancreatic, and breast cancers [64, 65]. EMT programs were also found to stimulate the production of LEP by cancer cells, suggesting a signaling loop in tumor progression. Other important signaling molecules involved in the process include integrins, growth factors, and cytokines, such as IL-8, IL-6, and TNF-α, which are often secreted by tumor stroma [66, 67]. Literature has also documented that EMT programs can stimulate the production of proinflammatory factors. Olea-Flores demonstrated the mechanism by which LEP promotes EMT programming, through Src and FAK activations that control the secretion and activation of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). Leptin promotes the expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells [68]. In a recent review, Tsung-Chieh and Michael indicated that cancer cells and the tumor microenvironment express LEP and LEPRs and suggested that the potential leptin autocrine/paracrine signaling loop could affect tumor progression [49].

Figure 2.

LEP and LEPR expression in a pancancer panel. From Lin and Hsiao [49].

Other studied theories on the involvement of LEP in carcinogenesis were described to be mediated by LEPR activation of PI3K, ERK1/2, and Jak2/Stat3 signaling pathways. These pathways regulate the expression of cancer-related genes, such as cyclin D1, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and potentiate several procarcinogenic processes, including angiogenesis, migration, and mesenchymal transformation [69, 70]. Additionally, in vitrostudies have documented the antiapoptotic and mitogenic effects of LEP on different cancer cell lines. Zhang and his team have shown that LEP can play the role of being an antiapoptotic by regulating the expression of proteins involved in the apoptotic pathway. They observed that LEP decreases the apoptotic potential of adipose tissue by increasing the Bcl2 and decreasing proapoptotic Bax and CD95 protein expression [71]. More importantly, LEP has been studied as an oncogenic factor due to its proinflammatory and proangiogenic effects.


5. Role of leptin as a proinflammatory factor

The immune system response, acute and chronic inflammation, is called into action when other homeostatic mechanisms are inadequate. Inflammatory mediators play a significant role, adjacent in importance to mutations and epigenetic alterations. In tumor initiation, LEP plays a pleiotropic role in the immune response and can appropriately be considered, both structurally and functionally, as a proinflammatory cytokine. LEP regulates both innate and adaptive immune responses through the modulation of immune cells’ survival and proliferation as well as its activity [72, 73, 74]. LEP has a modulatory impact on the course of inflammation, affecting the expression of proinflammatory cytokines and their receptors. In the innate immune response, LEP enhances the secretion of TNF-α, a proinflammatory mediator, and interacts with interleukin1beta (IL1β) [75]. IL1β has the ability to increase the levels of cytokines, such as Interleukin 6 (IL6), Interleukin 8 (IL8), and prostaglandin E2 (PGE2), by its mechanism on nitric oxide synthase-2 (NOS2) through the JAK2, PI3K, MAP2K1/MEK1, and MAPK14/p38 signaling pathways [76]. These cytokines also regulate the expression of LEP, creating a signaling loop that supports sustaining a chronic proinflammatory state [77]. In the adaptive immune response, LEP promotes the alteration of memory T-cells immune response toward T helper-1 cells, as well as escalating CD4+CD25– T-cell proliferation and reducing the autophagy process during T-cell receptor (TCR) stimulation by triggering MTOR signaling pathway and upregulating the synthesis of B-cell lymphoma 2 (BCL2) [78]. LEP controls the crosstalk between innate and adaptive immunity by affecting dendritic cell number, maturation, cytokine production, and capacity to induce CD4+ T-cell proliferation [79]. Chronic infectious, immune, and metabolic diseases may lead to LEP resistance, increasing LEP levels and further fueling the inflammatory state. LEP’s involvement in the immune and inflammatory response has become increasingly evident and, in turn, is important in cancer.


6. Role of leptin as an angiogenic growth factor

Angiogenesis, a hallmark of cancer, refers to the formation of new blood vessels from preexisting ones. It is a vital process that plays a role in normal physiological as well as pathological processes. Angiogenesis enables tumor growth and metastasis through a multistep progression commencing with endothelial cell migration, proliferation, invasion, and ultimately novel capillary formation. Though the basic steps of angiogenesis are similar in all tissue, it is likely that the vascular network of each organ will be established through tissue-specific key mechanisms. Angiogenesis requires a balance between proangiogenic and antiangiogenic factors; changes in equilibrium can lead to oncogenic angiogenesis.

White adipose tissue is embedded in a dense vascular network and is the most vascularized tissue in the human body. The hypervascularization of the white adipose tissue indicates the presence of an intimate interplay between both the vascular and adipose compartments. The functions of adipose vasculature are summarized in Table 2. It has been previously noted that the white adipose tissue regulates the production of various adipocytokines, but it also releases angiogenic factors; therefore, it influences and modulates angiogenesis as well as vascular structure [80, 81, 82]. Scientific research has been able to narrow the culprits of angiogenic growth in white adipose tissue to two possibilities: first, in response to signals initiating from neighboring adipocytes that are undergoing proliferation and enlargement; the other possibility is through metabolic signals produced locally or distally. These two possibilities are not mutually exclusive, and probably tissue expansion involves both local signals arising from expanding adipocytes and distant signals reflecting the developmental and metabolic state of the whole organism. It has been acknowledged that adipogenesis, angiogenesis, and vascular remodeling are tightly related and regulated processes. Dysfunction in the regulation of one or more of these processes leads to changes in vessel growth, vascular permeability, remodeling, adipose mass, and function, which will ultimately cause pathological angiogenesis or vascular regression [83].

Adipose vasculature functions
1Providing nutrients and oxygen essential for the maintenance of adipocyte survival and functions
2Removing metabolic products from adipose tissue
3Paracrine regulation of adipocyte functions through the production of various factors and cytokines from vascular cells
4Transporting adipose-tissue-derived growth factors, adipokines, and cytokines for removal of tissues globally regulating physiological functions via the endocrine mechanism
5Transporting non-adipose-tissue derived growth factors, cytokines, and hormones for modulating adipocyte functions and growth
6Alteration of the adipose microenvironment such as hypoxia and acidosis, which control adipocyte function, preadipocyte differentiation, and adipose tissue mass
7Supplying circulating stem cells from non-adipose tissues to adipose tissues
8Supplying adipocyte vessel wall stem and precursor cells that can eventually differentiate into mature adipocytes
9Supplying other cell types such as inflammatory cells that secondarily affect adipocyte function
10Preparation of adipose niche formation during embryonic development by the vasculature

Table 2.

Adipose vasculature functions in the modulation of adipocyte functions.

In white adipose tissue, LEP was found to be an important proangiogenic factor or an angiogenesis inducer [84]. In 1998, Sierra-Honigmann and colleagues produced one of the first studies to demonstrate that leptin-induced cell proliferation, cell survival, and 3D matrix formation of capillary-like tubes mimicking vascular endothelial growth factor (VEGF) 165 [85]. This supported the notion that LEP is an endothelial growth factor. LEP is able to act as a direct factor to induce the angiogenic potential of endothelial cells evident by the presence of LEPR on endothelial cells. Both in vivoand in vitrostudies have demonstrated the activation of endothelial LEPR by LEP, leading to capillary tube formation [86]. The indirect involvement of LEP in angiogenesis has been explored immensely. Garonna et al. showed that leptin enhances endothelial cyclooxygenase-2 (COX-2) expression and causes rapid VEGFR2 phosphorylation through the activation of P38 MAPK/AKT/COX-2, which is needed for leptin-stimulated neoangiogenesis [87]. LEP increases the levels and activity of enzymes involved in angiogenesis through metalloproteinase-2 (MMP-2) and MMP-9 activity [82]. Additionally, LEP has been shown to upregulate and act synergistically with the key angiogenic mediators like fibroblast growth factor (FGF)-2, VEGF, and its receptor VEGFR, resulting in stimulation of blood-vessel growth [88]. The VEGF and VEGFR have a special signaling transduction system that plays a significant role in the process of oncogenic angiogenesis. In vitroand in vivofindings have implicated the role of VEGFR in the facilitation of angiogenic growth and endothelial cell tube development [89]. LEP can upregulate VEGF expression and function, VEGF can, in turn, activate LEP demonstrating the functional interplay between both cytokines. The increase in the presence of both cytokines could generate and amplify a proangiogenic environment. Moreover, crosstalk between LEP and VEGF has been noted in other tissues, such as in cancerous breast tissue; LEP activates HIF-1α and NF-κB to upregulate VEGF [89]. Additionally, LEP is involved in tumor angiogenesis-related signaling pathways such as STAT3/ERK1/2, JAK2/STAT3, MAPK/ERK, PI3K/AKT, p38, p53, MAPK, and Wnt/β-catenin [90]. Less studied are the Akt and Wnt signaling pathways’ effect on the proliferation and angiogenic differentiation of endothelial cells, though LEP’s involvement was demonstrated [91]. Furthermore, distinct mechanisms, regulated Wnt-responsive GSK-3β and growth factor/Akt responsive GSK-3β, suggest that GSK-3β has a crucial role in the crosstalk between the Akt and Wnt signaling pathways [92]. However, the underlying cellular mechanism remains to be elicited. Of note, tumor angiogenesis is closely associated with the tumor microenvironment and is regulated by a variety of proangiogenic factors and/or angiogenic inhibitors. The genetic and epigenetic alterations of angiogenesis-associated genes might result in angiogenesis dysfunctions and promote tumorigenesis.



The author would like to thank Dr. Rayya Alharthi for her support and for editing this chapter.


  1. 1. Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. The Journal of Clinical Investigation. 2019;129(10):3990-4000
  2. 2. Poulos SP, Hausman DB, Hausman G, J. The development and endocrine functions of adipose tissue. Molecular and Cellular Endocrinology. 2010;323(1):20-34
  3. 3. Zinngrebe J, Debatin K, Fischer-Posovszky P. Adipocytes in hematopoiesis and acute leukemia: Friends, enemies, or innocent bystanders? Leukemia. 2020;34:2305-2316
  4. 4. Schoettl T, Fischer IP, Ussar S. Heterogeneity of adipose tissue in development and metabolic function. The Journal of Experimental Biology. 2018;7:221
  5. 5. Bruna B, Brandão BB, Guerra BZ, Mori MA. Shortcuts to a functional adipose tissue: The role of small non-coding RNAs. Redox Biology. 2017;12:82-102
  6. 6. Vazquez-Vela ME, Torres N, Tova AR. White adipose tissue as endocrine organ and its role in obesity. Archives of Medical Research. 2008;39(8):715-728
  7. 7. Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proceedings of the National Academy of Sciences. 2010;107(42):18226-18231
  8. 8. Niersmann C, Carstensen-Kirberg M, Maalmi H, Holleczek B, Roden M, Brenner H, et al. Higher circulating omentin is associated with increased risk of primary cardiovascular events in individuals with diabetes. Diabetologia. 2020;63:410-418
  9. 9. Juge-Aubry CE, Henrichot E, Meier CA. Adipose tissue a regulator of inflammation. Best Practice & Research. Clinical Endocrinology & Metabolism. 2005;19(4):547-566
  10. 10. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Molecular Endocrinology. 2008;22:1023-1031
  11. 11. Zorena K, Jachimowicz-Duda O, Slezak D, Robakowska M, Mrugacz M. Adiokines and obesity. Potential link to metabolic disorders and chronic complications. International Journal of Molecular Sciences. 2020;21(10):3570
  12. 12. Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR, et al. Adipsin: A circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science. 1993;237(4813):402-405
  13. 13. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87-91
  14. 14. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432
  15. 15. Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gómez-Reino JJ, et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nature Reviews Rheumatology. 2017;13:100-109
  16. 16. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. The Journal of Biological Chemistry. 1995;270:26746-26749
  17. 17. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. The Journal of Biological Chemistry. 1996;271:10697-10703
  18. 18. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochemical and Biophysical Research Communications. 1996;221(2):286-289
  19. 19. Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K. Obesity, adiponectin and vascular inflammatory disease. Current Opinion in Lipidology. 2003;14:561-566
  20. 20. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clinica Chimica Acta. 2007;380(1-2):24-30
  21. 21. Vega GL, Grundy SM. Metabolic risk susceptibility in men is partially related to adiponectin/leptin ratio. Journal of Obesity. 2013;2013:409679
  22. 22. Frühbeck G, Catalán V, Rodríguez A, Gómez-Ambrosi J. Adiponectin-leptin ratio: A promising index to estimate adipose tissue dysfunction. Relation with obesity-associated cardiometabolic risk. Adipocyte. 2018;7:57-62
  23. 23. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, et al. Nonadipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans. Nature Medicine. 1997;3(9):1029-1033
  24. 24. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, et al. The stomach is a source of leptin. Nature. 1998;394(6695):790-793
  25. 25. Smith-Kirwin SM, O’Connor DM, Johnston J, de Lancy E, Hassink SG, Funanage VL. Leptin expression in human mammary epithelial cells and breast milk. The Journal of Clinical Endocrinology and Metabolism. 1998;83(5):1810-1813
  26. 26. Cinti S, De Matteis R, Pico C, Ceresi E, Obrador A, Maffeis C, et al. Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin. International Journal of Obesity. 2000;24(6):789-793
  27. 27. Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proceedings of the National Academy of Sciences. 2006;103(22):8481-8486
  28. 28. Hausman GJ, Barb CR, Lents CA. Leptin and reproductive function. Biochimie. 2012;94(10):2075-2081
  29. 29. Friedman JM. Leptin and the endocrine control of energy balance. Nature Metabolism. 2019;1(8):754-764
  30. 30. Licinio J, Negrao AB, Wong ML. Plasma leptin concentrations are highly correlated to emotional states throughout the day. Translational Psychiatry. 2014;4(10):e475-e475
  31. 31. Lee SM, Choi HJ, Oh CH, Oh JW, Han JS. Leptin increases TNF-α expression and production through phospholipase D1 in Raw 264.7 cells. PLOS One. 2014;9(7):e102373
  32. 32. Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metabolism. 2016;23(5):770-784
  33. 33. Kumar R, Mal K, Razaq MK, Magsi M, Memon MK, Memon S, et al. Association of leptin with obesity and insulin resistance. Cureus. 19 Dec 2020;12(12):e12178
  34. 34. Dallner OS, Marinis JM, Lu Y-H, Birsoy K, Werner E, Fayzikhodjaeva G, et al. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity. Nature Medicine. 2019;25(3):507-516
  35. 35. Salageanu A, Tucureanu C, Lerescu L, Caras I, Pitica R, Gangura G, et al. Serum levels of adipokines resistin and leptin in patients with colon cancer. Journal of Medicine and Life. 2010;3:416-420
  36. 36. Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression. World Journal of Gastroenterology. 2014;20:5177-5190
  37. 37. Pan H, Deng LL, Cui JQ , Shi L, Yang YC, Luo JH, et al. Association between serum leptin levels and breast cancer risk: An updated systematic review and meta-analysis. Medicine. 2018;97:e11345
  38. 38. Andò S, Catalano S. The multifactorial role of leptin in driving the breast cancer microenvironment. Nature Reviews. Endocrinology. 2011;8:263-275
  39. 39. Inagaki-Ohara K. Gastric leptin and tumorigenesis: Beyond obesity. International Journal of Molecular Sciences. 2019;20(11):2622
  40. 40. Victoria B, Camelia BL. Serum leptin level as a diagnostic and prognostic marker in infectious diseases and sepsis: A comprehensive literature review. Medicine. 2021;100(17)
  41. 41. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor. OB-R. Cell. 1995;83:1263-1271
  42. 42. Tartaglia LA. The leptin receptor. The Journal of Biological Chemistry. 1997;272:6093-6096
  43. 43. Gorska E, Popko K, Stelmaszczyk-Emmel A, Ciepiela A, Wasik M. Leptin receptors. European Journal of Medical Research. 2010;15(2):50
  44. 44. Wauman J, Zabeau L, Tavernier J. The leptin receptor complex: Heavier than expected? Frontiers in Endocrinology. 2017;8:30
  45. 45. Peelman F, Zabeau L, Moharanna K, Savvides SN, Tavernier J. Insights into signaling assemblies of leptin receptor. The Journal of Endocrinology. 2014;223:T9-T23
  46. 46. Kamel HFM, Nassir AM, Al Refai A. Assessment of expression levels of leptin and leptin receptor as potential biomarkers for risk of prostate cancer development and aggressiveness. Cancer Medicine. 2020;9:5687-5696
  47. 47. Kieman K, Maclver NJ. The role of the adipokine leptin in immune cell function in health and disease. Frontiers in Immunology. 2021;11:622468
  48. 48. Pham D-V, Park P-H. Tumor metabolic reprogramming by adipokines as a critical driver of obesity-associated cancer progression. International Molecular Scencei. 2021;22(3):1444
  49. 49. Lin TC, Hsiao M. Leptin and cancer: Updated functional roles in carcinogenesis, therapeutic niches, and developments. International Journal of Molecular Sciences. 2021;22(6):2870
  50. 50. Ding Y, Cao Y, Wang B, Wang L, Zhang Y, Zhang D, et al. APPL1-mediating leptin signaling contributes to proliferation and migration of cancer cells. PLoS One. 2016;11(11):e0166172
  51. 51. Feng H, Liu Q , Zhang N, Zheng L, Sang M, Feng J, et al. Leptin promotes metastasis by inducing an epithelial-mesenchymal transition in A549 lung cancer cells. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics. 2014;21(3):165-171
  52. 52. Price RS, Cavazos DA, De Angel RE, Hursting SD, Degraffenried LA. Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells. Prostate Cancer and Prostatic Diseases. 2012;15(2):135-143
  53. 53. Yoon KW, Park SY, Kim JY, Lee SM, Park CH, Cho SB, et al. Leptin-induced adhesion and invasion in colorectal cancer cell lines. Oncology Reports. 2014;31(6):2493-2498
  54. 54. Oba J, Wei W, Gershenwald JE, Johnson MM, Wyatt CM, Ellerhorst JA, et al. Elevated serum leptin levels are associated with an increased risk of sentinel lymph node metastasis in cutaneous melanoma. Medicine. 2016;95(11):e3073
  55. 55. Wei X, Li Y, Gong C, Ji T, Zhou X, Zhan T, et al. Targeting leptin as a therapeutic strategy against ovarian cancer peritoneal metastasis. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2017;17(8):1093-1101
  56. 56. Campo-Verde-Arbocco F, López-Laur JD, Romeo LR, Giorlando N, Bruna FA, et al. Human renal adipose tissue induces the invasion and progression of renal cell carcinoma. Oncotarget. 2017;8(55):94223
  57. 57. Bowers LW, Rossi EL, McDonell SB, Doerstling SS, Khatib SA, Lineberger CG, et al. Leptin signaling mediates obesity-associated CSC enrichment and EMT in preclinical TNBC models. Molecular Cancer Research. 2018;16(5):869-879
  58. 58. Palhinha L, Liechocki S, Hottz ED, Aparecida de Pereira J, de Almeida CJ, Moraes-Vieira PM. Leptin induces proadipogenic and proinflammatory signaling in adipocytes. Frontiers in Endocrinology. 2019;1(1):15
  59. 59. He J, Xu G. LEP gene variant is associated with prostate cancer but not with colorectal cancer. Tumor Biology. 2013;34(5):3131-3136
  60. 60. Dallal C, Garte S, Ragin C, Chen J, Lloyd S, Modugno F, et al. Plasma leptin levels, LEPR Q223R polymorphism and mammographic breast density: A cross-sectional study. The International Journal of Biological Markers. 2013;28(2):161-167
  61. 61. Wang LQ , Shen W, Xu L, Chen MB, Gong T, Lu PH, et al. The association between polymorphisms in the leptin receptor gene and risk of breast cancer: A systematic review and pooled analysis. Breast Cancer Research and Treatment. 2012;136(1):231-239
  62. 62. Kim EY, Chin HM, Park SM, Jeon HM, Chung WC, Paik CN, et al. Susceptibility of gastric cancer according to leptin and leptin receptor gene polymorphisms in Korea. Journal of the Korean Surgical Society. 2012;83(1):7-13
  63. 63. Li Y, Geng J, Wang Y, Lu O, Du Y, Wang W, et al. The role of leptin receptor gene polymorphisms in determining the susceptibility and prognosis of NSCLC in Chinese patients. Journal of Cancer Research and Clinical Oncology. 2012;138(2):311-316
  64. 64. Lin T-C, Huang K-W, Liu C-W, Chang Y-C, Lin W-M, Yang T-Y, et al. Leptin signaling axis specifically associates with clinical prognosis and is multifunctional in regulating cancer progression. Oncotarget. 2018;9:17210-17219
  65. 65. Haque I, Ghosh A, Acup S, Banerjee S, Dhar K, Ray A, et al. Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway. BMC Cancer. 2018;18:99
  66. 66. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28(33):2940-2947
  67. 67. Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Research. 2011;71(15):5296-5306
  68. 68. Olea-Flores M, Zuñiga-Eulogio M, Tacuba-Saavedra A, Bueno-Salgado M, Sánchez-Carvajal A, Vargas-Santiago Y, et al. Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells. Cells. 2019;8(10):1133
  69. 69. Lim SC. Role of COX-2, VEGF and cyclin D1 in mammary infiltrating duct carcinoma. Oncology Reports. 2003;10(5):1241-1249
  70. 70. Jimenez-Cortegana C, Lopez-Saavedra A, Sanchez-Jimenez F, Perez-Perez A, Castineiras J, Virizuela-Echaburu JA, et al. Leptin, both bad and good actor in cancer. Biomolecules. 2021;11(6):913
  71. 71. Zange Y, Somers VK, Dong Y, Singh P. Abstract 604: Anti-apoptotic role of leptin in adipose tissue. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;38(1):604
  72. 72. Procaccini C, Lourenco EV, Matarese G, Cava AL. Leptin signaling: A key pathway in immune responses. Current Signal Transduction Therapy. 2009;4(1):22-30
  73. 73. La Cava A. Leptin in inflammation and autoimmunity. Cytokine. 2017;98:51-58
  74. 74. Song J, Deng T. Corrigendum: The adipocyte and adaptive immunity. Frontiers in Immunology. 2021;12
  75. 75. Pérez-Pérez A, Sánchez-Jiménez F, Vilariño-García T, Sánchez-Margalet V. Role of leptin in inflammation and vice versa. International Journal of Molecular Science. 2020;21(16):5587
  76. 76. Agrawal S, Gollapudi S, Su H, Gupta S. Leptin activates human Bcells to secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and P38MARK/ERK1/2 signaling pathway. Journal of Clinical Immunology. 2011;31(3):472-478
  77. 77. Finck BN, Johnson RW. Tumor necrosis factor (TNF)-α induces leptin production through the p55 TNF receptor. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2000;278:R537-R543
  78. 78. Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harbor Perspectives in Biology. 2013;5(2):a008722
  79. 79. Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell & Bioscience. 2020;10:31
  80. 80. Kim SY, Lim JH, Choi SW, Kim M, Kim ST, Kim MS, et al. Preferential effects of leptin on CD4 T cells in central and peripheral immune system are critically linked to the expression of leptin receptor. Biochemical and Biophysical Research Communications. 2010;394(4):562-568
  81. 81. Herold J, Kalucka J. Angiogenesis in adipose tissue: The interplay between adipose and endothelial cells. Frontiers in Physiology. 2021;11:624903
  82. 82. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, et al. Potential role of leptin in angiogenesis: Leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Experimental & Molecular Medicine. 2001;33(2):95-102
  83. 83. Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008;11(2):109-119
  84. 84. Gonzalez-Perez RR, Lanier V, Newman G. Leptin’s pro-angiogenic signature in breast cancer. Cancers. 2013;5(3):1140-1162
  85. 85. Sierra-Honigmann MR, Nath AK, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science. 1998;281:1683-1686
  86. 86. Samad N, R., T. Role of leptin in cancer-a systematic review. Biomedical Journal of Scientific & Technical Research. 2019;18(1):13226-13235
  87. 87. Garonna E, Botham KM, Birdsey GM, Randi AM, Gonzalex-Perez RR, Wheeler-Jones CPD. Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS One. 2011;6(4):e18823
  88. 88. Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proceedings of the National Academy of Sciences. 2001;98(11):6390-6395
  89. 89. Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR. Vascular endothelial growth factor receptor-2 in breast cancer. Biochimica et Biophysica Acta. 2010;1806:108-121
  90. 90. Zhou W, Guo S, Gonzalez-Perez RR. Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling. British Journal of Cancer. 2011;104:128-137
  91. 91. Pua LJW, Mai CW, Chung FFL, Khoo ASB, Leong CO, Lim WM, et al. Functional roles of JNK and p38 MAPK signaling in nasopharyngeal carcinoma. International Journal of Molecular Sciences. 2022;23(3):1108
  92. 92. Liang X, Wang S, Wang X, Zhang L, Zha H, Zhang L. Leptin promotes the growth of breast cancer by upregulating the Wnt/β-catenin pathway. Experimental and Therapeutic Medicine. 2018;16(2):767-771

Written By

Rowyda Nawwaf Al-Harithy

Submitted: March 8th, 2022 Reviewed: March 21st, 2022 Published: April 30th, 2022