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Leptin, Resistin and Visfatin: the Missing Link Between Endocrine Metabolic Disorders and Immunity Ebtesam a AL-Suhaimi1*† and Adeeb Shehzad2*†

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Leptin, Resistin and Visfatin: the Missing Link Between Endocrine Metabolic Disorders and Immunity Ebtesam a AL-Suhaimi1*† and Adeeb Shehzad2*† AL-Suhaimi and Shehzad European Journal of Medical Research 2013, 18:12 http://www.eurjmedres.com/content/18/1/12 EUROPEAN JOURNAL OF MEDICAL RESEARCH REVIEW Open Access Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity Ebtesam A AL-Suhaimi1*† and Adeeb Shehzad2*† Abstract Adipose tissue is still regarded as a principle site for lipid storage and mobilizing tissue with an important role in the control of energy homeostasis. Additionally, adipose tissue-secreted hormones such as leptin, visfatin, resistin, apelin, omentin, sex steroids, and various growth factors are now regarded as a functional part of the endocrine system. These hormones also play an important role in the immune system. Several in vitro and in vivo studies have suggested the complex role of adipocyte-derived hormones in immune system and inflammation. Adipokines mediate beneficial and detrimental effects in immunity and inflammation. Many of these adipocytokines have a physiological role in metabolism. The uncontrolled secretions of several adipocytokines were associated with the stimulation of inflammatory processes leading to metabolic disorders including obesity, atherosclerosis, insulin resistance and type 2 diabetes. Obesity leads to the dysfunction of adipocytes andcorrelated with the imbalance of adipokines levels. In obese and diabetic conditions, leptin deficiency inhibited the Jak/Stat3/PI3K and insulin pathways. In this review, ample evidence exists to support the recognition of the adipocyte’s role in various tissues and pathologies. New integral insights may add dimensions to translate any potential agents into the future clinical armamentarium of chronic endocrine metabolic and inflammatory diseases. Functional balance of both adipocytes and immune cells is important to exert their effects on endocrine metabolic disorders; furthermore, adipose tissue should be renamed not only as a functional part of the endocrine system but also as a new part of the immune system. Keywords: Adipocytokines, Obesity, Diabetes, Endocrine, Immunity Review The most abundant depots are visceral and subcutaneous Introduction adipose tissues, which produce unique profiles of adipokines Adipose tissue is a complex network of endocrine organs [2]. These molecules are orchestrated by a multifarious that has been divided into white adipose tissue (WAT) and network belonging to different functional categories brown adipose tissue (BAT). WAT is mainly responsible for such as immunity (complement factors, haptoglobulin), the insulation and mechanical support along with the endocrine function (leptin, adiponectin, visfatin, resistin, energy storage function in the body, while BAT specializes apelin, omentin, sex steroids, various growth factors), in thermogenesis and lipid oxidation [1]. Activation of BAT metabolic function (fatty acids, adiponectin, resistin, vaspin), also regulates channel efficiency to undertake triglyceride- cardiovascular function (angiotensinogen), fatty acid, and rich lipoprotein (TRL) clearance, as well as to prevent prostaglandins [3-7]. excess accumulation of lipids in the blood [1]. Adipose tissue secretes many biologically active adipokines with diverse functions [3]. Adipokines are pharmacologically active, low molecular weight proteins that exert pleiotropic functions through several metabolic pathways [8]. Around * Correspondence: [email protected]; [email protected] the turn of the 20th century several molecular mechanisms †Equal contributors 1Department of Biology, Sciences College, University of Dammam, Dammam, shed light on the importance of adipokines in the hu- Saudi Arabia man system. To date, more than 20 different hormones 2School of Life Sciences, College of Natural Sciences, Kyungpook National (both orexigenic and anorexigenic) have been identified. University, Daegu 702-701, South Korea © 2013 AL-Suhaimi and Shehzad; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. AL-Suhaimi and Shehzad European Journal of Medical Research 2013, 18:12 Page 2 of 13 http://www.eurjmedres.com/content/18/1/12 Adipokines are important due to their crucial mediator M. Friedman. Leptin is derived from the Greek word role and active participation in metabolic functions. leptos, which means ‘thin’. The serum concentration of These hormones also easily cross the blood-brain barrier, leptin is predominantly defined by body fat mass [14]. reach the main site of action located in the hypothalamic Leptin was the first identified adipocytokine, its primary region, exert their actions and mediate the balance of structure is composed of 167 amino acids, and it is pri- satiety and hunger. The adipokines have a central role marily expressed in adipose tissue. Leptin regulates energy in the control of energy metabolism, communicating homeostasis and interferes with several neuroendocrine the nutrient status of the organism including energy intake and immune functions [15]. A higher amount of leptin is and expenditure as well as insulin sensitivity [9]. secreted by subcutaneous adipocytes than by the visceral Adipokines have several mediators such as adiponectin, adipocytes. Its presence has also been detected in many pre-B cell colony-enhancing factor (PBEF) visfatin, leptin, other tissues, including the placenta, mammary glands, resistin and retinol-binding protein-4. Adiponectin is an breast milk, testes, ovaries, endometrium, stomach, hypo- intriguing adipokine with its serum level inversely corre- thalamus, and pituitary gland [16]. Leptin is generally syn- lated with fatness. It is related to the enhancement of insu- thesized and secreted by gastric chief cells in the stomach lin sensitivity, anti-inflammatory effects, anti-atherogenic [17]. Leptin circulating levels are directly proportional to actions, and regulation of metabolic homeostasis [10]. the body fat. These levels range from 5 to 10 ng/ml in Recent investigations have also emphasized the importance healthy individuals to 40 to 100 ng/ml in obese individuals of adipocytokines such as interleukin-6 (IL-6), tumor [18]. A transient increase occurs during a meal, whereas necrosis factor α (TNFα), plasminogen activator inhibitor-1, leptin levels decrease with fasting, evoking a profound or a chemokine, and monocyte chemoattractant protein-1 changes in energy balance and hormone levels [4,19,20]. (MCP-1). Nuclear factor-kappa B (NF-κB) is a transcription The adipose tissue secretes specific proteins including factor that has the potential to mediate immunity, stress, leptin into the blood stream, which controls body weight apoptosis, cytokines expression, inducible nitric oxide by regulating metabolic behavior. It has a fundamental synthase (iNOS), cyclo-oxygenase 2 (COX-2), cell growth role in the control of appetite and also in regulating factors, and development, as well as the potential to play an energy expenditures [21]. Leptin exerts pleiotropic effects important role in central nervous system and cell signaling. by binding and activating specific leptin receptors (obR) in It is also known that NF-κB induces overexpression of the hypothalamus and other organs. It has direct and transcriptional systems, which activate inflammation and indirect effects in metabolically active tissues and regu- develop cancer. NF-κB pathway inhibitors may be a useful lates several neuroendocrine axes [22,23]. So far, six therapeutic strategy to treat inflammation and cancer. different isoforms of leptin have been identified with Several studies have shown that lipid accumulation in the diverse biological actions that range from affecting liver leads to hepatic inflammation through NF-κB blood pressure to affecting immune functions [24,25]. activation and downstream cytokine production, which Leptin receptors such as ObRa and ObRb are present leads to insulin resistance hepatically, as well as systemically in the brain and regulate metabolic behaviors [26]. [11,12]. Some of the adipokines hormones such as leptin, Among leptin receptors, mRNA expression of the long adiponectin, resistin, and ghrelin play a role in the regula- form, ObRb, has been detected in the arcuate (ARC), tion of glucose metabolism and are involved in the develop- dorsomedial (DMH), ventromedial (VMH), and ventral ment of obesity, diabetes, inflammation, auto-immunity premamillary nuclei (PMV); moderate expression has and metabolic syndromes [13]. been found in the periventricular hypothalamic nucleus, The current review summarizes the recent knowledge in the lateral hypothalamic area (LHA), and at lower levels regarding the malfunction of adipokines such as leptin, of expression in the paraventricular nucleus (PVH) [27]. resistin, and visfatin in the initiation and progression Early research was focused on leptin and its receptors of many metabolic diseases including obesity, diabetes in the hypothalamus region and leptin was believed to and immunity. be an important regulatory hormone for signaling body fat status. However, it has become apparent that leptin Physiological and pro-inflammatory roles of adipokines receptors are expressed in many normal cell types The physiological, metabolic and pro-inflammatory role throughout the body as well as in malignant cells. It is of different adipokines, such as, leptin, resistin, visfatin noted
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