Leptin in Health and Disease: Facts and Expectations at its Twentieth Anniversary

Abstract

This year marks the twentieth anniversary of the discovery of leptin [[1]Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Google Scholar], the prototypical adipocyte-secreted hormone or adipokine, which was named after the Greek word “leptos” meaning thin [[2]Kelesidis T. Kelesidis I. Chou S. Mantzoros C.S. Narrative review: the role of leptin in human physiology: emerging clinical applications.Ann Intern Med. 2010; 152: 93-100Google Scholar]. The first notion for a circulating factor affecting body fat had been published long ago (1959) on the basis of a parabiosis study [[3]Hervey G.R. The effects of lesions in the hypothalamus in parabiotic rats.J Physiol. 1959; 145: 336-352Google Scholar], the findings of which were replicated and further expanded fifteen years later [[4]Coleman D.L. Effects of parabiosis of obese with diabetes and normal mice.Diabetologia. 1973; 9: 294-298Google Scholar], i.e. after the characterization of ob/ob and db/db mice. Leptin’s discovery radically changed our understanding of adipose tissue. Twenty years ago, adipose tissue was regarded as an inert energy-storage organ and even classic textbooks of physiology presented its existence within a couple of paragraphs. Nowadays, adipose tissue is considered to be a major, and in most cases, the largest endocrine organ, secreting multiple adipokines with multi-potent effects on health and disease. Consequently, adipose tissue is the focus of intense research efforts: more than 700 different proteins have been described to date as being potentially secreted by adipose tissue. These proteins need further study and validation regarding their expression, secretion and function, before full characterization as putative novel adipokines [[5]Lehr S. Hartwig S. Lamers D. Famulla S. Muller S. Hanisch F.G. et al.Identification and validation of novel adipokines released from primary human adipocytes.Mol Cell Proteomics. 2012; 11 (M111.010504; http://dx.doi.org/10.1074/mcp.M111.010504)Google Scholar]. Furthermore, publications are accumulating on the endocrine function of adipose tissue, and the new editions of physiology textbooks need to devote many pages to adipose tissue in order to present adipokines and their functions. This issue of “Metabolism, Clinical and Experimental” is published to celebrate the twentieth anniversary of leptin, or in other words, the maturity of the concept of adipose tissue as an endocrine organ. We are delighted that many distinguished experts in the field have accepted our invitations to contribute important pieces of scientific work to this issue, adding their personal and invaluable insights. In this issue, the structure, production and signaling of leptin and its physiologic role are initially presented. Subsequently, the roles of leptin in obesity and other metabolic and non-metabolic diseases are detailed. Finally, therapeutic perspectives, current and emerging, are summarized. The review articles to be published in this issue emphasize the importance of leptin as a key adipokine associated with several physiologic processes, but also its potential implications in the pathogenesis of several and diverse diseases. Given that many pieces of the pathogenetic puzzle linking leptin with pathophysiology and morbidity are missing, this issue desires to accurately present the current state of research in the field, but also to trigger future in-depth research, which may lead to a better understanding of leptin’s physiology, to establish its clinical role and to unfold its therapeutic potential in the years to come. Let us start by presenting some pieces of the knowledge and expectations that could possibly set the stage as we celebrate the twentieth anniversary of the discovery of leptin. Leptin is secreted mainly by white adipocyte tissue, and it circulates at levels positively correlated with fat mass [[6]Mantzoros C.S. Moschos S. Avramopoulos I. Kaklamani V. Liolios A. Doulgerakis D.E. et al.Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans.J Clin Endocrinol Metab. 1997; 82: 3408-3413Google Scholar], thus reflecting primarily the amount of energy stored in adipose tissue [[2]Kelesidis T. Kelesidis I. Chou S. Mantzoros C.S. Narrative review: the role of leptin in human physiology: emerging clinical applications.Ann Intern Med. 2010; 152: 93-100Google Scholar]. Leptin levels also change with acute changes in energy intake and thus, secondarily reflect acute energy availability [[7]Wolfe B.E. Jimerson D.C. Orlova C. Mantzoros C.S. Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin levels in healthy volunteers.Clin Endocrinol (Oxf). 2004; 61: 332-338Google Scholar]. Leptin has endogenous circadian rhythm, which peaks around the time of awakening [[8]Shea S.A. Hilton M.F. Orlova C. Ayers R.T. Mantzoros C.S. Independent circadian and sleep/wake regulation of adipokines and glucose in humans.J Clin Endocrinol Metab. 2005; 90: 2537-2544Google Scholar]. The identification of the leptin receptor (LepR) came soon after the discovery of leptin [[9]Tartaglia L.A. 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: 1263-1271Google Scholar], expanding our knowledge on its intracellular signaling. Indeed, we learned that leptin acts on multiple central (brain) and peripheral tissues. The arcuate nucleus of the hypothalamus is regarded as the primary central site of leptin’s activity, where leptin activates proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons, while it inhibits neuropeptide Y (NPY)/agouti-related peptide (AGRP) neurons [[10]Dalamaga M. Chou S.H. Shields K. Papageorgiou P. Polyzos S.A. Mantzoros C.S. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives.Cell Metab. 2013; 18: 29-42Google Scholar]. Leptin signaling, under normal circumstances, alters the function of the brain and other tissues to implement appropriate changes in food intake and energy expenditure [[11]Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar]. This system is especially sensitive to energy deprivation [[12]Ahima R.S. Prabakaran D. Mantzoros C. Qu D. Lowell B. Maratos-Flier E. et al.Role of leptin in the neuroendocrine response to fasting.Nature. 1996; 382: 250-252Google Scholar]. On the other end of the spectrum, this system is non-responsive in garden-variety obesity, due to leptin tolerance/resistance [[13]Mantzoros C.S. Magkos F. Brinkoetter M. Sienkiewicz E. Dardeno T.A. Kim S.Y. et al.Leptin in human physiology and pathophysiology.Am J Physiol Endocrinol Metab. 2011; 301: E567-E584Google Scholar]. Apart from this classic role of leptin in obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD), leptin seems to mediate changes in adiposity or food intake and adaptive responses in other systems, including, but not restricted to, autoimmune, gastrointestinal, musculoskeletal and reproductive systems [[11]Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar]. The importance of leptin is derived from many experimental and clinical studies. Mice homozygous for mutations in the leptin (ob) gene, which prevent leptin production or lead to the secretion of an inactive leptin molecule (ob/ob), exhibit hyperphagia, insulin resistance, early-onset obesity, diabetes, fatty liver and several neuroendocrine abnormalities, all of which can be improved by exogenous leptin administration [10Dalamaga M. Chou S.H. Shields K. Papageorgiou P. Polyzos S.A. Mantzoros C.S. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives.Cell Metab. 2013; 18: 29-42Google Scholar, 11Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar]. A similar phenotype is exhibited in db/db mice and fa/fa (Zucker) rats, which have dysfunctional LepR due to homozygous mutations; however, as expected, leptin treatment does not improve the observed metabolic or non-metabolic abnormalities in fa/fa rats [10Dalamaga M. Chou S.H. Shields K. Papageorgiou P. Polyzos S.A. Mantzoros C.S. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives.Cell Metab. 2013; 18: 29-42Google Scholar, 11Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar]. The discovery of leptin has also prompted a better characterization and deeper pathophysiologic understanding of lipodystrophy, a clinically heterogeneous and difficult-to-treat disease, characterized by the complete or partial loss of adipose tissue, and resulting in numerous metabolic and neuroendocrine derangements [14Bluher S. Shah S. Mantzoros C.S. Leptin deficiency: clinical implications and opportunities for therapeutic interventions.J Investig Med. 2009; 57: 784-788Google Scholar, 15Fiorenza C.G. Chou S.H. Mantzoros C.S. Lipodystrophy: pathophysiology and advances in treatment.Nat Rev Endocrinol. 2011; 7: 137-150Google Scholar]. The abnormal adipose tissue metabolism, a hallmark of lipodystrophy, leads to either loss of subcutaneous adipose tissue (lipoatrophy) or extra-adipose (i.e., hepatic, pancreatic, etc.) accumulation of fat (lipohypertrophy). Lipodystrophy is associated with varying degrees of insulin resistance, dyslipidemia, hyperglycemia or T2DM, and NAFLD, and can be congenital or acquired. Congenital forms of lipodystrophy are rarely seen, whereas the most common form of acquired lipodystrophy is that associated with human immunodeficiency virus (HIV) infection and highly active antiretroviral therapy (HAART) [[16]Foo J.P. Mantzoros C.S. Leptin in congenital or HIV-associated lipodystrophy and metabolic syndrome: a need for more mechanistic studies and large, randomized, placebo-controlled trials.Metabolism. 2012; 61: 1331-1336Google Scholar]. Patients with congenital or acquired lipodystrophy have complete or relative leptin deficiency, which implies that leptin replacement could be a rational therapeutic option [16Foo J.P. Mantzoros C.S. Leptin in congenital or HIV-associated lipodystrophy and metabolic syndrome: a need for more mechanistic studies and large, randomized, placebo-controlled trials.Metabolism. 2012; 61: 1331-1336Google Scholar, 17Tsoukas M.A. Farr O.M. Mantzoros C.S. Leptin in congenital and HIV-associated lipodystrophy.Metabolism. 2014; ([in press])https://doi.org/10.1016/j.metabol.2014.07.017Google Scholar]. Recently, the US Food and Drug Administration (FDA) and the Japanese Pharmaceuticals and Medical Devices Agency have approved recombinant human methionyl leptin (metreleptin) replacement therapy for the treatment of congenital generalized or acquired generalized (non-HIV-associated) lipodystrophy, on the basis of uncontrolled, non-randomized, open-label studies [18Chan J.L. Lutz K. Cochran E. Huang W. Peters Y. Weyer C. et al.Clinical effects of long-term metreleptin treatment in patients with lipodystrophy.Endocr Pract. 2011; 17: 922-932Google Scholar, 19Oral E.A. Simha V. Ruiz E. Andewelt A. Premkumar A. Snell P. et al.Leptin-replacement therapy for lipodystrophy.N Engl J Med. 2002; 346: 570-578Google Scholar, 20Ebihara K. Kusakabe T. Hirata M. Masuzaki H. Miyanaga F. Kobayashi N. et al.Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.J Clin Endocrinol Metab. 2007; 92: 532-541Google Scholar]. For safety reasons, metreleptin is currently available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program, which requires monitored enrollment of patients and the training of prescribers and pharmacists. The discovery of leptin had initially born expectations for the treatment of common obesity [[11]Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar], but clinical trials have demonstrated no or minimal effects of leptin on obesity [21Heymsfield S.B. Greenberg A.S. Fujioka K. Dixon R.M. Kushner R. Hunt T. et al.Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.JAMA. 1999; 282: 1568-1575Google Scholar, 22Shetty G.K. Matarese G. Magkos F. Moon H.S. Liu X. Brennan A.M. et al.Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet.Eur J Endocrinol. 2011; 165: 249-254Google Scholar]. This fact is mainly attributed to leptin tolerance/resistance and the generation of anti-leptin antibodies. Most patients with obesity and associated co-morbidities, including T2DM and NAFLD, have hyperleptinemia, presumably in response to leptin tolerance/resistance, and thus, the normal actions of leptin are impaired [[21]Heymsfield S.B. Greenberg A.S. Fujioka K. Dixon R.M. Kushner R. Hunt T. et al.Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.JAMA. 1999; 282: 1568-1575Google Scholar]. Therefore, despite initial expectations, recombinant leptin administration in obese and hyperleptinemic individuals has not been associated with significant weight loss or significant reductions in metabolic complications [11Moon H.S. Dalamaga M. Kim S.Y. Polyzos S.A. Hamnvik O.P. Magkos F. et al.Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.Endocr Rev. 2013; 34: 377-412Google Scholar, 23Mantzoros C.S. Flier J.S. Editorial: leptin as a therapeutic agent—trials and tribulations.J Clin Endocrinol Metab. 2000; 85: 4000-4002Google Scholar]. Although the discovery of leptin has opened new windows into human pathophysiology and therapeutics, many other pieces of the energy homeostasis and endocrine function of adipose tissue puzzles remain unknown. First, although a receptor-mediated transportation of leptin has been proposed, it is unclear how leptin produced by adipose tissue crosses the blood–brain barrier (BBB) to affect central nervous system functions. LepR on astrocytes have been proposed to actively regulate leptin transport across the BBB, a finding consistent with evidence that central regulatory changes of LepR during obesity and inflammation often occur in astrocytes [[24]Hsuchou H. Kastin A.J. Tu H. Joan Abbott N. Couraud P.O. Pan W. Role of astrocytic leptin receptor subtypes on leptin permeation across hCMEC/D3 human brain endothelial cells.J Neurochem. 2010; 115: 1288-1298Google Scholar]. Leptin transport through the BBB has been shown to be saturable [[25]Hsuchou H. Mishra P.K. Kastin A.J. Wu X. Wang Y. Ouyang S. et al.Saturable leptin transport across the BBB persists in EAE mice.J Mol Neurosci. 2013; 51: 364-370Google Scholar] and decreased in obese rats, thereby potentially enhancing leptin tolerance/resistance [[26]Burguera B. Couce M.E. Curran G.L. Jensen M.D. Lloyd R.V. Cleary M.P. et al.Obesity is associated with a decreased leptin transport across the blood–brain barrier in rats.Diabetes. 2000; 49: 1219-1223Google Scholar], although other studies have reported similar transport capacities in lean and diet-induced obese rats [[27]Nave H. Kuhlmann S. Brabant G. Pabst R. Changes in cerebral endothelial barrier antigen, without alteration of permeability for intravenously injected leptin in diet-induced obesity in rats.Exp Toxicol Pathol. 2003; 55: 45-49Google Scholar]. Lipopolysaccharide, which is known to increase circulating leptin levels and to affect the passage of other regulatory proteins across the BBB, also decreases leptin transport through the BBB in a dose-dependent manner [[28]Nonaka N. Hileman S.M. Shioda S. Vo T.Q. Banks W.A. Effects of lipopolysaccharide on leptin transport across the blood–brain barrier.Brain Res. 2004; 1016: 58-65Google Scholar]. On the other hand, chronic alcohol ingestion, which is known to decrease appetite, has been shown to increase leptin permeation across the BBB [[29]Pan W. Barron M. Hsuchou H. Tu H. Kastin A.J. Increased leptin permeation across the blood–brain barrier after chronic alcohol ingestion.Neuropsychopharmacology. 2008; 33: 859-866Google Scholar]. Interestingly, a cholecystokinin-1 receptor agonist was also shown to increase leptin permeability through the BBB [[30]Cano V. Merino B. Ezquerra L. Somoza B. Ruiz-Gayo M. A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin.Br J Pharmacol. 2008; 154: 1009-1015Google Scholar]. The above evidence highlights not only the complexity of leptin transport through the BBB, but also the need for a deeper knowledge and understanding, which may lead to therapeutic techniques and pharmaceutics which could diminish leptin tolerance/resistance, if indeed limited leptin transportation to the brain may partially underlie leptin tolerance or resistance. Leptin is mainly produced by white adipose tissue, but it may also be expressed in tissues other than the adipose tissue, including the brain [[31]Wiesner G. Vaz M. Collier G. Seals D. Kaye D. Jennings G. et al.Leptin is released from the human brain: influence of adiposity and gender.J Clin Endocrinol Metab. 1999; 84: 2270-2274Google Scholar], bone [[32]Morroni M. De Matteis R. Palumbo C. Ferretti M. Villa I. Rubinacci A. et al.In vivo leptin expression in cartilage and bone cells of growing rats and adult humans.J Anat. 2004; 205: 291-296Google Scholar], macrophages [[33]Lee K. Santibanez-Koref M. Polvikoski T. Birchall D. Mendelow A.D. Keavney B. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture.Atherosclerosis. 2013; 226: 74-81Google Scholar], thyroid [[34]Fan Y.L. Li X.Q. Expression of leptin and its receptor in thyroid carcinoma: distinctive prognostic significance in different subtypes.Clin Endocrinol (Oxf). 2014; https://doi.org/10.1111/cen.12598Google Scholar], breast [[35]Smith-Kirwin S.M. O'Connor D.M. De Johnston J. Lancey E.D. Hassink S.G. Funanage V.L. Leptin expression in human mammary epithelial cells and breast milk.J Clin Endocrinol Metab. 1998; 83: 1810-1813Google Scholar], placenta [[36]Iciek R. Wender-Ozegowska E. Zawiejska A. Mikolajczak P. Mrozikiewicz P.M. Pietryga M. et al.Placental leptin and its receptor genes expression in pregnancies complicated by type 1 diabetes.J Physiol Pharmacol. 2013; 64: 579-585Google Scholar], and even the dental pulp [[37]Martin-Gonzalez J. Perez-Perez A. Sanchez-Jimenez F. Carmona-Fernandez A. Torres-Lagares D. Sanchez-Margalet V. et al.Leptin receptor is up-regulated in inflamed human dental pulp.J Endod. 2013; 39: 1567-1571Google Scholar]. Under normal conditions, the extra-adipose leptin production is minimal. However, this production increases in certain pathological processes, including inflammation and malignant transformation. For instance, low birth weight and premature delivery have also been linked to lower leptin levels in newborns [[38]Mantzoros C.S. Varvarigou A. Kaklamani V.G. Beratis N.G. Flier J.S. Effect of birth weight and maternal smoking on cord blood leptin concentrations of full-term and preterm newborns.J Clin Endocrinol Metab. 1997; 82: 2856-2861Google Scholar]. More studies are needed to elucidate the role of leptin in certain diseases, including distinct cancers, atherosclerosis, osteoarthritis, pregnancy complications and even periodontitis, and subsequently to determine whether leptin has any therapeutic potential for these conditions. Another important field for further research is the proinflammatory actions of leptin and the cross-talk between leptin and other adipokines, myokines and extra-adipose tissue hormones, including insulin and thyroid hormones. Leptin administration restores Th1/Th2 balance and is part of feedback loops along with several cytokines. For example, TNF-α activates leptin expression [[39]Finck B.N. Johnson R.W. Anti-inflammatory agents inhibit the induction of leptin by tumor necrosis factor-alpha.Am J Physiol Regul Integr Comp Physiol. 2002; 282: R1429-R1435Google Scholar] and upregulates the LepR [[40]Gan L. Guo K. Cremona M.L. McGraw T.E. Leibel R.L. Zhang Y. TNF-alpha up-regulates protein level and cell surface expression of the leptin receptor by stimulating its export via a PKC-dependent mechanism.Endocrinology. 2012; 153: 5821-5833Google Scholar], whereas leptin increases tumor necrosis factor (TNF)-α expression [[41]Lee S.M. Choi H.J. Oh C.H. Oh J.W. Han J.S. Leptin increases TNF-alpha expression and production through phospholipase D1 in Raw 264.7 cells.PLoS One. 2014; 9: e102373https://doi.org/10.1371/journal.pone.0102373Google Scholar]. TNF-α also suppresses adiponectin transcription, secretion and action [42Tilg H. Hotamisligil G.S. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance.Gastroenterology. 2006; 131: 934-945Google Scholar, 43Polyzos S.A. Kountouras J. Zavos C. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in nonalcoholic fatty liver disease.Hippokratia. 2009; 13: 127Google Scholar]. In turn, there is evidence that adiponectin inhibits leptin [44Handy J.A. Fu P.P. Kumar P. Mells J.E. Sharma S. Saxena N.K. et al.Adiponectin inhibits leptin signalling via multiple mechanisms to exert protective effects against hepatic fibrosis.Biochem J. 2011; 440: 385-395Google Scholar, 45Beales I.L. Garcia-Morales C. Ogunwobi O.O. Mutungi G. Adiponectin inhibits leptin-induced oncogenic signalling in oesophageal cancer cells by activation of PTP1B.Mol Cell Endocrinol. 2014; 382: 150-158Google Scholar] and TNF-α [42Tilg H. Hotamisligil G.S. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance.Gastroenterology. 2006; 131: 934-945Google Scholar, 43Polyzos S.A. Kountouras J. Zavos C. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in nonalcoholic fatty liver disease.Hippokratia. 2009; 13: 127Google Scholar] signaling. Overall, it seems that there is a positive loop between leptin and TNF-α, which may be negatively regulated by adiponectin. Regarding leptin-irisin interaction, there is evidence that leptin downregulates the expression of fibronectin type III domain-containing protein (FNDC)5, the irisin precursor, in subcutaneous adipose tissue for non-obese individuals [[46]Gutierrez-Repiso C. Garcia-Serrano S. Rodriguez-Pacheco F. Garcia-Escobar E. Haro-Mora J.J. Garcia-Arnes J. et al.FNDC5 could be regulated by leptin in adipose tissue.Eur J Clin Invest. 2014; https://doi.org/10.1111/eci.12324Google Scholar]. Other authors reported a dual effect of leptin in mice, in which leptin was shown to activate irisin-induced myogenesis, but also to reduce irisin effect on subcutaneous fat browning [[47]Rodriguez A. Becerril S. Mendez-Gimenez L. Ramirez B. Sainz N. Catalan V. et al.Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice.Int J Obes (Lond). 2014; https://doi.org/10.1038/ijo.2014.166Google Scholar]. It was also recently shown that circulating irisin tends to follow a similar pattern to leptin in histological endpoints of patients with NAFLD, including inflammation and fibrosis [[48]Polyzos S.A. Kountouras J. Anastasilakis A.D. Geladari E.V. Mantzoros C.S. Irisin in patients with nonalcoholic fatty liver disease.Metabolism. 2014; 63: 207-217Google Scholar]. Certainly, much more research is needed in the area of pathophysiology and potential therapeutic use of leptin in NAFLD and similar disease states. There is also evidence for an overlap between leptin and insulin signaling [49Polyzos S.A. Kountouras J. Zavos C. Deretzi G. The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of literature.J Clin Gastroenterol. 2011; 45: 50-54Google Scholar, 50Moon H.S. Huh J.Y. Dincer F. Schneider B.E. Hasselgren P.O. Mantzoros C.S. Identification, and saturable nature, of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo and in vitro administration.Diabetes. 2014; https://doi.org/10.2337/db14-0625Google Scholar]. It was initially shown that circulating insulin was independently associated with leptin levels [[51]Mantzoros C.S. Liolios A.D. Tritos N.A. Kaklamani V.G. Doulgerakis D.E. Griveas I. et al.Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men.Obes Res. 1998; 6: 179-186Google Scholar]. At the intracellular level, the src homology 2 domain-containing adapter protein B (SH2B) interacts with both Janus kinase (JAK)2, one of the main intracellular leptin pathways, and insulin receptor substrate (IRS)-1 and IRS-2 and promotes IRS-1/2 mediated activation of phosphatidylinositol-4,5-bisphosphate 3-kinase in response to leptin [[52]Duan C. Li M. Rui L. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin.J Biol Chem. 2004; 279: 43684-43691Google Scholar]. SH2B loss-of-function mutation leads to both hyperleptinemia and hyperinsulinemia [53Ren D. Li M. Duan C. Rui L. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice.Cell Metab. 2005; 2: 95-104Google Scholar, 54Sheng L. Liu Y. Jiang L. Chen Z. Zhou Y. Cho K.W. et al.Hepatic SH2B1 and SH2B2 regulate liver lipid metabolism and VLDL secretion in mice.PLoS One. 2013; 8: e83269https://doi.org/10.1371/journal.pone.0083269Google Scholar]. Furthermore, the suppressor of cytokine signaling (SOCS)-3, which can be induced by either leptin or insulin [[55]Emanuelli B. Peraldi P. Filloux C. Sawka-Verhelle D. Hilton D. Van O.E. SOCS-3 is an insulin-induced negative regulator of insulin signaling.J Biol Chem. 2000; 275: 15985-15991Google Scholar] and protects overactivation of leptin signaling under normal conditions, impairs both leptin and insulin signaling when overexpressed, thereby playing a crucial role in both leptin and insulin resistance [56Myers M.G. Cowley M.A. Munzberg H. Mechanisms of leptin action and leptin resistance.Annu Rev Physiol. 2008; 70: 537-556Google Scholar, 57Ueki K. Kondo T. Kahn C.R. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms.Mol Cell Biol. 2004; 24: 5434-5446Google Scholar, 58Kievit P. Howard J.K. Badman M.K. Balthasar N. Coppari R. Mori H. et al.Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.Cell Metab. 2006; 4: 123-132Google Scholar]. Central leptin and insulin administration modulate changes in circulating cytokines, thus promoting inflammation [[59]Burgos-Ramos E. Sackmann-Sala L. Baquedano E. Cruz-Topete D. Barrios V. Argente J. et al.Central leptin and insulin administration modulates serum cytokine- and lipoprotein-related markers.Metabolism. 2012; 61: 1646-1657Google Scholar]. Mice lacking leptin and insulin receptors in POMC neurons display systemic insulin resistance; both leptin and insulin actions on POMC neurons of the arcuate nucleus are required to achieve glucose homeostasis and fertility [[60]Hill J.W. Elias C.F. Fukuda M. Williams K.W. Berglund E.D. Holland W.L. et al.Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility.Cell Metab. 2010; 11: 286-297Google Scholar]. In clinical terms, leptin replacement in lipodystrophy improves insulin sensitivity [[61]Magkos F. Brennan A. Sweeney L. Kang E.S. Doweiko J. Karchmer A.W. et al.Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study.Metabolism. 2011; 60: 1045-1049Google Scholar]. The above representative examples are indicative of the sophisticated interactions among adipokines, myokines and extra-adipose hormones, which may have certain consequences in health and disease [[62]Polyzos S.A. Kountouras J. Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines.Curr Mol Med. 2009; 72: 299-314Google Scholar]. The deeper knowledge of these interactions and their ever-changing, non-linear, dynamic interactions may result in more focused treatment strategies; for example, anti-TNF-α treatment might decrease hyperleptinemia and leptin tolerance/resistance, or a controlled SOCS3 impairment might improve both leptin and insulin resistance. Deeper insights into the pathogenesis of leptin tolerance/resistance might aid in the management of obesity. Apart from the aforementio