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1.
The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease.
Kiernan, K, MacIver, NJ
Frontiers in immunology. 2020;:622468
Abstract
Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.
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2.
Leptin: A new therapeutic target for treatment of diabetes mellitus.
Rehman, K, Akash, MSH, Alina, Z
Journal of cellular biochemistry. 2018;(7):5016-5027
Abstract
Leptin is an endogenous protein having 167 amino acids and is derived from adipocytes. It has tertiary structure that resembles with that of the pro-inflammatory cytokines family. The fundamental role of leptin is to maintain the energy homeostasis with the aid of its counter hormone called ghrelin, known as the "hunger hormone." Small quantities of leptin are also present in various tissues like ovary, placenta, pituitary gland, mammary gland, skeletal muscle, stomach, and lymphoid tissue. Expression of leptin is strongly associated with various inflammatory responses and immune system, and plays crucial role in the pathophysiology of obesity and development of diabetes mellitus (DM) and insulin resistance. The metabolic action of leptin is equally important as that of insulin in the pathophysiology of obesity and DM. Thereby, this review article tends to discuss the diverse and complicated role of leptin in the pathogenesis of DM. Furthermore, this article will highlight the signifying role of leptin as a therapeutic target by indicating the targeted treatment of DM through the appropriate understanding of advanced therapeutic approaches using leptin as a treatment strategy for DM.
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3.
Leptin in bipolar disorder: A systematic review and meta-analysis.
Fernandes, BS, Dash, S, Jacka, F, Dodd, S, Carvalho, AF, Köhler, CA, Steiner, J, da Graça Cantarelli, M, Nardin, P, Gonçalves, CA, et al
European psychiatry : the journal of the Association of European Psychiatrists. 2016;:1-7
Abstract
BACKGROUND Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD. METHODS This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in people with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges' adjusted g using random effects. RESULTS Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g=-0.99, 95% CI -2.43 to 0.43, P=0.171), in depression (g=0.17, 95% CI -0.45 to 0.79, P=0.584), or in euthymia (g=0.03, 95% CI -0.39 to 0.46, P=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of the individuals, the greater the difference in leptin levels between BD and controls; and the higher the BMI, the greater the difference in leptin levels between BD and controls. CONCLUSIONS Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.
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4.
Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development.
Pietrzyk, L, Torres, A, Maciejewski, R, Torres, K
Asian Pacific journal of cancer prevention : APJCP. 2015;(10):4161-8
Abstract
Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression).
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5.
[Novel adipokines: their potential role in the pathogenesis of obesity and metabolic disorders].
Korek, E, Krauss, H
Postepy higieny i medycyny doswiadczalnej (Online). 2015;:799-810
Abstract
Since identification in 1994 of leptin, a hormone produced by adipocytes, adipose tissue has become the subject of intensive research. These studies contributed to the discovery that adipocytes have the ability to synthesize and secrete biologically active substances called "adipokines". Adipokines include a variety of cytokines, peptide hormones and enzymes that play a role in a wide variety of biological functions. For example, they are involved in the regulation of appetite, energy homeostasis, vascular hemostasis, blood pressure, inflammatory and immune processes and play a role in the metabolism of carbohydrates and fats. In obese patients, the secretion of adipokines is frequently abnormal. These changes may predispose to the development of insulin resistance, hypertension and inflammation. Therefore, adipokines are the subject of ongoing clinical trials. The family of adipokines is increasing by the newly discovered peptides. This paper presents the current state of knowledge about retinol binding protein 4 (RBP-4), fasting-induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4), fibroblast growth factor-21 (FGF21), dipeptidyl peptidase-4 (DPP-4), irisin and their potential role in the pathogenesis of metabolic disorders associated with obesity. The knowledge of the role of newly discovered adipokines may help in the treatment of metabolic syndrome.
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6.
Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity.
Delort, L, Rossary, A, Farges, MC, Vasson, MP, Caldefie-Chézet, F
Life sciences. 2015;:37-48
Abstract
More than one million new cases of breast cancer are diagnosed worldwide each year and more than 400,000 deaths are caused by the disease. The origin of this pathology is multifactorial and involved genetic, hormonal, environmental and nutritional factors including obesity in postmenopausal women. The role played by the adipose tissue and their secretions, ie adipokines, is beginning to be recognized. Plasma adipokine levels, which are modulated during obesity, could have “remote” effects on mammary carcinogenesis. Breast cancer cells are surrounded and locally influenced by an adipocyte microenvironment, which is probably more extensive in obese people. Hence, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the local pro-inflammatory mechanisms, especially in obese patients, who have increased metastatic potential and greater risk of mortality. This review presents the multifaceted role of leptin in breast cancer development and the different molecular pathways involved such as inflammation, oxidative stress and antitumor immunity.
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7.
Interrelationship between bone turnover markers, calciotropic hormones and leptin in obese Saudi children.
Saber, LM, Mahran, HN, Baghdadi, HH, Al Hawsawi, ZM
European review for medical and pharmacological sciences. 2015;(22):4332-43
Abstract
OBJECTIVE Fat-bone relationship involves the interaction among endocrine, inflammatory, immune processes and bone turnover. We tried to assess the association between Leptin and bone turnover markers (OCN, β-CTx, ALP), calciotropic hormones PTH and 25(OH)D in obese Saudi children. PATIENTS AND METHODS A cross-sectional study performed with 60 obese children and 36 lean children. For all subjects, OCN, ALP, β-CTx, PTH, 25(OH)D, leptin, Ca and Pi were investigated. Levels of leptin were measured by [ELISA] method, and OCN, β-CTx, PTH and 25-(OH)D by an electrochemiluminescence immunoassay. RESULTS Sixty obese Saudi children had means weight (38.3 vs. 13.8 kg), height (121.0 vs. 91.8 cm) leptin (23.04 vs.16.88 ng/ml), PTH (31.5 vs. 14.7 pg/ml), Pi (1.67 vs. 1.54 mmol/l) were significantly higher and 25(OH)D (21.02 vs. 29.45 ng/ml) was significantly lower than controls. There was no difference in serum OCN, β-CTx, ALP and calcium between groups (p > 0.05). In the correlation study, OCN were significantly positively correlated with height, ALP, age, PTH, and β-CTx (r = 0.347, 0.32, p < 0.05), (r = 0.35, 0.51, 0.66, p < 0.01 respectively), while serum 25(OH)D was negatively correlated with PTH, weight, height and BMI (r = -0.45, -0.55, -0.55, -0.47, p < 0.01 respectively). PTH was positively correlated with leptin and β-CTx (r = 0.41, 0.44, p < 0.01), but not to ALP and BMI percentile. β-CTx correlated significantly positive with Pi (r = 0.34 p < 0.05) and ALP with BMI percentile (r = 0.42, p < 0.05). Multiple regression analysis demonstrated that PTH was predicted by leptin and β-CTx (R2 = 0.55); β-CTx by leptin and OCN (R2 = 0.498); OCN by PTH and β-CTx (R2 = 0.47); and 25(OH)D by PTH (R2 = 0.21). CONCLUSIONS The obese children had increased levels of leptin and PTH with strong associated with bone turn over markers OCN, β-CTx and deficiency of 25(OH)D which may be playing an important role in the pathogenesis of obesity and related bone metabolic risk diseases as osteoporosis and fractures.
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8.
[Cardiovascular exercise on obese women: effects on adiponectine, leptine, and tumour necrosis factor-alpha].
Landeros-Olvera, E, López-Alvarenga, JC, Nava-González, EJ, Gallegos-Cabriales, E, Lavalle-González, F, Bastarrachea, RA, Salazar González, BC
Archivos de cardiologia de Mexico. 2014;(3):177-82
Abstract
INTRODUCTION The relationship of hormones adiponectin, leptin and tumor necrosis factor-alpha in adipose tissue on the atherogenic process is one of the most promising models in preventive medicine. The numerous tests performed to identify the effect of exercise on these hormones have not been clear on the type of exercise routine and physical effort calculated to contribute to changing plasma concentrations in obese women. OBJECTIVE Analyze controlledcardiovascular exercise effect on serum level of adiponectin, leptin, and tumournecrosis factor-alpha in obese young women. METHOD A simple blind clinical essay. The intervention covered a 10-week controlled, cardiovascular exercise program by 34 women (cases n=17, controls n=17) with a body mass index>27kg/m(2). Molecular analysis was performed by immune-fluorescence. RESULTS Following the intervention, cases and controls means were as follows: adiponectin 19.0 vs. 12.2μ/ml (P=.008); leptin 20.0 vs. 28.0μ/L (P=.02); and tumour necrosis factor-alpha 4.7 vs. 5.1pg/ml (P=.05). CONCLUSIONS The established exercise (5 sessions a week of exercise of 40min each for 10 weeks with a heart rate reserve of 40 to 80%) improved plasma concentrations of these hormones in the expected direction. This finding highlights an unpublished amount of exercise, controlled by the reserve cardiac frequency that might contribute the cardiovascular and metabolic protection to obese women.
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9.
Is a child's growth pattern early in life related to serum adipokines at the age of 10 years?
Flexeder, C, Thiering, E, Kratzsch, J, Klümper, C, Koletzko, B, Müller, MJ, Koletzko, S, Heinrich, J, ,
European journal of clinical nutrition. 2014;(1):25-31
Abstract
BACKGROUND/OBJECTIVES Growth parameters during infancy and early childhood might predict adipokine levels later in life. This study investigates the association between peak growth velocities, body mass index (BMI) and age at adiposity rebound (AR), with leptin and adiponectin levels at age 10 years. SUBJECTS/METHODS Peak height (PHV) and weight (PWV) velocities were calculated from height and weight measurements obtained between birth and age 2 years from 2880 children participating in the GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics) birth cohorts. BMI and age at AR were calculated using BMI measurements between age 1.5 and 12 years. Blood samples were collected during a physical examination at age 10. Adiponectin and leptin levels were measured by radioimmunoassay. Linear regression models were fitted after adjustment for potential confounding factors and results are presented per interquartile range increase in the exposure. RESULTS Age at AR was negatively associated with leptin in males and females (percent difference β*: -41.71%; 95% confidence interval: (-44.34;-38.96) and β*: -43.22%; (-45.59; -40.75), respectively). For both males and females PWV (β*: 14.23%; (7.60; 21.26) and β*: 18.54%; (10.76; 26.87), respectively) and BMI at AR (β*: 63.08%; (55.04; 71.53) and β*: 67.02%; (59.30; 75.10), respectively) were positively associated with leptin levels. PHV showed a positive effect on leptin in females only (β*: 10.75%; (3.73; 18.25)). Growth parameters were not significantly associated with adiponectin except for age at AR among females (β: 0.75 ng/ml; (0.42; 1.09)) and PWV among males (β: 0.45 ng/ml; (0.11; 0.79)). CONCLUSION Growth patterns in early life may be associated with leptin levels at age 10 years.
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10.
Leptin-based adjuvants: an innovative approach to improve vaccine response.
White, SJ, Taylor, MJ, Hurt, RT, Jensen, MD, Poland, GA
Vaccine. 2013;(13):1666-72
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Abstract
Leptin is a pleiotropic hormone with multiple direct and regulatory immune functions. Leptin deficiency or resistance hinders the immunologic, metabolic, and neuroendocrinologic processes necessary to thwart infections and their associated complications, and to possibly protect against infectious diseases following vaccination. Circulating leptin levels are proportional to body fat mass. High circulating leptin concentrations, as observed in obesity, are indicative of the development of leptin transport saturation/signaling desensitization. Leptin bridges nutritional status and immunity. Although its role in vaccine response is currently unknown, over-nutrition has been shown to suppress vaccine-induced immune responses. For instance, obesity (BMI ≥30 kg/m(2)) is associated with lower antigen-specific antibody titers following influenza, hepatitis B, and tetanus vaccinations. This suggests that obesity, and possibly saturable leptin levels, are contributing factors to poor vaccine immunogenicity. While leptin-based therapies have not been investigated as vaccine adjuvants thus far, leptin's role in immunity suggests that application of these therapies is promising and worth investigation to enhance vaccine response in people with leptin signaling impairments. This review will examine the possibility of using leptin as a vaccine adjuvant by: briefly reviewing the distribution and signal transduction of leptin and its receptors; discussing the physiology of leptin with emphasis on its immune functions; reviewing the causes of attenuation of leptin signaling; and finally, providing plausible inferences for the innovative use of leptin-based pharmacotherapies as vaccine adjuvants.