The Adipose Tissue as an Endocrine Organ

The Adipose Tissue as an Endocrine Organ Marcin Adamczak, MD, PhD, and Andrzej Wiecek, MD, PhD, Prof, FRCP (Edin) Summary: During the past 2 decades, results of both basic science and clinical studies have changed the physicians’ views about adipocyte pathophysiology. Since leptin was discovered in 1994, white adipose tissue was recognized as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. Inappropriate secretion of several adipokines by the excessive amount of white adipose tissue seems to participate in the pathogenesis of obesity-related pathologic processes including endothelial dysfunction, inflammation, atherosclerosis, diabetes mellitus, and chronic kidney disease. In this review endocrine action of selected adipokines (mainly leptin and adiponectin) in the context of kidney diseases is discussed. Specifically, the role of these adipokines in malnutrition, chronic kidney disease progression, and pathogenesis of cardiovascular complications is presented. Semin Nephrol 33:2-13 © 2013 Elsevier Inc. All rights reserved. Keywords: Adipose tissue, adipokines, leptin, adiponectin

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istorically, for centuries obesity was regarded as a sign of well-being and healthy condition. However, the epidemiologic studies performed in the second half of the past century significantly changed this view. Obesity, especially the visceral type, has since been recognized as an important risk factor of many chronic diseases, including atherosclerosis, arterial hypertension, diabetes mellitus, osteoarthritis, certain forms of cancer, and, last but not least, chronic kidney disease (CKD). The modern Western diet coupled with a sedentary lifestyle has led to a pandemic of obesity and the latter became a serious public health issue. Based on the World Health Organization estimation, currently there are 300 million subjects who suffer from obesity worldwide.1 One consequence of obesity-related comorbidities is a shorter life expectancy. The Prospective Studies Collaboration, with data obtained from 4 continents from almost 900,000 participants from 57 prospective studies, showed that the median survival rate is reduced by 8 to 10 years for morbidly obese subjects with a body mass index (BMI) of 40 to 45 kg/m2 compared with those with a normal BMI, mainly because of increased cardiovascular mortality.2 In the past few decades in the field of obesity research, besides epidemiologic studies, important basic science studies have been performed. Results of these studies have improved our knowledge concerning the pathophysiology of obesity and have changed our view of adipocyte physiology. Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland. Financial disclosure and conflict of interest statements: none. Address reprint requests to Professor Dr Med. Andrzej Wiecek, FRCP (Edin), Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Francuska Str. 20/24, 40-027 Katowice, Poland. E-mail: [email protected] 0270-9295/ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2012.12.008

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In addition to its roles in providing insulation and mechanical support, adipose tissues traditionally have been recognized as the major site for storage of surplus fuel.3 It plays a crucial role in the regulation of wholebody fatty acid homeostasis. In periods of calorie abundance it stores free fatty acids in the form of triglycerides through their esterification to glycerol, and releases them back into circulation in times of energy shortage. The first to suggest a role of adipose tissue beyond being a repository for lipids was Von Gierke,4 who in 1905 described the role of adipose tissue in glycogen storage. Since leptin was discovered in 1994,5 white adipose tissue (WAT) was recognized as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines.6-8 Inappropriate secretion of several adipokines by an excessive amount of WAT (mainly visceral) seems to participate in the pathogenesis of obesity-related pathologic processes including endothelial dysfunction, inflammation, atherosclerosis, diabetes mellitus, and CKD.

ENDOCRINE FUNCTION OF WHITE ADIPOSE TISSUE Adipokines may exert their endocrine, paracrine, and autocrine action. In this review, we mainly discuss the endocrine action of selected adipokines (leptin and adiponectin) in the context of kidney diseases. An incomplete list of such adipokines (among others hormones, inflammatory cytokines, chemokines, growth factors, and complement proteins) is provided in Table 1. The major physiological functions of these adipokines are shown in Figure 1. It is important to mention that in addition to adipokine secretion, WAT also is involved in the conversion of cortisone to cortisol by 11␤-hydroxysteroid dehydrogenase type 1.6 Histologically and functionally, adipose tissue is subdivided into WAT and brown adipose tissue (BAT).3,9 The main physiological role of BAT is thermogenesis and regulation of body temperature. In the past it was Seminars in Nephrology, Vol 33, No 1, January 2013, pp 2-13

Adipose tissue as an endocrine organ

Table 1. Adipokines (Among Other Hormones, Cytokines, Chemokines, Growth Factors, and Complement Factors) Produced in Adipose Tissue Adiponectin Leptin Visfatin Apelin Resistin Vaspin Agouti protein Acylation stimulating protein (ASP) Omentin Chemerin Zinc-␣2 glycoprotein (ZAG) Retinol binding protein-4 (RBP-4) Autotaksin Lipokain-2 Asymmetric dimetylarginin (ADMA) Nitric oxide (NO) Hydrogen peroxide (H2O2) Hydrogen sulfide (H2S) Atrial natriuretic peptide (ANP) Neuropeptide Y (NPY) Renin Macrophage migration inhibitory factor (MIF) Prostaglandins E2, F2 (PGE2, PGF2) Endocannabinoids: 2-arachidonoyl glycerol (2-AG), arachidonylethanolamide (anandamide) Colony stimulating factor-1 (CSF-1) Hepatocyte growth factor (HGF) Vascular endothelial growth factor (VEGF) Nerve growth factor (NGF) Heparin binding epidermal growth factor–like growth factor (HB-EGF) Osteopontin Insulin-like growth factor-1 (IGF-1) Complement factor D (adipsin) Complement factors B, C, C3, C1q Plasminogen activator inhibitor-1 (PAI-1) TNF-␣ IL-1␤, 6, 8, 10 IFN-␥–inducible protein 10 (IP-10) Macrophages and monocyte chemoattractant protein 1 (MCP-1) Adrenomedulin Angiotensinogen Serum amyloid A3 Lipocalin-2

believed that BAT regulates body temperature by lipid metabolism only in newborns.9 Recent studies have shown that healthy adult human beings still possess a substantial amount of metabolically active BAT in the supraclavicular and neck regions, and in paravertebral, mediastinal, para-aortic, and suprarenal locations.10,11 Moreover, an inverse correlation between BMI and BAT activity was observed in human beings.10,12 Most adipose tissue in human beings, however, is WAT.3 White adipose tissue comprises up to 20% to 25% of total human body weight.3 White adipose tissue is not both a histologically and functionally homogenous organ.

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It consists of a heterogeneous mixture of the following cellular structures: adipocytes, preadipocytes, endothelial cells, fibroblasts, macrophages, and leukocytes, as well as the following tissue structures: blood vessels and nerves.3,13,14 The predominant type of cells in WAT are adipocytes. Adipocytes are unique and highly specified cells. Ninety-five percent of the volume of the adipocyte consists of single-organelle, centrally localized vacuole filled with triglyceride droplets.3,13 In the past 2 decades it was shown that the remaining 5% of adipocyte volume ie, cytoplasm is highly metabolically active, producing different adipokines.3,13 Adipokines also are produced by other cells localized in WAT. As shown in Table 2, synthesis of adiponectin and leptin takes place in adipocytes while the other adipokines are mainly in cells localized in tissue matrix (among others in macrophages). Such a complex composition of WAT allows integration of multiple metabolic processes.8 Obesity is characterized by increased storage of fatty acids localized in an expanded adipose tissue mass. An increase of both adipocyte number and volume is observed in obese subjects.15 It is believed that adipocyte hypertrophy is associated with the dysregulation of its endocrine function.16,17 This dysregulation also may be caused by local inflammation,18,19 oxidative stress,20 hypoxia,21-23 and, last but not least, mechanical trauma.24 The dysregulation of adipocyte secretory function leads, among others, to the increase of leptin and decrease of adiponectin secretion. Moreover, in obesity the infiltration of adipose tissue by inflammatory cells (mainly macrophages) is observed.19 Such infiltration and activation of macrophages may lead to increased plasma and local concentrations produced by these cells adipokines (eg, resistin, interleukin [IL]-6, and tumor necrosis factor [TNF]-␣).6,8 White adipose tissue is functionally heterogeneous with respect to body site. The differing fat deposits in the body are differentially sensitive to the action of hormones and secrete different sets of adipokines. Visceral WAT is more sensitive to actions of catecholamines and glucocorticoids,25,26 whereas subcutaneous WAT is more sensitive to insulin.27 In general, visceral WAT compared with subcutaneous WAT shows more intensive endocrine activity. It was shown that 30% of genes expressed in visceral WAT and 20% of genes expressed in subcutaneous WAT encode secretory proteins.28 Visceral WAT is characterized by a higher synthesis of vascular endothelial growth factor, plasminogen activator inhibitor-1, and IL-6,29 whereas subcutaneous WAT is characterized by leptin and adiponectin.30-32 There are also important differences in adipokine secretion patterns between WAT deposits in different parts of the body. It is believed that such specialized WAT plays an important role in the regulation of the function of adjacent organs (eg, perivascular WAT regulates vascular tone or epicardial WAT stimulates inflammation in the heart).7,33

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M. Adamczak and A. Wiecek

Energy homeostasis and metabolism - leptin - adiponectin - visfatin - interleukin 6 - tumour necrosis factor-α

Lipid metabolism and energy storage - lipoprotein lipase - acylation stimulating protein - angiopoietin like protein 4

Hematopoiesis - leptin

Bone metabolism - leptin - adiponectin - interleukin 1 and 6 - tumour necrosis factor-α

Modulation of immune system - interleukin 6 and 8 - monocyte chemoatractant protein-1 - migration inhibitory factor - leptin - resistin - adipsin

Adipose tissue

Steroid hormones conversion - 11β–hydroxysteroid dehydrogenase type 1 Coagulation and fibrinolysis - plasminogen activator inhibitor-1 - leptin

Angiogenesis - vascular endothelial growth factor - leptin - angiopoetin-2 - adiponectin

Kidney function - leptin - adiponectin

Sexual maturation - leptin

-Vasoconstriction/vasorelaxation -- nitrix oxide -- prostaglandin E2 -- angiotensin II - asymetric dimethylarginine -- adrenomedullin -- adiponectin -- hydrogene sulfide -- angiotensin 1-7 -- omentin -- visfatin -- leptin -- resistin

Figure 1. The major physiological functions of adipose tissue secretory products.

In this review, endocrine action of selected adipokines (mainly leptin and adiponectin) in the context of kidney diseases is discussed. Leptin Leptin is a protein predominantly produced by adipocytes.34 It is encoded by the ob gene. Structural studies have shown that leptin is a member of the growth hormone 4-helical cytokine subfamily.35 Five isoforms of leptin receptors (leptin receptor isoform [OBR]a, OBRb, OBRc, OBRd, and OBRe) are known.36,37 OBRb couples

Table 2. Adipose Tissue Cells Involved in the Synthesis of Selected Adipokines

Adiponectin Leptin Resistin Visfatin Hepatic growth factor Vascular endothelial growth factor TNF-␣ IL-1␤, 6, 10 IL-8 Plasminogen activator inhibitor-1 Angiotensin II

Adipocyte

Cells Localized in Adipose Tissue Matrix

⫹⫹⫹ ⫹⫹⫹ ⫹/⫺ ⫹/⫺ ⫹/⫺ ⫹/⫺

⫹/⫺ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

⫹/⫺ ⫹/⫺ ⫹ ⫹⫹

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

⫹

⫹⫹⫹

to the Janus kinase/signal transducer and activator of transcription signal transduction pathway.38 OBRb is expressed primarily in the hypothalamus, where its action is important in the regulation of energy homeostasis.36,37 Stimulation of OBRb activates proopiomelanocortic neurons and triggers the release of ␣-melanocyte–stimulating hormone,39 which activates the type 4 melanocortin receptor (MC-4R), leading to reduced food intake and increased energy expenditure.40 Leptin also suppresses the activity of arcuate nucleus neuropeptide Y neurons,39 which physiologically stimulates appetite.41 OBRb expression also is detected in a large number of peripheral tissues including skeletal muscles, heart, adrenals, kidneys, adipocytes, immune cells, liver, and pancreatic cells.42 Thus, leptin may have a wide spectrum of peripheral functions. The functions of other isoforms of the leptin receptor with shortened cytoplasmic domains (OBRa, OBRc, OBRd) have yet to be determined. It is suggested that the functions of these receptor isoforms are leptin clearance and to facilitate leptin transport into the central nervous system.43,44 Physiologically, it is presumed that leptin is involved in the regulation of appetite, food intake and energy expenditure, sexual maturation and fertility, hematopoiesis, bone metabolism, and activity of the hypothalamicpituitary-gonadal axis.42,45,46 Higher plasma leptin concentrations are present in obese than in lean subjects, as well as in females than in males.34,45 Patients with CKD, even in the nonadvanced stages of the disease, are characterized by increased plasma leptin concentrations. In a cross-sectional study of 219 patients

Adipose tissue as an endocrine organ

with various degrees of CKD, a significant negative correlation was found between plasma leptin concentration and glomerular filtration rate (GFR).46 This observation was confirmed by Okpechi et al47 in a study conducted among approximately 300 subjects. Recently, Shankar et al48 examined 5,820 participants of the third National Health and Nutrition Examination Survey. The investigators found that higher plasma leptin concentrations were associated with CKD after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, BMI, diabetes mellitus, arterial hypertension, and serum cholesterol concentration. Patients with CKD stage 5 have an approximately 4-fold higher plasma leptin concentration compared with BMI- and sex-matched healthy individuals.49 Plasma leptin concentrations in these patients are normalized after a successful kidney transplantation.50 Interestingly, the influence of impaired kidney function on the plasma leptin concentration is less pronounced in noninflammatory acute kidney injury than in CKD, suggesting the participation of other factors influencing leptin secretion in this state.51 It was shown that the decreased leptin clearance by failed kidneys leads to its accumulation in the circulation.52,53 Results of kinetic studies have suggested that the renal metabolism of leptin involves active uptake of leptin by renal tissue.54 Cumin et al55 studied changes of plasma leptin concentration in Zucker obese rats subjected to a bilateral nephrectomy or a bilateral ureteral ligation. A bilateral ureteral ligation was followed by a significant reduction of GFR owing to increased tubular pressure and increased plasma leptin concentration by 50%. However, after the bilateral nephrectomy performed in this experiment, plasma leptin concentrations increased by 300%. Results of this elegant experimental study suggest that leptin elimination is only partly dependent on GFR. Therefore, renal elimination is not necessarily affected by the disease in direct proportion to changes in GFR. The increased plasma leptin concentration in patients with CKD does not result in oversecretion of this protein. It was shown that leptin gene expression in adipocytes in CKD patients is significantly lower than in healthy individuals.46,56 Leptin plasma concentration is not reduced by lowflux dialysis membranes, whereas high-flux dialysis membranes and hemodiafiltration decrease leptin levels.57-59 Peritoneal dialysis patients are characterized by higher plasma leptin concentrations than hemodialysis patients.60 It is well known that CKD-associated malnutrition is linked to higher morbidity and mortality rates. It initially was believed that hyperleptinemia is an adequate explanation for malnutrition in CKD patients.61 The results of experimental studies confirmed this hypothesis. It was shown that experimental uremic cachexia was attenuated in a mice strain with leptin-receptor deficiency: db/db mice. Nephrectomy in these animals did not result in changes in

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weight gain, body composition, resting metabolic rate, or food consumption. Furthermore, MC-4R knockout mice or mice receiving the MC-4R antagonist were resistant to uremia-induced loss of lean body mass and maintained normal basal metabolic rates.62,63 However, a few small clinical studies addressing the relationship between nutritional status and plasma leptin concentration in CKD yielded conflicting results.64-70 Daschner et al64 found that increased serum leptin was associated with lower dietary intake and higher catabolic rate in uremic children. Odamaki et al,65 in a study of 185 patients, showed that the serum leptin/body fat mass ratio was correlated significantly with the weight change of the patients during a follow-up evaluation period of 17 months, indicating that a high level of serum leptin had induced weight loss in the hemodialysis patients. Castaneda et al66 showed that high leptin levels were associated with decreased muscle mass in CKD patients, leading to the development of malnutrition. In peritoneal dialysis patients, Stenvinkel et al67 also found higher plasma leptin concentrations in patients with a loss of muscle mass. In contrast, Bossola et al68 found similar plasma leptin concentrations in anorexic and in nonanorexic patients, and in patients with a dietary energy intake of less than 30 or 30 or more kcal/kg/d, and between those with a dietary protein intake of less than 1.2 or 1.2 or more g/kg/d. Moreover, according to our own results, in hemodialysis patients with CKD stage 5, a gain or loss of body weight (and fat mass or lean mass assessed by the dual-energy x-ray absorptiometry method) during the 12 months of initial hemodialysis therapy was independent of their plasma leptin concentration.69 It was hypothesized that a state of relative leptin resistance may occur in CKD patients similar to that in obese patients who do not respond to these increased leptin levels with reduced food intake. In view of the above-mentioned conflicting results of the clinical studies, the role of leptin in pathogenesis of malnutrition in CKD patients is still a matter of controversy.70 There is growing evidence that leptin, originally considered exclusively an anorexigenic hormone, exerts actions in the periphery outside of the central nervous system.42,45 Leptin stimulates the proliferation and the differentiation of hematopoietic stem cells.71 It is likely that the effects of leptin and erythropoietin are synergistic. The theory that high plasma leptin concentrations in CKD patients counteract the development of anemia when a plasma erythropoietin concentration is relatively decreased deserves consideration. Leptin also may participate in CKD progression. In murine models, the leptin-overexpressing db/db mice are characterized by more advanced renal disease than the leptin-deficient ob/ob mice. In normal rats, short-term (72 hours) infusion of recombinant leptin induces transforming growth factor-␤ (TGF-␤1) expression and also

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M. Adamczak and A. Wiecek

Table 3. Insulin-Sensitizing Properties of Adiponectin Glucose utilization stimulation in skeletal muscles and in liver Stimulation of fatty acid oxidation in skeletal muscles and in liver Enhancement of insulin signaling in skeletal muscle through facilitations of glucose Uptake by increasing expression and translocation of glucose transporter 4 Suppression of gluconeogenesis in the liver

increases the total number of proliferating cells. Longterm infusion (3 weeks) led to increased glomerular expression of type IV collagen and proteinuria.72 Leptinstimulated synthesis of type I and type IV collagen may contribute to extracellular mesangial matrix deposition and glomerulosclerosis. In glomerular endothelial cells, leptin stimulates cell proliferation, increased TGF-␤, and increased type IV collagen synthesis. Moreover, in mesangial cells, leptin increases TGF-␤ type 2–receptor expression and increased type I collagen synthesis.73 Apart from this, leptin likely plays a pathophysiological role in the pathogenesis of hypertension and cardiovascular diseases.74 Leptin may contribute to the development of arterial hypertension mainly through increased sympathetic nervous activity, and the development of endothelial dysfunction through the regulation of blood vessel tonus and imbalance between endothelial nitric oxide synthase expression and intracellular L-arginine.75-77 Leptin receptors are highly expressed in carotid plaques where leptin receptor expression correlates with macrophage density. Leptin also may participate in the pathogenesis of atherogenesis through the stimulation of platelet aggregation, inflammation, endothelial dysfunction, neointimal hyperplasia, neutrophil chemotaxis, and vascular smooth muscle cell proliferation and migration.42,45,78,79 Whether the removal of leptin by dialysis techniques and the down-regulation of leptin production by pharmaceutical agents may translate into clinical improvements such as improvement of appetite, nutrition status, inflammation, and decrease of cardiovascular risk in CKD patients remains unexplored. Adiponectin Adiponectin is a 30-kDa, 244 –amino acid protein hormone produced by the apM1 gene with a structural homology similar to collagen VIII and X and complement factor C1q.80 Adiponectin is secreted almost exclusively by adipocytes and presents with insulin-sensitizing and antiatherogenic properties (Tables 3 and 4).81 Adiponectin circulates in the bloodstream in high concentrations (almost 0.01% of total plasma protein). Within the circulation, adiponectin is present as a wide range of multimers: from trimers (low molecular weight), hexamers (medium molecular weight), to dodecamers or 18mers (high molecular weight [HMW]).82 It was shown that HMW is the most active form of adiponectin to improve insulin sensitivity.82 In contrast to leptin, plasma

adiponectin concentration is lower in obese than in lean subjects. Plasma adiponectin concentration is also lower in males than in females, and in patients with coronary artery disease, diabetes mellitus type 2, and essential hypertension than in healthy subjects.81,83 Two types of adiponectin receptors (adipoR1 and adipoR2) mediating antiatherogenic, anti-inflammatory, and insulin-sensitizing properties were discovered in skeletal muscle, liver, and endothelial cells.81 In hemodialysis patients, plasma adiponectin concentrations are approximately 3 times higher than in healthy subjects.84-86 Patients treated with peritoneal dialysis appear to have a less marked increase in plasma adiponectin concentration than hemodialysis patients, mainly because of a higher fat mass.87 Impaired kidney function affects the relative proportion of plasma fractions of adiponectin (ie, HMW, medium-molecular-weight, or low-molecularweight adiponectin) with a more pronounced increase of HMW fraction.88-90 The issue of whether or not a high plasma concentration of adiponectin is biologically active is still a matter of debate. Komura et al91 found that in cultured endothelial cells cystatin C abolished the suppressive effects of adiponectin on TNF-␣–induced expression of monocyte adhesion molecules. The expression of adiponectin receptors in CKD patients is preserved and similar to those observed in healthy subjects.92 The increased plasma adiponectin concentration in CKD patients is owing to the disturbances of its biodegradation and elimination by the failed kidneys. An experimental study using fluorescently labeled recombinant adiponectin proved that the kidney clears adiponectin.93 Results of several clinical observations confirmed

Table 4. Antiatherogenic Properties of Adiponectin Inhibition of monocyte attachment to vascular bed by decreasing expression of adhesion molecules Suppression of TNF-␣ and IL-6 production by macrophages, and suppression of IL-8 production by endothelial cells Stimulation of anti-inflammatory cytokine–IL-10 production by macrophages Suppression of superoxide generation Increase of nitric oxide synthase activity by endothelial cells Suppression of lipid accumulation in monocyte-derived macrophages and inhibition of transformation of macrophages into foam cells Down-regulation of scavenger low-density lipoproteins receptors Attenuation of growth-factor–induced proliferation of vascular smooth muscle cells and inhibition of oxidized modified lowdensity lipoproteins induced proliferation of endothelial cells Inhibition of the biological actions of growth factors by prereceptor binding with platelet-derived growth factor BB, basic fibroblast growth factor, and heparin-binding epidermal growth factor-like growth factor Stabilization of atherosclerotic plaque structures (through increasing expression of tissue inhibitor of metalloproteinases in infiltrating macrophages)þ Attenuation of thrombus formation and platelet aggregation

Adipose tissue as an endocrine organ

that the kidney is an important organ participating in the biodegradation and elimination of adiponectin from circulation. Thus, successful kidney transplantation is accompanied by a prompt reduction of plasma adiponectin concentration.94 Another piece of evidence is provided by the inverse relationship between plasma adiponectin concentration and GFR in apparently healthy individuals,95 mild or moderate CKD,96 and kidney transplant patients.97 Iwashima et al98 showed a gradual increase of plasma adiponectin concentration in parallel to the stages of CKD. An additional argument supporting renal elimination of adiponectin is the lower concentration of this protein in plasma samples from renal veins than in samples from the aorta.99 The increased plasma adiponectin concentration in CKD patients cannot be explained by its oversecretion by adipose tissue. The expression of the adiponectin gene (ApM1) in adipocytes is decreased even in patients with advanced CKD.100 Possible causes of lower adiponectin gene expression in CKD patients are the frequently coexisting microinflammation, increased oxidative stress, and increased sympathetic nervous activity. It is well known that oxidative stress increases with decreasing GFR, reaching the highest intensity in patients with CKD stage 5.101 In cultured adipocytes it was found that oxidative stress inhibits adiponectin gene expression and adiponectin release.102 In obese KKAy mice, increased oxidative stress is accompanied by a decreased plasma adiponectin concentration.102 Treatment of KKAy mice with apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, leads to an increase of adiponectin gene expression and plasma adiponectin concentration.102 Moreover, Furukawa et al102 showed a negative correlation between lipid peroxidation products represented by plasma thiobarbituric acid reactive substance or urinary 8-epi-prostaglandin-F2␣ and plasma adiponectin concentration in healthy subjects. Also, in diabetic patients with coronary heart disease, a negative correlation between plasma concentrations of oxidized low-density lipoprotein and adiponectin was shown.103 Similarly, in nondiabetic hemodialysis patients, Barazzoni et al104 showed that increased oxidative stress measured by plasma thiobarbituric acid reactive substance concentration is associated with low adiponectin expression in adipocytes. In addition, Lim et al105 found a negative correlation between plasma concentrations of another oxidative stress marker—malonyldialdehyde—and plasma adiponectin in hemodialysis patients. In the general population,106 as well as in dialysis patients, an inverse relationship was found between plasma concentrations of adiponectin and C-reactive protein87,107 or IL-6.107 These clinical observations were confirmed by in vitro studies indicating that TNF-␣, IL-6, and C-reactive protein inhibit adiponectin gene expression in cultured adipocytes.108-110 An additional factor participating in the pathogenesis of lower adiponectin gene expression in CKD patients

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seems to be an increased sympathetic nervous system activity, which frequently is observed in CKD.111 Fasshauer et al112 showed in cultured adipocytes that adiponectin gene expression is inhibited by ␤-adrenergic stimulation. In patients with essential hypertension and in healthy individuals it was shown that stimulation of sympathetic nervous activity by acute dietary sodium restriction leads to a decrease of plasma adiponectin concentration.113 It should be stressed that there are no published studies analyzing the relationship between sympathetic nervous activity and plasma adiponectin concentration in CKD patients. Finally, lower adiponectin gene expression in CKD patients partially may be explained by hyperadiponectinemia itself. In an animal model, high plasma adiponectin inhibited its production in adipocytes.114 It has been shown that in hemodialysis patients, similar to subjects with normal kidney function, lower plasma adiponectin concentrations are associated with cardiovascular complications such as coronary artery disease or peripheral arterial occlusive disease.115,116 Similarly, plasma adiponectin concentrations in peritoneal dialysis patients with carotid artery plaques was lower than in those without.107 Moreover, in the general population,117 as well as in hemodialysis patients, an inverse relationship was found between plasma adiponectin concentrations and intima-media thickness of the common carotid artery, an early marker of atherosclerotic changes.118 Even in interlobular kidney arteries the presence and complexity of arteriosclerotic lesions was related negatively to plasma adiponectin concentration as shown by Iwasa et al119 in kidney biopsy specimens of patients with IgA nephropathy. All of the earlier-mentioned clinical findings suggest that in CKD patients, as in subjects with normal kidney function, lower than expected plasma adiponectin concentration is involved in the pathogenesis or in progression of atherosclerosis. The impact of low plasma adiponectin concentration on the cardiovascular system may be restricted not only to acceleration of atherosclerosis, but also to an increase of the risk of left ventricular hypertrophy and diastolic dysfunction. Maeda et al,120 in a small cohort of hemodialysis patients, found a negative correlation between plasma adiponectin concentration and left ventricular mass, but a positive correlation between concentration and diastolic function index (mitral valve ratio of peak early to late diastolic filling velocity [E/A]). However, these findings were not confirmed in a study by Komaba et al.121 Also, in our study, no correlation was shown between plasma adiponectin concentration and left ventricular mass in kidney transplant recipients.122 Clinical studies addressing the relationship between plasma adiponectin concentration and prognosis in CKD patients yielded conflicting results. In the seminal pioneering study by Zoccali et al,84 low plasma adiponectin concentration was recognized as a new risk factor for

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cardiovascular morbidity in hemodialysis patients. They performed a 31-month follow-up evaluation of 227 such patients. Plasma adiponectin concentration in patients with cardiovascular events was significantly lower than in event-free patients.84 This observation by Zoccali et al84 was later confirmed by Rao et al,115 Ignacy et al,86 and, recently, by Abdallah et al.123 Yu et al107 published results from a 39-month follow-up evaluation of 59 peritoneal dialysis patients. The cumulative survival without new cardiovascular events was markedly better in patients with higher than in those with lower plasma adiponectin concentrations. Becker et al96 studied a group of 227 patients with mild or moderate nondiabetic CKD (measured GFR, 38-96 mL/min). They found that CKD patients with a history of cardiovascular events are characterized by approximately 50% lower plasma adiponectin concentrations, in comparison with those with an event-free follow-up period. Subsequently, they observed this cohort for 54 months. Also during the follow-up period, plasma adiponectin concentration was significantly lower in patients with cardiovascular events than in event-free patients. Iwashima et al124 observed 150 patients with CKD stages 1 to 5 (nonhemodialysis CKD patients) during a follow-up period of 32 months. They showed a significantly lower event-free survival rate in the lower adiponectin group. Recently, Roos et al125 studied a group of 206 renal transplant recipients during 36 months of follow-up evaluation. They found that low pretransplant plasma adiponectin concentration independently predicted an increased risk of allograft failure in kidney-transplant recipients. In all the earlier-mentioned studies it was shown that in CKD patients a relatively low plasma adiponectin concentration was associated with worsened cardiovascular outcome. However, in contrast to the results of the earlier-mentioned studies, other data have shown the opposite (ie, that high, rather than low, plasma adiponectin levels were associated with a higher risk of cardiovascular complications in CKD patients). Menon et al126 measured plasma adiponectin concentration in stage 3 or 4 CKD patients participating in the Modification of Diet in Renal Diseases study. In this study, 820 patients were observed during a 10-year follow-up period. In multivariable adjusted Cox regression models, each 1-␮g/mL increase of plasma adiponectin concentration was associated with a 3% increase of risk for all-cause mortality and a 6% increase of risk for cardiovascular mortality. Jorsal et al127 observed 373 patients with type I diabetes and diabetic nephropathy during an 8-year follow-up period. In a Cox regression analysis they found that high serum adiponectin concentration predicted mortality in these patients. Drechsler et al128 estimated plasma adiponectin concentration in type 2 diabetic hemodialysis patients from

M. Adamczak and A. Wiecek

the German Diabetes and Dialysis Study. In this study, 1,255 patients were observed during a 4-year follow-up period. They found the significant relationship between risk of cardiovascular events with high adiponectin levels. The results of the earlier-mentioned studies126-128 suggest that high, rather than low, plasma adiponectin concentration is associated with increased mortality or cardiovascular morbidity in CKD patients. Why are the results of the above-mentioned clinical studies contradictory? A recent study by Tsigalou et al129 can help. They observed 60 hemodialysis patients during 4.5 years and found that there was a U-shaped association of BMI with mortality, whereas there was an inverse U-shaped association between plasma adiponectin concentration and mortality. In patients with a BMI of 24 kg/m2 or greater, an increase in plasma adiponectin concentration was associated with a decreased mortality. In patients with a BMI less than 24 kg/m2, no significant association was observed between adiponectin and mortality. Therefore, malnutrition possibly may modify the effect of adiponectin on all-cause mortality in hemodialysis patients, thus explaining the conflicting published results in the literature regarding the association of plasma adiponectin concentration and mortality in CKD. The plasma adiponectin level may be high in relation to wasting, that is, a low-fat mass. Higher plasma adiponectinemia might be a surrogate marker of the poor nutritional status or wasting process, which are the more direct causes of increased mortality rates in CKD. Thus, the paradoxic unfavorable effect of high adiponectin, observed in some studies, might not necessarily reflect a direct detrimental effect of adiponectin, but, rather, it could be a consequence of a concurrent process of wasting. Animal experiments suggest that adiponectin normalizes albuminuria and improves podocyte foot process effacement. Sharma et al130 showed increased albuminuria in adiponectin knockout mice. This effect was especially pronounced after diabetes induction by streptozotocin and was reversed by adiponectin administration. After 5/6 nephrectomy in adiponectin knockout mice, increased albumin excretion despite similar creatinine clearance and blood pressure compared with nephrectomized wild-type mice was observed.131 Adiponectin knockout mice also are characterized by increased markers of inflammation and fibrosis in kidney. Exogenous adiponectin improved these parameters.132 Therefore, it could be hypothesized that a high plasma adiponectin concentration slows CKD progression. However, current clinical evidence suggests the opposite (ie, that high, not low, adiponectin is associated with CKD progression in patients with diabetic and nondiabetic kidney disease). Saraheimo et al132 observed 1,330 patients with type I diabetes during a 5-year follow-up period. They found in a Cox regression analysis that a high serum adiponectin concentration predicted progression from macroalbuminuria to CKD stage 5 in these

Adipose tissue as an endocrine organ

patients. Kollerits et al133 examined the effect of plasma adiponectin concentration on CKD progression in patients from the Mild to Moderate Kidney Disease study. In that study, 177 adult patients were followed up for up to 7 years to determine CKD progression, defined as requiring renal replacement therapy or doubling of serum creatinine concentration. They showed that a higher plasma adiponectin concentration predicted progression of CKD. In view of the earlier-mentioned conflicting results of the experimental and clinical studies, the role of adiponectin in the pathogenesis of CKD progression is still a matter of controversy. The Other Adipokines: Resistin and Visfatin Space does not permit us to exhaustively review the other adipokines with respect to kidney diseases. However, some remarks concerning resistin and visfatin should be provided. Resistin is a 12.5-kDa, 108 –amino acid protein hormone. In human beings it is expressed in macrophages from WAT.134 Several clinical studies have shown that the plasma concentration of resistin is increased in CKD and there is an inverse correlation between plasma resistin concentration and estimated GFR in these patients.135-137 Moreover, Kawamura et al138 found in the general Japanese population that resistin plasma concentration is increased with decreasing renal function. Therefore, the main cause of high plasma resistin concentrations in CKD is its reduced renal clearance. Hemodialysis is not able to lower the plasma resistin concentration.139 Resistin, at concentrations seen in patients with advanced CKD, was shown to inhibit neutrophil activity.140 Therefore, it may participate in the pathogenesis of the increased risk of infections in CKD patients. Resistin also appears to have a potential role in the pathogenesis of cardiovascular disease and contributes to an increased atherosclerotic risk. It stimulates endothelin-1 secretion by endothelial cells141 and increases expression of endothelial cell adhesion molecules.142 Surprisingly, Chung et al143 recently found in a prospective study, lasting 18 months, that hemodialysis patients with the lowest quartile of serum resistin concentration had the poorest hospitalization-free survival. Visfatin is a 52-kDa, 491–amino acid protein hormone.144 The plasma concentration of visfatin gradually increases with the loss of kidney function.145 Visfatin plasma concentration is related positively to endothelial dysfunction. It was found in CKD patients that visfatin plasma concentration correlated negatively with flowmediated vasodilatation.146 Moreover, this adipokine stimulates adhesion of monocytes to endothelial cells by increasing the expression of endothelial cell adhesion molecules.147 Visfatin also may play a role in the pathogenesis of malnutrition in CKD. In hemodialysis patients, a negative relationship between plasma visfatin and amino acid concentrations was found.148 A high plasma

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visfatin concentration predicted mortality in patients with CKD.145 Renin-Angiotensin System in Adipose Tissue Because of the obvious interest of the nephrologic community, we provide some remarks concerning the renin-angiotensin system (RAS) in adipose tissue. All components of the RAS are expressed in adipose tissue. Angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 and type 2 receptors have been localized to rodent and human adipocytes.149,150 This local adipose RAS exerts important autocrine/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis, as well as systemic and adipose tissue inflammation.149,150 Local adipose RAS also may participate in the pathogenesis of obesity-related arterial hypertension.151 Weight changes are related to alteration in RAS activity.152 Secretion of adipose tissue– derived angiotensinogen (AGT) into the systemic circulation has been shown in human beings.149 A strong relationship between adipose tissue AGT expression and circulating AGT levels in human beings was observed.152 The amount of angiotensinogen messenger RNA in adipose tissue reflecting the AGT production is 68% of that found in the liver.153 The importance of this AGT source in blood pressure regulation by the RAS was shown in mice in which adipocyte-derived angiotensinogen was overexpressed.154 Interestingly, it was suggested that the RAS in the adipose tissue is not related to sodium homeostasis.155

REFERENCES 1. World Health Organization Report. Fact sheet: obesity and overweight. Available from: http://www.who.int./dietphysicalactivity/ publications/facts/obesity/en/. 2. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373:1083-96. 3. Mariman EC, Wang P. Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci. 2010; 67:1277-92. ¨ ber fett metabolism. Der Deutsch Ges Path. 4. Von Gierke E. U 1906;10:182-5. 5. 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;372:425-32. 6. Chudek J, Adamczak M, Nieszporek T, Wiecek A. The adipose tissue as an endocrine organ–a nephrologists’ perspective. Contrib Nephrol. 2006;151:70-90. 7. Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009; 54:1847-56. 8. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316:129-39. 9. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277-359. 10. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509-17.

10 11. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444-52. 12. Seale P, Lazar MA. Brown fat in humans: turning up the heat on obesity. Diabetes. 2009;58:1482-4. 13. Trujillo ME, Scherer PE. Adipose tissue-derived factors: impact on health and disease. Endocr Rev. 2006;27:762-78. 14. Avram AS, Avram MM, James WD. Subcutaneous fat in normal and diseased states: 2. Anatomy and physiology of white and brown adipose tissue. J Am Acad Dermatol. 2005;53:671-83. 15. Ailhaud G. Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. C R Biol. 2006;329:570-7. 16. Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. The correlation between adiposity and adiponectin, tumor necrosis factor alpha, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults? J Endocrinol Invest. 2007;30:210-4. 17. Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007;92:1023-33. 18. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-9. 19. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796-808. 20. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752-61. 21. Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, et al. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun. 2006; 341:549-56. 22. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007;293:E1118-28. 23. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56:901-11. 24. Pachler C, Ikeoka D, Plank J, Weinhandl H, Suppan M, Mader JK, et al. Subcutaneous adipose tissue exerts proinflammatory cytokines after minimal trauma in humans. Am J Physiol Endocrinol Metab. 2007;293:E690-6. 25. Arner P, Hellström L, Wahrenberg H, Brönnegård M. Betaadrenoceptor expression in human fat cells from different regions. J Clin Invest. 1990;86:1595-600. 26. Brönnegård M, Arner P, Hellström L, Akner G, Gustafsson JA. Glucocorticoid receptor messenger ribonucleic acid in different regions of human adipose tissue. Endocrinology. 1990;127: 1689-96. 27. Giorgino F, Laviola L, Eriksson JW. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiol Scand. 2005;183:13-30. 28. Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K. Analysis of an expression profile of genes in the human adipose tissue. Gene. 1997;190:227-35. 29. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145:2273-82. 30. Van Harmelen V, Reynisdottir S, Eriksson P, Thörne A, Hoffstedt J, Lönnqvist F, et al. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes. 1998;47:913-7. 31. Lihn AS, Bruun JM, He G, Pedersen SB, Jensen PF, Richelsen B. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol. 2004; 219:9-15.

M. Adamczak and A. Wiecek 32. Fisher FM, McTernan PG, Valsamakis G, Chetty R, Harte AL, et al. Differences in adiponectin protein expression: effect of fat depots and type 2 diabetic status. Horm Metab Res. 2002;34: 650-4. 33. Maenhaut N, Van de Voorde J. Regulation of vascular tone by adipocytes. BMC Med. 2011;9:25. 34. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292-5. 35. Huising MO, Kruiswijk CP, Flik G. Phylogeny and evolution of class-I helical cytokines. J Endocrinol. 2006;189:1-25. 36. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A. 1997;94:7001-5. 37. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379:632-5. 38. Gao J, Tian J, Lv Y, Shi F, Kong F, Shi H, et al. Leptin induces functional activation of cyclooxygenase-2 through JAK2/ STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci. 2009;100:389-95. 39. Morrison CD. Leptin signaling in brain: a link between nutrition and cognition? Biochim Biophys Acta. 2009;1792:401-8. 40. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001; 411:480-4. 41. Stanley BG, Leibowitz SF. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 1984;35:2635-42. 42. Blüher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr. 2009;89:991S-7S. 43. Bjorbaek C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, et al. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology. 1998;139:3485-91. 44. Hileman SM, Pierroz DD, Masuzaki H, Bjørbaek C, ElHaschimi K, Banks WA, et al. Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology. 2002;143:775-83. 45. Dardeno TA, Chou SH, Moon H, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Front Neuroendocrinol. 2010;31:377-93. 46. Nordfors L, Lonnqvist F, Heimburger O, Danielsson A, Schalling M, Stenvinkel P. Low leptin gene expression and hyperleptinemia in chronic renal failure. Kidney Int. 1998;54:1267-75. 47. Okpechi IG, Pascoe MD, Swanepoel CL, Rayner BL. Microalbuminuria and the metabolic syndrome in non-diabetic black Africans. Diabetes Vasc Dis Res. 2007;4:365-7. 48. Shankar A, Syamala S, Xiao J, Muntner P. Relationship between plasma leptin level and chronic kidney disease. Int J Nephrol. 2012;2012:269532. 49. Heimbürger O, Lönnqvist F, Danielsson A, Nordenström J, Stenvinkel P. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol. 1997;8:1423-30. 50. Kokot F, Adamczak M, Wiecek A. Plasma leptin concentration in kidney transplant patients during the early post-transplant period. Nephrol Dial Transplant. 1998;13:2276-80. 51. Ficek R, Kokot F, Chudek J, Adamczak M, Ficek J, Wiecek A. Plasma leptin concentration in patients with acute renal failure. Clin Nephrol. 2004;62:84-91. 52. Cumin F, Baum HP, Levens N. Mechanism of leptin removal from the circulation by the kidney. J Endocrinol. 1997;155: 577-85.

Adipose tissue as an endocrine organ 53. Meyer C, Robson D, Rackovsky N, Nadkarni V, Gerich J. Role of the kidney in human leptin metabolism. Am J Physiol. 1997; 273:E903-7. 54. Zeng J, Patterson BW, Klein S, Martin DR, Dagogo-Jack S, Kohrt WM, et al. Whole body leptin kinetics and renal metabolism in vivo. Am J Physiol. 1997;273:E1102-6. 55. Cumin F, Baum HP, de Gasparo M, Levens N. Removal of endogenous leptin from the circulation by the kidney. Int J Obesity Relat Metab Disord. 1997;21:495-504. 56. Witasp A, Carrero JJ, Heimburger O, et al. Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients. J Intern Med. 2011; 269:410-9. 57. Wiesholzer M, Harm F, Hauser AC, Pribasnig A, Balcke P. Inappropriately high plasma leptin levels in obese haemodialysis patients can be reduced by high flux haemodialysis and haemodiafiltration. Clin Sci (Lond). 1998;94:431-5. 58. van Tellingen A, Grooteman MP, Schoorl M, Wee PM, Bartels PC, Schoorl M, et al. Enhanced long-term reduction of plasma leptin concentrations by super-flux polysulfone dialysers. Nephrol Dial Transplant. 2004;19:1198-203. 59. Kim S, Oh KH, Chin HJ, Na KY, Kim YS, Chae DW, et al. Effective removal of leptin via hemodiafiltration with on-line endogenous reinfusion therapy. Clin Nephrol. 2009;72:442-8. 60. Fontan MP, Rodriguez-Carmona A, Cordido F, García-Buela J. Hyperleptinemia in uremic patients undergoing conservative management, peritoneal dialysis, and hemodialysis: a comparative analysis. Am J Kidney Dis. 1999;34:824-31. 61. Young GA, Woodrow G, Kendall S, Oldroyd B, Turney JH, Brownjohn AM, et al. Increased plasma leptin/fat ratio in patients with chronic renal failure: a cause of malnutrition? Nephrol Dial Transplant. 1997;12:2318-23. 62. Cheung W, Yu PX, Little BM Marks DL, Mak RH. Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest. 2005;115:1659-65. 63. Mak RH, Cheung W, Cone RD, Marks DL. Leptin and inflammation-associated cachexia in chronic kidney disease. Kidney Int. 2006;69:794-7. 64. Daschner M, Tonshoff B, Blum WF, Englaro P, Wingen AM, Schaefer F, et al. Inappropriate elevation of serum leptin in children with chronic renal failure. European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. J Am Soc Nephrol. 1998;9:1074-9. 65. Odamaki M, Furuya R, Yoneyama, Nishikino M, Hibi I, Miyaji K, et al. Association of the serum leptin concentration with weight loss in chronic hemodialysis patient. Am J Kidney Dis. 1999;33:361-8. 66. Castaneda-Sceppa C, Sarnak MJ, Wang X, Greene T, Madero M, Kusek JW, et al. Role of adipose tissue in determining muscle mass in patients with chronic kidney disease. J Ren Nutr. 2007;17:314-22. 67. Stenvinkel P, Lindholm B, Lonnqvist F Katzarski K, Heimbürger O. Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body mass. J Am Soc Nephrol. 2000;11:1303-9. 68. Bossola M, Muscaritoli M, Valenza V, Panocchia N, Tazza L, Cascino A, et al. Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Pract. 2004;97:c76-82. 69. Chudek J, Adamczak M, Kania M, Hołowiecka A, Rozmus W, Kokot F, et al. Does plasma leptin concentration predict the nutritional status of hemodialyzed patients with chronic renal failure? Med Sci Monit. 2003;9:CR377-82. 70. Wiecek A. How does leptin contribute to uraemic cachexia? Nephrol Dial Transplant. 2005;20:2620-2. 71. Stenvinkel P, Heimburger O, Lonnqvist F, Bárány P. Does the ob gene product leptin stimulate erythropoiesis in patients with chronic renal failure? Kidney Int. 1998;53:1430-1. 72. Wolf G, Hamann A, Han DC, Helmchen U, Thaiss F, Ziyadeh FN, et al. Leptin stimulates proliferation and TGF-beta expres-

11

73. 74.

75. 76.

77.

78.

79.

80.

81. 82.

83. 84.

85.

86.

87.

88.

89.

90.

91.

92.

sion in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int. 1999;56:860-72. Wolf G, Ziyadeh FN. Leptin and renal fibrosis. Contrib Nephrol. 2006;151:175-83. Carrero JJ, Cordeiro AC, Lindholm B, Stenvinkel P. The emerging pleiotrophic role of adipokines in the uremic phenotype. Curr Opin Nephrol Hypertens. 2010;19:37-42. Maenhaut N, Van de Voorde J. Regulation of vascular tone by adipocytes. BMC Med. 2011;9:25. Li FY, Cheng KK, Lam KS, Vanhoutte PM, Xu A. Cross-talk between adipose tissue and vasculature: role of adiponectin. Acta Physiol (Oxf). 2011;203:167-80. Yiannikouris F, Gupte M, Putnam K, Cassis L. Adipokines and blood pressure control. Curr Opin Nephrol Hypertens. 2010;19: 195-200. Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation. 2008;117: 3238-49. Ottonello L, Gnerre P, Bertolotto M, Mancini M, Dapino P, Russo R, et al. Leptin as a uremic toxin interferes with neutrophil chemotaxis. J Am Soc Nephrol. 2004;15:2366-72. Wong GW, Wang J, Hug C, Tsao TS, Lodish HF. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A. 2004;101:10302-7. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26:439-51. Fisher M, Trujillo ME, Hanif W, Barnett AH, McTernan PG, Scherer PE, et al. Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia. 2005;48: 1084-7. Adamczak M, Chudek J, Wiecek A. Adiponectin in patients with chronic kidney disease. Semin Dial. 2009;22:391-5. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol. 2002;13:134-41. Stenvinkel P, Marchlewska A, Pecoits-Filho R, Heimbürger O, Zhang Z, Hoff C, et al. Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int. 2004;65:274-81. Ignacy W, Chudek J, Adamczak M, Funahashi T, Matsuzawa Y, Kokot F, et al. Reciprocal association of plasma adiponectin and serum C-reactive protein concentration in haemodialysis patients with end-stage kidney disease–a follow-up study. Nephron Clin Pract. 2005;101:c18-24. Park GH, Gil HW, Yang JO, Lee EY, Hong SY. Total and high molecular weight adiponectin concentrations in plasma of patients with end-stage renal disease before and after peritoneal dialysis. Nephrology (Carlton). 2008;13:181-5. Hara K, Uchida T, Takebayashi K, Sakai Y, Inoue T, Inukai T, et al. Determinants of serum high molecular weight (HMW) adiponectin levels in patients with coronary artery disease: associations with cardio-renal-anemia syndrome. Intern Med. 2011;50:2953-60. Lo MM, Salisbury S, Scherer PE, Furth SL, Warady BA, Mitsnefes MM. Serum adiponectin complexes and cardiovascular risk in children with chronic kidney disease. Pediatr Nephrol. 2011;26:2009-17. Shen YY, Charlesworth JA, Kelly JJ, Loi KW, Peake PW. Up-regulation of adiponectin, its isoforms and receptors in endstage kidney disease. Nephrol Dial Transplant. 2007;22:171-8. Komura N, Kihara S, Sonoda M, Maeda N, Tochino Y, Funahashi T, et al. Increment and impairment of adiponectin in renal failure. Cardiovasc Res. 2010;86:471-7. Shen YY, Charlesworth JA, Kelly JJ, Peake PW. The effect of renal transplantation on adiponectin and its isoforms and receptors. Metabolism. 2007;56:1201-8.

12 93. Halberg N, Schraw TD, Wang ZV, Kim JY, Yi J, Hamilton MP, et al. Systemic fate of the adipocyte-derived factor adiponectin. Diabetes. 2009;58:1961-70. 94. Chudek J, Adamczak M, Karkoszka H, Budzin´ski G, Ignacy W, Funahashi T, et al. Plasma adiponectin concentration before and after successful kidney transplantation. Transplant Proc. 2003; 35:2186-9. 95. Adamczak M, Rzepka E, Chudek J, Wiecek A. Ageing and plasma adiponectin concentration in apparently healthy males and females. Clin Endocrinol. 2005;62:114-8. 96. Becker B, Kronenberg F, Kielstein JT, Haller H, Morath C, Ritz E, et al. Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study. J Am Soc Nephrol. 2005; 16:1091-8. 97. Adamczak M, Szotowska M, Chudek J, Karkoszka H, Cierpka L, Wiecek A. Plasma adiponectin concentration in patients after successful kidney transplantation–a single centre, observational study. Clin Nephrol. 2007;67:381-90. 98. Iwashima Y, Horio T, Kumada M, Suzuki Y, Kihara S, Rakugi H, et al. Adiponectin and renal function, and implication as a risk of cardiovascular disease. Am J Cardiol. 2006;98:1603-8. 99. Adamczak M, Czerwienska B, Chudek J, Wiecek A. Renal extraction of circulating adiponectin in patients with renovascular hypertension. Acta Physiol Hung. 2007;94:143-8. 100. Marchlewska A, Stenvinkel P, Lindholm B, Danielsson A, Pecoits-Filho R, Lönnqvist F, et al. Reduced gene expression of adiponectin in fat tissue from patients with end-stage renal disease. Kidney Int. 2004;66:46-50. 101. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62:1524-38. 102. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114: 1752-61. 103. Lautamäki R, Rönnemaa T, Huupponen R, Lehtimäki T, Iozzo P, Airaksinen KE, et al. Low serum adiponectin is associated with high circulating oxidized low-density lipoprotein in patients with type 2 diabetes mellitus and coronary artery disease. Metabolism. 2007;56:881-6. 104. Barazzoni R, Bernardi A, Biasia F, Semolic A, Bosutti A, Mucci M, et al. Low fat adiponectin expression is associated with oxidative stress in nondiabetic humans with chronic kidney disease–impact on plasma adiponectin concentration. Am J Physiol Regul Integr Comp Physiol. 2007;293:R47-54. 105. Lim PS, Chen SL, Wu MY, Hu CY, Wu TK. Association of plasma adiponectin levels with oxidative stress in hemodialysis patients. Blood Purif. 2007;25:362-9. 106. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, et al. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation. 2003;107:671-4. 107. Yu ZZ, Ni ZH, Gu LY, Lin AW, Fang W, Yao Q, et al. Adiponectin is related to carotid artery plaque and a predictor of cardiovascular outcome in a cohort of non-diabetic peritoneal dialysis patients. Blood Purif. 2008;26:386-93. 108. Kappes A, Loffler G. Influences of ionomycin, dibutyrylcycloAMP and tumour necrosis factor-alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes. Horm Metab Res. 2000;32:548-54. 109. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, et al. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2003;301:1045-50. 110. Yuan G, Chen X, Ma Q, Qiao J, Li R, Li X, et al. C-reactive protein inhibits adiponectin gene expression and secretion in 3T3-L1 adipocytes. J Endocrinol. 2007;194:275-81.

M. Adamczak and A. Wiecek 111. Neumann J, Ligtenberg G, Klein II, Koomans HA, Blankestijn P. Sympathetic hyperactivity in chronic kidney disease: pathogenesis, clinical relevance, and treatment. Kidney Int. 2004;65: 1568-76. 112. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett. 2001;507:142-6. 113. Lely AT, Krikken JA, Bakker SJL, Boomsma F, Dullaart RPF, Wolffenbuttel BHR, et al. Low dietary sodium and exogenous angiotensin II infusion decrease plasma adiponectin concentrations in healthy men. J Clin Endocrinol Metab. 2007;92:1821-6. 114. Bauche IB, Ait El Mkadem S, Rezsohazy R, Funahashi T, Maeda N, et al. Adiponectin downregulates its own production and the expression of its AdipoR2 receptor in transgenic mice. Biochem Biophys Res Commun. 2006;345:1414-24. 115. Rao M, Li L, Tighiouart H, Jaber BL, Pereira BJ, Balakrishnan VS. Plasma adiponectin levels and clinical outcomes among haemodialysis patients. Nephrol Dial Transplant. 2008;23: 2619-28. 116. Saito O, Saito T, Okuda K, Okuda K, Kotoda A, Akimoto T, et al. Serum adiponectin and markers of endothelial injury in hemodialysis patients with arteriosclerosis obliterans. Clin Exp Nephrol. 2008;12:58-64. 117. Iglseder B, Mackevics V, Stadlmayer A, Tasch G, Ladurner G, Paulweber B. Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis: data from the SAPHIR Study. Stroke. 2005;36:2577-82. 118. Karakitsos D, De Groot E, Patrianakos AP, Parthenakis F, Boletis J, Karabinis A, et al. Adiponectin and cardiovascular remodeling in end-stage renal disease and co-morbid diabetes mellitus. Am J Nephrol. 2006;26:340-7. 119. Iwasa Y, Otsubo S, Ishizuka T, Uchida K, Nitta K. Influence of serum high-molecular-weight and total adiponectin on arteriosclerosis in IgA nephropathy patients. Nephron Clin Pract. 2008; 108:c226-32. 120. Maeda T, Taniguchi S, Sasaki H. Relationship between plasma adiponectin and cardiac function in patients with end-stage renal disease [abstract]. J Hypertens. 2006;24 Suppl 6:302 121. Komaba H, Igaki N, Goto S, Yokota K, Takemoto T, Hirosue Y, et al. Adiponectin is associated with brain natriuretic peptide and left ventricular hypertrophy in hemodialysis patients with type 2 diabetes mellitus. Nephron Clin Pract. 2007;107:c103-8. 122. Adamczak M, Blach A, Kolonko A, Szotowska M, Chudek J, Franek E, et al. Plasma adiponectin concentration and left ventricular hypertrophy in kidney transplant patients. Clin Transplant. 2011;25:561-8. 123. Abdallah E, Waked E, Nabil M, El-Bendary O. Adiponectin and cardiovascular outcomes among hemodialysis patients. Kidney Blood Press Res. 2012;35:247-53. 124. Iwashima Y, Horio T, Kumada M, Suzuki Y, Kihara S, Rakugi H, et al. Adiponectin and renal function, and implication as a risk of cardiovascular disease. Am J Cardiol. 2006;98:1603-8. 125. Roos M, Baumann M, Liu D, Heinemann FM, Lindemann M, Horn PA. Low pre-transplant adiponectin multimers are associated with adverse allograft outcomes in kidney transplant recipients a 3-year prospective study. Regul Pept. 2012;178:11-5. 126. Menon V, Li L, Wang X, Greene T, Balakrishnan V, Madero M, et al. Adiponectin and mortality in patients with chronic kidney disease. J Am Soc Nephrol. 2006;17:2599-606. 127. Jorsal A, Tarnow L, Frystyk J, Lajer M, Flyvbjerg A, Parving HH, et al. Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type I diabetes and diabetic nephropathy. Kidney Int. 2008;74:649-54. 128. Drechsler C, Krane V, Winkler K, Dekker FW, Wanner C. Changes in adiponectin and the risk of sudden death, stroke, myocardial infarction, and mortality in hemodialysis patients. Kidney Int. 2009;76:567-75.

Adipose tissue as an endocrine organ 129. Tsigalou C, Chalikias G, Kantartzi K, Tziakas D, Kampouromiti G, Vargemezis V, et al. Differential effect of baseline adiponectin on all-cause mortality in hemodialysis patients depending on initial body mass index. Long-term follow-up data of 4.5 years. J Ren Nutr. In press. 130. Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 2008;118:1645-56. 131. Ohashi K, Iwatani H, Kihara S, Nakagawa Y, Komura N, Fujita K, et al. Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice. Arterioscler Thromb Vasc Biol. 2007;27:1910-7. 132. Saraheimo M, Forsblom C, Thorn L, Saraheimo M, Forsblom C, Thorn L, et al. Serum adiponectin and progression of diabetic nephropathy in patients with type 1 diabetes. Diabetes Care. 2008;31:1165-9. 133. Kollerits B, Fliser D, Heid IM, Reitz E, Kronenberg F. Genderspecific association of adiponectin as a predictor of progression of chronic kidney disease: the mild to moderate kidney disease study. Kidney Int. 2007;71:1279-86. 134. Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol. 2012;165:622-32. 135. Kielstein JT, Becker B, Graf S, Brabant G, Haller H, Fliser D. Increased resistin blood levels are not associated with insulin resistance in patients with renal disease. Am J Kidney Dis. 2003;42:62-6. 136. Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, et al. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int. 2006;69:596-604. 137. Nusken KD, Kratzsch J, Wienholz V, Stöhr W, Rascher W, Dötsch J. Circulating resistin concentrations in children depend on renal function. Nephrol Dial Transplant. 2006;21:107-12. 138. Kawamura R, Doi Y, Osawa H, Ninomiya T, Hata J, Yonemoto K, et al. Circulating resistin is increased with decreasing renal function in a general Japanese population: the Hisayama Study. Nephrol Dial Transplant. 2010;25:3236-40. 139. Filippidis G, Liakopoulos V, Mertens PR, Kiropoulos T, Stakias N, Verikouki C, et al. Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif. 2005;23:421-8. 140. Cohen G, Ilic D, Raupachova J, Hörl WH. Resistin inhibits essential functions of polymorphonuclear leukocytes. J Immunol. 2008;181:3761-8. 141. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, et al. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation. 2003;108:736-40. 142. Skilton MR, Nakhla S, Sieveking DP, Caterson ID, Celermajer DS. Pathophysiological levels of the obesity related peptides

13

143.

144.

145.

146.

147.

148.

149.

150.

151. 152.

153.

154.

155.

resistin and ghrelin increase adhesion molecule expression on human vascular endothelial cells. Clin Exp Pharmacol Physiol. 2005;32:839-44. Chung W, Jung ES, Shin D, Choi SH, Jung JY, Chang JH, et al. Low resistin level is associated with poor hospitalization-free survival in hemodialysis patients. J Korean Med Sci. 2012;27: 377-81. Sommer G, Garten A, Petzold S, Beck-Sickinger AG, Blüher M, Stumvoll M, et al. Visfatin/PBEF/Nampt: structure, regulation and potential function of a novel adipokine. Clin Sci (Lond). 2008;115:13-23. Axelsson J, Witasp A, Carrero JJ, Qureshi AR, Suliman ME, Heimbürger O, et al. Circulating levels of visfatin/pre-B-cell colony-enhancing factor 1 in relation to genotype, GFR, body composition, and survival in patients with CKD. Am J Kidney Dis. 2007;49:237-44. Yilmaz MI, Saglam M, Carrero JJ, Qureshi AR, Caglar K, Eyileten T, et al. Serum visfatin concentration and endothelial dysfunction in chronic kidney disease. Nephrol Dial Transplant. 2008;23:959-65. Kim SR, Bae YH, Bae SK, Choi KS, Yoon KH, Koo TH, et al. Visfatin enhances ICAM-1 and VCAM-1 expression through ROS-dependent NF-kappaB activation in endothelial cells. Biochim Biophys Acta. 2008;1783:886-95. Carrero JJ, Witasp A, Stenvinkel P, Qureshi AR, Heimbürger O, Bárány P, et al. Visfatin is increased in chronic kidney disease patients with poor appetite and correlates negatively with fasting serum amino acids and triglyceride levels. Nephrol Dial Transplant. 2010;25:901-6. Kalupahana NS, Moustaid-Moussa N. The adipose tissue reninangiotensin system and metabolic disorders: a review of molecular mechanisms. Crit Rev Biochem Mol Biol. 2012;47:379-90. Cassis LA, Police SB, Yiannikouris F, Thatcher SE. Local adipose tissue renin-angiotensin system. Curr Hypertens Rep. 2008;10:93-8. Dorresteijn JAN, Visseren FLJ, Spiering W. Mechanisms linking obesity to hypertension. Obes Rev. 2012;13:17-26. Engeli S, Böhnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005;45:356-62. Lu H, Boustany-Kari CM, Daugherty A, Cassis LA. Angiotensin II increases adipose angiotensinogen expression. Am J Physiol Endocrinol Metab. 2007;292:E1280-7. Massiéra F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc JM, et al. Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J. 2001;15:2727-9. Engeli S, Boschmann M, Frings P, Beck L, Janke J, Titze J, et al. Influence of salt intake on renin–angiotensin and natriuretic peptide system genes in human adipose tissue. Hypertension. 2006;48:1103-8.