Adipokines - Literature review

Adipokines Physiology of adipose tissue Jaswinder K. Sethi and Antonio J. Vidal-Puig JOURNAL OF LIPID RESEARCH – THEMATIC REVIEW SERIES Thematic Review Series on Adipocyte Biology: Adipose Tissue Function and Plasticity Orchestrate Nutritional Adaptation Brown adipose tissue (BAT) - store triglycerides in multilocular adipocytes as quick access fuel for heat production through mitochondrial "uncoupling" of oxidative phosphorylation of FFA. This thermogenic process is vital in neonates exposed to the cold but may no longer be required and appears to be lost in adults who have developed additional strategies to keep warm. White adipose tissue- store excess energy as triglycerides, in large unilocular droplets and release it in the form of FFA. Function - Provides insulation and mechanical support and is a major site for storage of surplus fuel in the form of neutral triglycerides. During times of increased food intake and/or decreased energy expenditure, surplus energy is deposited efficiently in adipose tissue in the form of lipids. However, when food is scarce and/or energy expenditure requirements increase, these lipid reserves are released to provide fuel for energy generation. Adipose tissues therefore contain ―lipases‖ that break down triglycerides into glycerol and fatty acids that can then be transported in the blood to the liver, muscle and BAT, where they are used in fatty-acid oxidation . Adipose tissue as an endocrine organ In 1994, the discovery of leptin, a satiety factor produced predominantly by adipose tissue, added a further dimension to our understanding of adipose tissue function. It demonstrated that this tissue was capable of emitting signals to regulate food intake and energy expenditure and thereby orchestrate changes in energy balance and whole body nutritional status. Subsequent advances have identified many more adipose derived secreted products, which together with electron microscopic evaluations have reinforced this notion and led to the re-classification of adipose tissue as an endocrine organ. An important aspect of adipose tissue endocrinology is the recognition that numerous other cell types, in addition to adipocytes, are also present and play important roles in regulating adipose tissue function. The additional cell types present in the adipose tissue or its stroma-vascular fraction include; pericytes and endothelial cells, monocytes, macrophages and pluripotent stem cells (including pre-adipocytes). Interestingly, these non-adipocyte cells may also be the main source of some adipokines. Adipose tissue derived secreted factors (particularly from WAT depots), can have effects on multiple biological systems including energy homeostasis (lipid and carbohydrate metabolism, appetite, thermogenesis), immune system, reproductive function, haemostasia, blood pressure and angiogenesis. Some of these actions underscore the links between obesity and its related pathologies such as insulin resistance, hypertension, hyperlipidemia, type 2 diabetes and coronary heart disease. Adipose Tissue Is a Mediator of Inflammation and Innate Immunity A total of 99% of the world‘s metazoan species rely solely on innate immunity to defend them selves from infection. For insects, an organ called the fat body mostly mediates this response. The fat body has a receptor for bacterial and fungal cell wall constituents called the Toll receptor. This receptor activates the nuclear factor κB (NF-κB) signalling cascade and induces the secretion of antibacterial peptides and other defence mechanisms. The insect fat body simultaneously manages the animal‘s liver functions and the storage of lipids. At some point during evolution, vertebrates split these metabolic duties between the liver and adipose tissue. But what happened to the functions of innate immunity? Since the discovery of innate immunity and the acute phase response in humans, it has been thought that these functions were primarily the domain of the liver, but more recent evidence shows that when fat storage was delegated to adipose tissue, the ability to fulfil some aspects of innate immunity was preserved in adipose tissue as well. In addition to adipocytes, adipose tissue contains fibroblasts, preadipocytes, tissue resident macrophages, and vascular constituents. Macrophages are known to be crucial contributors to inflammation, but more recently, it has been recognized that adipocytes demonstrate significant intrinsic inflammatory properties as well. Like macrophages, the adipocyte is exquisitely sensitive to infectious disease agents and cytokine-mediated inflammatory signals; it expresses a host of receptors, enabling it to sense the presence of pathogens and inflammation and on stimulation of these receptors, it activates multiple inflammatory signal transduction cascades, and induces and secretes a number of potent inflammatory cytokines and acute phase reactants. Adipocytes are sensitive to the effects of tumor necrosis factor-α (TNF-α), which, through its p55 and p75 TNF receptors, stimulates NF-κB, extracellular signal-regulated kinase, and p38 mitogenactivated protein kinases PI-3 kinase and jun-N-terminal kinase cascades. The mammalian toll-like lipopolysaccharide (LPS) receptor TLR4 is expressed in tissue and in vitro cultured adipocytes. Adipose tissue derived secreted factors (particularly from WAT depots), can have effects on multiple biological systems including energy homeostasis (lipid and carbohydrate metabolism, appetite, thermogenesis), immune system, reproductive function, haemostasia, blood pressure and angiogenesis (Table 1). As discussed below, some of these actions underscore the links between obesity and its related pathologies such as insulin resistance, hypertension, hyperlipidemia, type 2 diabetes and coronary heart disease. Nonetheless, in non-obese situations, the cytokine-mediated interplay between the immune system and adipose tissue biology appears a valuable network whereby surplus fuel can be made readily available for utilisation by activated immune cells during infection and/or inflammation. Table 1: Factors Secreted by Adipose Tissue Lipid Metabolism Lipoprotein lipase (LPL), Free Fatty Acids, Glycerol, Apoprotein E Steroid Hormones: Oestrone, Oestradiol, Testosterone Growth factors & Cytokines: IGF-1, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), Leptin, Tumour necrosis factor a (TNF-α), IL-1beta Interleukin-6 (IL6) Vasoactive factors: Monobutyrin, Angiotensinogen Angiotensin II, Atrial natriuretic peptide Eicosanoids: Prostaglandins E2 (PGE2), Prostaglandins F2a (PGF2a), Prostacyclin (Prostaglandin I2/ PGI2) Complement system: Factor B, Factor C, C3, C1q, Factor D (adipsin/Acylation-stimulating protein (ASP/ C3desARg)) Binding proteins: Retinol BP, IGF-BPs sTNFRs Extracellular matrix proteins: monocyte chemotactic protein-1 (MCP-1) Others: Adiponectin (Acrp30/AdipoQ), Cholesterol ester transfer protein, Plasminogen activator-inhibitor 1 haptoglobin LPA, lysophosphatidic acid, Resistin, Visfatin/PBEF, Omentin, Fasting induced adipose factor, Metallothionen, Apelin Jerzy Chudek, Andrzej Wiêcek. Adipose tissue, inflammation and endothelial dysfunction. Pharmacological Reports 2006,58,suppl,81-88 Adipose tissue is not a homogenous organ. It consists of a variety of different cell types: adipocytes, preadipocytes, stromal/vascular cells and macrophages. Each of these cells presents its own secretion profile and specific regulation. Obesity is related not only to the increased number and size of adipocytes but also to infiltration of adipose tissue by macrophages. - Leptin is a protein predominantly produced by adipocytes. First, leptin was believed to be a satiety hormone involved in the regulation of appetite. A few years later, leptin appeared to be mostly a marker of nutrition, unable to decrease food intake even in markedly obese humans with its extremely high plasma levels. Low plasma leptin concentration should be regarded to be a ‗starvation signal‘, decreasing the energy expenditure and stimulating the search for food in food deprived rodents. - Leptin receptors were identified in peripheral tissues including endothelial cells, platelets and monocytes /macrophages. These receptors may potentially mediate the direct vascular injury and deteriorative impact of adipose tissue on the cardiovascular system in obese humans, beyond the stimulation of the sympathetic nervous system via leptin receptors located in the brainstem. There is also indirect evidence that high plasma leptin concentration may promote atherosclerosis. The prolonged stimulation of the immune system seems to be one of the potential mechanisms since leptin may stimulate both proliferation and differentiation of hemopoietic cells, including T cells. Moreover it was recently shown that leptin treatment promoted thrombus formation in apolipoprotein Edeficient mice. Adiponectin is a protein hormone secreted almost exclusively by adipocytes that exhibits antiatherogenic and insulin-sensitizing properties. Lower adiponectin concentrations were found in patients with coronary artery disease, diabetes mellitus type 2 and essential Hypertension. Adiponectin can occur as a full length molecule (almost all) or a smaller globular C terminal domain fragment. In the circulation, adiponectin forms a wide range of multimers: from trimers (low molecular weight – LMW), hexamers (medium molecular weight – MMW) to dodecamers or 18-mers (high molecular weight – HMW). It was shown that HMW was an active form of adiponectin improving insulin-sensitivity. Adiponectin receptors have been found in skeletal muscle, liver and endothelial cells etc. Ouchi et al. found that endothelium-dependent vasorelaxation was impaired in subjects with low plasma adiponectin concentration. According to Chen et al., this endothelium-dependent mechanism entails the stimulation of nitric oxide production by adiponectin. Adiponectin also decreases expression of adhesion molecules (VCAM-1; ICAM-1, E-selectin) in endothelial cells in response to inflammatory stimuli, such as tumor necrosis factor-α (TNF-α) and finally attenuates neointimal proliferation. Thus, it has been suggested that low plasma adiponectin concentration might be an important mechanism linking obesity with hypertension and atherosclerosis. The antiatherogenic effect of adiponectin was confirmed in ApoE-deficient mice, a well-known model of spontaneous atherosclerosis. The antiatherogenic properties of adiponectin include also endothelium-independent mechanisms. Adiponectin suppresses production of cytokines, like TNF-α by macrophages, suppresses accumulation of lipids in monocyte-derived macrophages and inhibits transformation of macrophages into foam cells. It also inhibits cell proliferation stimulated by oxidized low density lipoprotein (LDL). Moreover, adiponectin participates in the stabilization of atherosclerotic plaques by increasing expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in infiltrating macrophages. Low plasma adiponectin concentration is now recognized to be a new potential risk factor of cardiovascular morbidity. The experimental studies indicate that inflammatory processes may modulate adiponectin secretion. TNF-α and IL-6 inhibit adiponectin gene expression in cultured adipocytes. In general population, an inverse relationship was found between plasma concentrations of adiponectin and C-reactive protein (CRP). IL-6 is one of the main proinflammatory mediator primarily secreted by the immune system cells. However, 20–30% of this cytokine in the circulation is produced by the adipose tissue. In the liver, IL-6 stimulates synthesis of acute phase response proteins including CRP, fibrinogen, serum amyloid-A and α-1 antichymotrypsin. It is already well known that CRP is both a marker and important risk factor of cardiac events and atherosclerosis in general population. Recently it was suggested that CRP might directly elicit endothelial dysfunction. It is also worth stressing that IL-6 stimulates fibrinogen production and platelet activity, which increases the risk of clot formation. TNF-α is predominantly synthesized by macrophages infiltrating adipose tissue. This cytokine reduces adiponectin secretion by adipocytes and is involved in the pathogenesis of inflammation and insulin resistance. TNF-α stimulates adhesion of monocytes to the surface of endothelial cells by enhancing the expression of adhesion molecules (ICAM-1, VCAM-1), stimulates infiltration of vascular wall by monocytes (macrophage chemoattractive protein1 – MCP-1) and their transformation to macrophages (macrophage colony stimulating factor – M-CSF). MICHAEL W. RAJALA AND PHILIPP E. SCHERER. Minireview: The adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis. Endocrinology, September 2003, 144(9):3765–3773. Leptin is a highly conserved 16-kDa hormone that is predominately expressed in adipose tissue and is found both in circulation and cerebrospinal fluid. Circulating leptin levels are positively correlated with body mass index (BMI) with concentrations in human serum at approximately 1–10 ng/ml. Leptin crosses the blood brain barrier by a saturable transport system and effectively serves as an afferent signal to the central nervous system originating from adipose tissue. One site of leptin action is in the arcuate nucleus of the hypothalamus in a region known to control the regulation of food intake. Centrally, it is capable of altering food intake, body weight, energy expenditure, and neuroendocrine function, whereas it also has peripheral effects on skeletal muscle, liver, pancreas, adipose tissue, and numerous other cell types. The mechanism by which leptin is capable of exerting its metabolic affects has been an area of intense research. A recently reported mechanism is based on the observation that leptin is capable of activating 5-AMP-activated protein kinase (AMPK) in muscle and liver both by acting directly on these tissues and by acting centrally through the central nervous system. When activated, AMPK decreases ATPconsuming anabolic pathways such as glucose-regulated transcription, protein synthesis, cholesterol synthesis, and fatty acid and triglyceride synthesis, and it also increases ATP-producing catabolic pathways such as increased glucose transport, βoxidation, glycolysis, and mitochondrial biogenesis. Beyond its central metabolic functions, leptin has profound effects on a number of other physiologic processes, such as fertility and normal immune function. The influence of leptin in immune function can be clearly seen in the context of nutritional status. Normal immune function is suppressed during times of nutritional deprivation, a state associated with low levels of circulating leptin. The immunosuppression associated with acute starvation is reversed when leptin is exogenously administered. In line with these observations, ob/ob mice have impaired T cell immunity. Leptin also alters the regulation of hormones in the hypothalamus-pituitary-adrenal axis and affects GH, prolactin, and a number of other anterior pituitary hormones. Similar to other hormones, diurnal and ultradian leptin rhythms have been identified with peak circulating levels at night reaching the nadir in the morning. This rhythm can be altered by meal timing but does not seem to be entrained by the circadian clock. It has been postulated that a leptin resistance can develop in the face of high circulating levels of the hormone. This is supported by the fact that leptin levels are increased in most mouse models of insulin resistance associated with obesity. The effectiveness of intracerebral ventricular injections of leptin in a number of models of genetic and diet induced obesity suggest that leptin resistance can occur at several levels, from the transport across the blood brain barrier, to downstream targets of the receptor. The inability of high endogenous leptin to prevent weight gain may partly be explained by the reduced cerebrospinal fluid: peripheral ratio of leptin in obese individuals. Leptin may have evolved to deal with limited energy availability, and its main function may be to mediate responses necessary to increase those energy stores, i.e. including effects on feeding behaviour.As such, it is unfortunately not capable of preventing overconsumption or obesity and does not appear to be a viable treatment for obesity at this stage. Adiponectin Adiponectin is a 30-kDa adipose-specific secreted protein that circulates in human serum at 5–30 ng/ml concentrations, with circulating levels approximately two to three times higher in females than in males. The mature protein consists of an amino-terminal collagen-like domain and a carboxyterminal head domain with structural similarities to complement factor C1q. Serum adiponectin (FL-Ad) is found as a low-molecular-weight complex consisting of a dimer of trimers as well as a high-molecular-weight complex consisting of up to six trimers. A third form, generated by cleavage of the collagenous stalk region that results in globular trimer (gAd), has not conclusively been shown to exist as a physiological intermediate but has potent pharmacological activity . Adiponectin, the product of the transcript-1 (apM1) gene, which is exclusively and most abundantly expressed in adipose tissue, is a 244 amino-acid protein structurally homologous to collagen VIII, collagen X and complement fraction C1q. Chia-Chu Chang, Ching-Hui Hung, Chaun-Shu Yen, Kai-Lin Hwang and ChingYuang Lin. The relationship of plasma ghrelin level to energy regulation, feeding and left ventricular function in non-diabetic haemodialysis patients. Nephrol Dial Transplant (2005) 20: 2172–2177 Ghrelin isolated mostly from the stomach, is an endogenous ligand for the growth hormone secretagogue receptor (GHSR) and potently stimulates growth hormone release [2]. It is also involved in energy homeostasis [3] and has orexigenic properties. Meanwhile, the diurnal pattern of plasma ghrelin levels has been defined in studies of healthy volunteers Miguel Perez-Fontan, Fernando Cordido, Ana Rodrıguez-Carmona, Javier Peteiro, Rafael Garcıa-Naveiro and Jesus Garcıa-Buela. Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal dialysis Nephrol Dial Transplant (2004) 19: 2095–2100 Ghrelin is a post-translationally modified (octanoylated) 28 amino acid peptide that is secreted predominantly, but not exclusively, by the X/A oxyntic cells of the stomach [1,2]. Initially characterized as an endogenous growth hormone (GH) secretagogue [1], there is now strong evidence that ghrelin plays a prominent role in the physiologic regulation of appetite and body weight [3]. By acting as a potent blood-borne orexigenic signal from the gut to the brain [4], ghrelin stimulates spontaneous food intake and induces fat and weight gain by GHindependent mechanisms. Plasma ghrelin (PGhr) levels are strongly influenced by oral intake and peak during fasting but decrease rapidly after meals [3]. Rodriguez Ayala E, Pecoits-Filho R,Heimburger O, Lindholm B,Nordfors L, Stenvinkel P Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study. Nephrol Dial Transplant. 2004 Feb;19(2):421-6. Ghrelin, first described by Kojima et al. [8], is a peptide of 28 amino acids (3315 Da) that stimulates growth hormone release from the pituitary [7]. Ghrelin is secreted into the bloodstream primarily from endocrine cells within the stomach [7]. However, recent evidence suggests that other tissues also synthesize ghrelin, including the kidney [9]. Ghrelin has been reported to regulate feeding and body weight regulation through stimulation of hypothalamic appetite centres [10] and coordination of energy balance [11]. Although its initial discovery was as a novel growth hormone secretagogue, it has been found to regulate feeding behaviour by modulating expression levels of orexigenic peptides in the hypothalamus. Ghrelin has been implicated in the coordination of energy balance and weight regulation, and its dysregulation may be important in obesity. It should be pointed out that ghrelin also has several other physiological actions besides the potential regulation of food intake [11].Recent studies demonstrated that ghrelin antagonizes leptin action and promotes the production of orexigenic neuropeptides, such as neuropeptide Y, resulting in an increase in feeding and body weight [12]. Atul Singhal. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proceedings of the Nutrition Society (2005), 64, 15–22 The primary role of the adipocyte-derived hormone leptin is in the regulation of appetite and body weight. Leptin concentrations rise exponentially with increasing percentage body fat, and obese individuals have markedly increased leptin production, probably as a consequence of resistance to its actions. However, the widespread distribution of functioning leptin receptors on vascular cells and other cell populations and on atherosclerotic lesions suggests that leptin also plays an important role in vascular physiology. In experimental models leptin has been shown to have angiogenic activity, to increase oxidative stress in endothelial cells and to promote vascular calcification and smooth muscle cell proliferation. Adiponectin is unique amongst the adipocytokines in that increasing fatness is associated with a lower concentration. Adiponectin is suggested to have important anti-atherogenic and anti-diabetic properties and is found in lower concentrations in patients with insulin resistance, type 2 diabetes and CHD (Kumada et al. 2003). Recently, hypoadiponectinaemia has been associated with impaired endothelial function in patients with mild hypertension and type 2 diabetes, and in healthy adult controls (Tan et al. 2004). However, there are relatively few data for man, especially for young individuals, that support an independent anti-atherogenic action of adiponectin. In contrast to previous reports, preliminary analyses suggest that hypoadiponectinaemia is associated with indices of insulin resistance but not with vascular function in healthy adolescents (A Singhal, unpublished results). These findings suggest that adiponectin contributes to the maintenance of insulin sensitivity in young, non-obese individuals but does not affect the development of early endothelial dysfunction. Adipokines in non renal disease Anders H. Berg, Philipp E. Scherer.Adipose Tissue, Inflammation, and Cardiovascular Disease. Circ. Res. 2005;96;939-949 Although leptin is not usually thought of as an inflammatory cytokine, hyperleptinemia has been shown to be induced by inflammatory signals such as endotoxin and has important effects on Th1 immune responses and activates blood monocytes in culture. Furthermore, leptin levels are correlated with the CRP and other inflammatory markers in healthy and morbidly obese subjects. Better known is the role of elevated leptin levels in the obese state. Here, leptin is thought to contribute to insulin resistance and considered to be one of the links between obesity, insulin resistance, and atherosclerosis. However, a recent study looking at type 2 diabetics demonstrated that hyperleptinemia is associated with atherosclerosis independent of insulin resistance. Leptin has also been demonstrated to contribute to vasculopathy via obesity-associated hypertension, not through metabolic actions, but instead via its action on central sympathoregulatory pathways. Finally, leptin plays a role in diet-induced neointimal thickening after vascular injury. These activities, in addition to possible contributions to atheromatous inflammation through monocyte and Th1 activation, may explain the epidemiological association between elevated levels and cardiovascular risk. Retrospective case-control studies demonstrate that patients with the highest levels of adiponectin have a dramatically reduced 6-year risk of myocardial infarction compared with case controls with the lowest adiponectin levels, and this relationship persists even when controlling for family history, BMI, alcohol, history of diabetes and hypertension, haemoglobin A1c, CRP, and lipoprotein levels. Animal models also corroborate these observations, showing that adiponectin is particularly important for preventing diet-induced progression of atherosclerosis. The exact mechanism of the antiatherosclerotic activity of adiponectin has not been completely elucidated. The association between adiponectin levels and cardiovascular risk independent of other variables suggests that adiponectin mediates direct effects on vascular health, as opposed to indirect effects through insulin sensitivity and diabetes. A number of studies have shown direct effects of adiponectin on endothelial and vascular smooth muscle cells. It has also been hypothesized that adiponectin has inflammatory-modulating activities, and clinical studies have demonstrated inverse associations between adiponectin levels and serum markers of inflammation. F. Mallamaci, G. Tripepi, C. Zoccali.Leptin in end stage renal disease (ESRD): A link between fat mass, bone and the cardiovascular system J NEPHROL 2005; 18: 464468 In overfed animals, any increase in fat mass is accompanied by a proportional rise in plasma leptin concentration. This physiological relationship serves to modulate energy intake. Indeed high leptin inhibits appetite and food intake in the hypothalamus, a response aimed at restoring fat stores. Peripherally, leptin modulates insulin sensitivity and high leptin engenders insulin resistance. It has long been known that sympathetic system activity undergoes important changes in relationship with nutritional status. In fact it is increased in obesity to facilitate energy dissipation and it is depressed during starvation to reduce energy expenditure. Haynes et al in a well controlled experiment in Sprague Dawley rats provided evidence that leptin administered intra-cerebroventricularly plays a significant role in the modulation of sympathetic activity. Adipokine levels and non renal disease Anderson PD, Mehta NN, Wolfe ML, Hinkle CC, Pruscino L, Comiskey LL, TabitaMartinez J, Sellers KF, Rickels MR, Ahima RS, Reilly MP.Innate immunity modulates adipokines in humans.J Clin Endocrinol Metab. 2007 Jun;92(6):2272-9 The adipokines adiponectin, leptin and resistin regulate insulin resistance, lipoprotein metabolism and vascular inflammation. Rodent and early human studies support insulin sensitizing, anti-inflammatory, and atheroprotective functions for adiponectin in vivo. Indeed, adipose and plasma adiponectin are reduced in human obesity and cardiovascular disease (CVD). In contrast, leptin levels are increased in human obesity, and leptin signalling in inflammatory and vascular cells has been linked to atherothrombosis in the setting of resistance to its central anorectic effects. Resistin, a member of a novel family of inflammatory proteins, derives largely from adipose in rodents, and deficiency in mice protects against dietinduced insulin resistance and type 2 diabetes mellitus (DM2). In humans, however, resistin arises from leukocytes and is induced during inflammation; its role in human insulin resistance and atherosclerosis remains controversial. Table . Proposed mechanisms of insulin-sensitizing action of adiponectin  Stimulation of glucose utilization in skeletal muscles and in liver,  Stimulation of fatty acid oxidation in skeletal muscles and in liver,  Enhancement of insulin signalling in skeletal muscle,  Facilitations of glucose uptake (through increase of GLUT-4 expression in skeletal muscle),  Suppression of gluconeogenesis in the liver. Fitsum Guebre-Egziabher, Jacques Bernhard, Tohru Funahashi, Aoumeur HadjAissa,Denis Fouque. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant (2005) 20: 129–134 Although adipose tissue is the only source of ADPN, the relationship of this protein to fat and body mass is opposite to that of leptin, and ADPN levels are significantly reduced among obese subjects, in comparison with lean, healthy, control subjects. The link between body mass and ADPN seems to be a causal one, because weight loss induces a marked increase in plasma ADPN levels among both normal individuals and type 2 diabetic patients. Like plasma leptin levels, plasma ADPN concentrations seem to be gender-dependent, being higher among women than men. Interestingly, plasma ADPN levels, independently of body mass, are subnormal among diabetic patients and seem to be inversely related to plasma glucose, insulin, and triglyceride levels. In addition to these metabolic relationships, ADPN is emerging as a pleiotropic cytokine linked not only to fat mass but also to other fundamental body functions, such as hematopoiesis and immunity. The directions of the relationships between ADPN and several metabolic risk factors, such as insulin, triglycerides, and HDL cholesterol, are all in agreement with the hypothesis that ADPN may have a protective role for the cardiovascular system among dialysis patients. Although it is slight, the relationship with von Willebrand factor (a biochemical marker of endothelial dysfunction) supports such an hypothesis. Ernesto Rodriguez Ayala, Roberto Pecoits-Filho, Olof Heimburger, Bengt Lindholm,Louise Nordfors,Peter Stenvinkel. Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study. Nephrol Dial Transplant (2004) 19: 421–426 Peripheral infusion of ghrelin stimulates food intake in both rats [12] and humans [13]. In general, loss of body fat mass and wasting due to cancer [14], cardiac cachexia [15] or anorexia nervosa [16] is associated with elevated circulating levels of ghrelin. Surprisingly, circulating ghrelin levels seem to be downregulated in human obesity, and negative correlations between ghrelin and both serum leptin and plasma insulin have been reported [17]. Thus, it is unlikely that overproduction of ghrelin causes the obesity syndrome. Jaswinder K. Sethi and Antonio J. Vidal-Puig JOURNAL OF LIPID RESEARCH – THEMATIC REVIEW SERIES Thematic Review Series on Adipocyte Biology: Adipose Tissue Function and Plasticity Orchestrate Nutritional Adaptation The adipokines adiponectin, leptin and resistin regulate insulin resistance, lipoprotein metabolism and vascular inflammation. Leptin levels are increased in human obesity, and leptin signaling in inflammatory and vascular cells has been linked to atherothrombosis in the setting of resistance to its central anorectic effects (5, 6). Resistin, a member of a novel family of inflammatory proteins (7), derives largely from adipose in rodents, and deficiency in mice protects against diet-induced insulin resistance and type 2 diabetes mellitus (DM2) (8, 9). In humans, however, resistin arises from leukocytes and is induced during inflammation (10); its role in human insulin resistance and atherosclerosis remains controversial. Adiponectin circulates in distinct multimeric isoforms with different signaling properties, providing the physiologic basis for recent work (17, 18) suggesting different forms may contribute differentially to adiponectin‘s multiple functions as an antiatherogenic and antiinflammatory hormone and mediator of insulin sensitivity. Leptin levels correlate with reduced insulin sensitivity, increased inflammatory markers and atherosclerotic CVD (30, 31) independent of body fat mass. In contrast to mice, human resistin is produced by leukocytes via an inflammatory cytokine pathway (10, 37), and our group reported that plasma resistin levels were associated with inflammatory markers, reduced HDLC and coronary atherosclerosis in a large, non-diabetic sample (38). Consistent with our preliminary observations (10), we confirmed a marked induction of whole blood resistin mRNA and plasma resistin during endotoxemia and found that monocytes are one source of increased circulating resistin in inflammation. Given these findings, resistin, like cytokines, may function as an inflammatory endocrine or paracrine signal to antagonize insulin actions and contribute to metabolic and atherogenic changes in human inflammation. Intervention studies in non renal disease Fitsum Guebre-Egziabher, Jacques Bernhard, Tohru Funahashi, Aoumeur HadjAissa,Denis Fouque. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant (2005) 20: 129–134 Like many other metabolic hormones, body composition is a strong determinant of plasma adiponectin in other non-renal diseases patients as well as in renal patients. Plasma adiponectin is mainly inversely correlated with body fat mass, BMI or total body weight. Two recent studies have shown increases in plasma adiponectin after substantial weight loss following either gastroplasty or hypocaloric diet. By contrast, exercise training had no effect on plasma adiponectin, although it significantly improved insulin sensitivity (but it may not have changed body composition enough to alter plasma adiponectin). Another major determinant of plasma adiponectin is serum leptin . How to increase plasma adiponectin concentration? Adiponectinaemia can be now recognized as a new, potentially modified, nontraditional cardiovascular risk factor. The introduction of strategies increasing plasma adiponectin concentration may be a promising new concept for the prevention of cardiovascular diseases in hypertensive or CKD patients and perhaps also in the general population. Weight reduction in obese subjects, by gastric reduction surgery, lifestyle modifications or medical therapy, was accompanied by an increased plasma adiponectin concentration. Similarly, treatment with thiazolidinediones strongly increases plasma adiponectin concentrations. It is of interest that these two interventions, i.e. weight reduction and treatment with thiazolidinediones, particularly increase plasma concentration of insulinsensitizing HMW adiponectin form. Other drugs which increase to a certain extent plasma adiponectin concentration are: angiotensin-converting enzyme inhibitors (temocapril and ramipril), angiotensin II receptor 1 blockers (losartan, candesartan, valsartan and telmisartan), clonidine-like sympatoinhibitory antihypertensive agent (rilmenidine), fenofibrate and cannabinoid-1 receptor blocker (rimonabant). This might provide a scientific rationale for a more frequent use of these drugs, in order also to increase plasma adiponectin concentration in high risk populations. In contrast to the aforementioned drugs, therapy with indapamide (thiazide-like diuretic) does lead to the reduction of plasma adiponectin concentration in patients with essential hypertension. The importance of this observation for clinical outcome remains to be elucidated. The majority of the strategies, described earlier in this article, aimed at increasing plasma adiponectin concentration, were studied only in patients with normal renal function. Only two studies were performed in different groups of CKD patients . Yenicesu et al. showed that in patients with type 2 diabetes mellitus and proteinuria but normal plasma creatinine, concentration treatment with ramipril was accompanied by an increased plasma adiponectin concentration. Furuya et al. observed that plasma adiponectin concentration was higher in peritoneal dialysis patients after candesartan therapy. However, it should be stressed that up to now, there is no single interventional study evaluating the potential effect of increased plasma adiponectin concentration on cardiovascular morbidity and mortality. Therefore, the effectiveness of cardiovascular risk reduction by increasing plasma adiponectin concentration should be a matter for future studies in the general population, hypertensive or CKD patients. International Journal of Obesity (2003) 27 Plasma adiponectin levels do not change with a 6-month moderate weight reduction program even when accompanied by aerobic or resistive exercise training in overweight and obese postmenopausal women. J Clin Endocrinol Metab 91: 2310–2316, 2006 Circulating adiponectin and AdipoR1/ R2 mRNA expression in human skeletal muscle in a cross sectional study of 140 subjects with normal or impaired glucose tolerance or type 2 diabetes were assessed. Plasma adiponectin increased by 13% in the NGT group after 4 wk of physical training and was elevated significantly more in the IGT and T2D groups, with increases of 97 and 86%, respectively. The greater improvements in adiponectin levels among individuals with any form of IGT compared with those with no insulin resistance could not be fully explained by changes in body weight, body fat, or fasting plasma insulin, because the interaction of training and glucose tolerance group weakened, but remained significant after adjusting for each of these factors (P < 0.01 for all). AdipoR1 and -R2 mRNA expression was significantly increased after 4 wk of physical training in all groups. There was a strong positive correlation between changes in adiponectin levels and changes in whole body glucose uptake (r = 0.44; P< 0.001) and a negative correlation between changes in adiponectin levels and changes in FFA levels (r=0.46; P< 0.001). Results: Circulating adiponectin was negatively associated, whereas AdipoR1/R2 mRNA levels were positively associated with obesity, glucose and lipid levels, and insulin resistance. Physical training for 4 wk resulted in increased circulating adiponectin levels and AdipoR1/ R2 mRNA expression in muscle. Exercise for 3 h increased AdipoR1/R2 mRNA expression as well as phosphorylation of AMPK and acetyl coenzyme A carboxylase in muscle, but had no effect on circulating adiponectin. Conclusions: Adiponectin, AdipoR1, and AdipoR2 are all associated with body composition, insulin sensitivity, and metabolic parameters. Physical training increases circulating adiponectin and mRNA expression of its receptors in muscle, which may mediate the improvement of insulin resistance and the metabolic syndrome in response to exercise. A more recent study of 19 overweight males (29) found significant increases in adiponectin with two or three exercise training sessions in more than 1 wk that were sustained after 10 wk of training with no significant weight loss. In summary, the studies presented in this report demonstrate that 1) baseline circulating adiponectin levels are decreased, whereas AdipoR1 and -R2 expression in skeletal muscle is increased, in subjects with IGT or T2D compared with subjects with NGT; 2) circulating adiponectin is strongly negatively associated, whereas AdipoR1 and -R2 expression in muscle is positively associated with markers of obesity, impaired glucose metabolism, and insulin resistance; 3) improvement of insulin resistance in response to chronic (4 wk) physical training is associated with increases not only in circulating adiponectin, but also in AdipoR1 and -R2 expression in muscle; and 4) acute (3 h) intensive exercise has no effect on circulating adiponectin, but increases AdipoR1 and -R2 expression as well as phosphorylation of AMPK and ACC in muscle. O'leary VB, Jorett AE, Marchetti CM, Gonzalez F, Phillips SA, Ciaraldi TP, Kirwan JP. Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E421-7. Part of the improvement in insulin sensitivity following exercise and diet may be due to changes in the adiponectin oligomeric distribution and enhanced membrane receptor expression. Likewise, increased physical activity, weight loss and/or caloric restriction have been shown to successfully reduce insulin resistance (14, 26, 36). However, inconsistent findings have emerged from studies investigating the effects of exercise on circulating adiponectin levels (1, 3, 6, 20, 23, 29). Twelve weeks of supervised exercise did not induce significant changes in total serum adiponectin levels despite decreases in body fat and increases in insulin sensitivity. However, the ratio between the oligomeric forms of circulating adiponectin, expressed as the SA ratio was significantly increased after both interventions. Our data also show that the increase in adiponectin SA ratio following the exercise/diet interventions significantly correlated (p<0.01) with the increase in insulin sensitivity. Our data are consistent with a recent finding that diet-induced weight loss is associated with changes in adiponectin oligomer composition (7). However the present study provides new knowledge on adiponectin biology and shows for the first time that exercise per se can significantly alter adiponectin multimeric distribution, and that this change is related to improvements in insulin sensitivity in older obese adults with abnormal metabolic function. While previous reports have indicated that reduced circulating adiponectin levels are partially reversible by weight reduction in obese and insulin resistant subjects (16, 39), weight loss and exercise training were shown to successfully decrease insulin resistance without affecting total adiponectin levels (18). Likewise, data in the present study showed significant decreases in body weight and improvements in aerobic fitness without total adiponectin being affected. This might be explained by suggestions that at least a 10% threshold reduction in body weight is required before an increase in circulatory adiponectin levels is observed (8, 18). Alternatively, as adiponectin circulates in the blood as multimers, the level of one or more of these isoforms might actually be of greater relevance rather than total adiponectin. The alteration in adiponectin multimer ratio with exercise indicates a potential source of increased defence capability even in individuals with metabolic abnormalities. Addressing the crucial issue of adiponectin isoform distribution may lead to an enhanced understanding of adiponectin’s role for future therapeutic interventions. MATTHEW W. HULVER, DONGHAI ZHENG, CHARLES J. TANNER,JOSEPH A.HOUMARD, WILLIAM E. KRAUS, CRIS A. SLENTZ, MADHUR K. SINHA,WALTER J. PORIES, KENNETH G. MACDONALD, G. LYNIS DOHM Adiponectin is not altered with exercise training despite enhanced insulin action. Am J Physiol Endocrinol Metab 283: E861–E865, 2002 An insulin sensitivity index (SI) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for 45 min at 65– 80% peak O2 consumption) with no loss of body mass or fat mass. Insulin action significantly (P=0.05) improved with exercise training; however, plasma adiponectin concentration did not change. In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin, which was accompanied by enhanced insulin action. These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity. O'leary VB, Jorett AE, Marchetti CM, Gonzalez F, Phillips SA, Ciaraldi TP, Kirwan JP. Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E421-7. Impaired glucose tolerant older (>60 years) obese (BMI, 30-40 kg.m(2)) men (n=7) and women (n=14) were randomly assigned to 12 weeks of supervised aerobic exercise combined with either a hypocaloric (ExHypo, ~500 kcal reduction, N=11) eucaloric diet (ExEu, N=10) Adiponectin multimers (high, middle and low molecular weight, HMW, MMW and LMW, respectively) were measured by non-denaturing Western blot analysis. Comparison of multimer isoforms revealed a decreased percentage in MMW relative to HMW and LMW (p<0.03). The adiponectin SA ratio (HMW/Total) was increased following both interventions (p<0.05) and correlated with the percent change in insulin sensitivity (p<0.03). Post intervention adiponectin receptor mRNA expression was also significantly increased (AdipoR1 p<0.03; AdipoR2 p<0.02). These data suggest that part of the improvement in insulin sensitivity following exercise and diet may be due to changes in the adiponectin oligomeric distribution and enhanced membrane receptor expression. Taylor J. Marcell, Kirsten A. McAuley, Tinna Traustadottir, Peter D. Reaven.Exercise training is not associated with improved levels of C-reactive protein or adiponectin. Metabolism Clinical and Experimental 54 (2005) 533– 541 Study participants included 51 middle-aged (45.3±8.3 years), overweight (33.7± 4.8 BMI), insulin-resistant, nondiabetic individuals. Subjects had their insulin sensitivity, body fat, CRP, and adiponectin levels measured, and their predicted maximal fitness calculated before and after 16 weeks of moderate, intense, or no exercise training… These results are consistent with those reported in a recent 18-month study of moderate exercise with or without simultaneous caloric restriction in a large group (N50 subjects per intervention arm) of older overweight individuals. Whereas subjects in the weight loss–only group demonstrated substantially more weight loss and a small but significant decline in CRP and other inflammatory markers, the combined weight loss and exercise group and the control group showed no change in markers of inflammation [46]. Interestingly, in a much smaller study in postmenopausal women, these same investigators have found that lesser amounts of diet-induced weight loss were not associated with declines in CRP, but in those both exercising and dieting (and achieving slightly greater weight loss), CRP levels declined significantly [47]. These data taken together seem to imply that moderate regular aerobic exercise alone in sedentary persons is not associated with declines in CRP. On the other hand, if sufficient weight loss occurs with or without concurrent exercise, declines in CRP and changes in other inflammatory markers may occur. Our results are also consistent with the findings from other prospective studies that evaluated the effects of exercise training on plasma adiponectin [48,49]. Thus, it appears that neither exercise training nor the modest weight loss that frequently accompanies it effectively raises adiponectin. The fact that CRP was not reduced in our intervention groups, when it is known to be responsive to moderate weight loss, is consistent with reports that exercise itself may have some inflammatory consequences [24,50,51]. Exercise can induce striking elevations in IL-6 and other cytokines [24,52,53], which may stimulate increases in CRP. Several of these cytokines (in particular IL-6) are not only inversely related to levels of adiponectin, but have been implicated in the downregulation of adiponectin expression [54]. Thus, exercise-enhanced release of cytokines can be directly implicated in alteration of both CRP and adiponectin levels. The severity of exercise required to elicit these inflammatory responses is not well established, but it appears that the more intense and prolonged the exercise the greater the cytokine elevations [24,51]. Thus, more frequent and more intense exercise is not likely to translate into greater reductions in all measures of inflammation. The time course of these cytokine responses to exercise is not completely established, but the levels of IL-6 and CRP may take up to 2 days to return to baseline levels after intense exercise [55]. As our blood samples were drawn 24 to 48 hours after the last exercise bout, it is conceivable that exercise-induced inflammatory responses had not yet been resolved. Thus, it may be important to conduct more careful time-course assessments of exercise markers will remain elevated for much of the time. There are several other important implications of this study. Changes in insulin resistance resulting from exercise training did not appear to be associated with changes in CRP or adiponectin, even after adjustment for other variables. These data suggest that this important benefit of exercise does not appear to be related to reductions in inflammation or elevations in mediators of glucose disposal such as adiponectin. Although CRP has been used successfully in many studies to provide additional assessment of CVD risk, this study points out several limitations in using a general marker of systemic inflammation, such as CRP, to assess individual CVD risk. Individuals that exercise regularly may indeed reduce their CVD risk by such activity, yet this decrease in risk may not be reflected by ambient CRP levels. In fact, it is possible that strenuous activity may in fact raise CRP levels in the acute and recovery phase, indicating a level of risk that is not appropriate. In addition, as demonstrated in this study, there appears a very strong association of CRP with obesity, with remarkably high values in those with body fat values above 35%. It remains to be determined whether this elevation is more a function of fat mass rather than true cardiovascular risk. With obesity increasing dramatically in our population, we may need to at least consider modification of our use of CRP, or its threshold risk levels, in inactive, markedly obese individuals. Several potential caveats to the findings of this study deserve mention. Although there were both direct evidence (from changes in VO2 MAX) and indirect support (from changes in anthropomorphic features and laboratory values) that the exercise interventions improved physical fitness, we recognize that the level of exercise intensity conducted by even our intense exercise group may be considered moderate in intensity [56]. We also understand the potential limitations and increased variation of measurement that may occur by extrapolating VO2 MAX from a submaximal test. Although we measured 2 different factors suggested to be important markers and/or regulators of inflammation, there are many other pro- or anti-inflammatory factors that could be measured. However, CRP in particular has proven to be a relatively useful marker of systemic inflammation and predictor of clinically relevant outcomes [2,3] and is the most commonly measured inflammatory marker. Similarly, there is increasing evidence that adiponectin may be a critical regulator of inflammatory events in a variety of tissues, including the vascular wall. It is also important to note, however, that different forms of adiponectin and its receptors have been identified in animals and humans [57], and it is possible that the biological action of adiponectin may be related more closely to levels of these structural variants rather than to total adiponectin levels [58]. We cannot exclude the possibility that with more prolonged exercise training; exercise-related inflammation may become blunted, eventually leading to more favourable changes in inflammatory markers. It is also possible that more intense exercise, as occurred in a small observational study of marathon runners [59] or as part of a comprehensive risk modification program (including changes in diet composition and caloric intake), may contribute to declines in CRP [60]. However, these latter findings as well as a report [61] suggesting that frequent habitual exercise may contribute to reduced levels of CRP in postmenopausal women who were taking estrogens will need to be confirmed in carefully controlled randomized prospective studies. Moreover, as demonstrated in this and our original study, clinically relevant improvements in insulin sensitivity can occur even at these more moderate exercise intensity levels without improvements in markers of inflammation. In summary, although exercise has many well-recognized beneficial effects [21-23, 25, 26], this study indicates that (1) moderate-duration exercise training did not have favourable improvements on plasma levels of CRP and adiponectin, and (2) exerciseinduced changes in insulin resistance could not be explained by changes in plasma levels of these particular inflammation markers. George P. Nassis, Katerina Papantakou, Katerina Skenderi, Maria Triandafillopoulou, Stavros A. Kavouras, Mary Yannakoulia, George P. Chrousos, Labros S. Sidossis. Aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, adiponectin, and inflammatory markers in overweight and obese girls. Metabolism Clinical and Experimental 54 (2005) 1472– 1479 The aim of this study was to examine the effect of aerobic exercise training on insulin sensitivity in overweight and obese girls. Increased physical activity may ameliorate the metabolic abnormalities associated with obesity in children with a mechanism other than the parameters cited earlier. Adiponectin concentration did not change after 12 weeks of training in the present study. However, insulin sensitivity improved in these children. Similar results have been reported in adults [33-35]. In a recent study [35], 3-week aerobic training resulted in 26% improvement in insulin sensitivity without change in adiponectin levels. Based on our results, it seems that adiponectin did not contribute to the exercise-induced improvement in insulin sensitivity observed in our subjects. Robert H Mak, Wai Cheung, Roger D Cone, Daniel L Marks. Mechanisms of Disease: cytokine and adipokine signaling in uremic cachexia. Nat Clin Practice Nephrology 2006;9:527-534 As renal function deteriorates during the course of CKD progression, concentrations of plasma proinflammatory cytokines increase. Decreased renal clearance, increased oxidative stress, reduced tissue perfusion, altered gut permeability, fluid overload, uremic toxins, and factors related to the dialysis procedure all contribute to elevated levels of circulating cytokines in patients with CKD and ESRD. Circulating levels of TNF-α, IL-1β, and IL-6 are increased in patients on dialysis, and correlate with their nutritional status. MICHAEL W. RAJALA AND PHILIPP E. SCHERER. Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis Endocrinology, September 2003, 144(9):3765–3773 Plasma adiponectin has been reported to be increased in end-stage renal disease (ESRD) before dialysis and in patients on maintenance dialysis (haemodialysis and peritoneal dialysis) [9–11], and to be inversely related to incident cardiovascular events. Whether or not this increase reflects impaired adiponectin clearance by the kidney or whether it is a compensatory mechanism aimed at counteracting increased cardiovascular risk factors is not elucidated yet. In a more recent paper, Zoccali et al. [12] report that adiponectin is increased in patients with nephrotic syndrome and that proteinuria is strongly related to circulating adiponectin. 9. Zoccali C, Mallamaci F, Triperi G et al. Adiponectin, metabolic risk factors, and cardiovascular events among patient with end stage renal disease. J Am Soc Nephrol 2002; 13: 134–141 10. Huang JW, Yen CJ, Chiang HW et al. Adiponectin in peritoneal dialysis patients: a comparison with hemodialysis patients and subjects with normal renal function. Am J Kidney Dis 2004; 43: 1047–1055 11. Stenvinkel P, Marchlewska A, Pecoits-Filho R et al. Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int 2004; 65: 274–281 12. Zoccali C, Mallamaci F, Panuccio V et al. Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors. Kidney Int 2003; 63 [Suppl 84]: S98–S102 Fitsum Guebre-Egziabher, Jacques Bernhard, Tohru Funahashi, Aoumeur HadjAissa Denis Fouque. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant (2005) 20: 129–134 The rise in plasma adiponectin during progressive renal failure and before ESRD may be the consequence of the well-described increase of serum leptin that occurs when GFR falls. These results disagree with those obtained in MHD patients by Zoccali et al., who reported an inverse relationship between serum leptin and plasma adiponectin. There is presently no clear understanding why adiponectin is low in patients with increased fat mass when adiponectin is produced by adipose tissue. This may result from a negative feedback. Our hypothesis is that such a feedback is impaired in CKD. Alternatively, since serum leptin in obese adults seems to depend on subcutaneous fat while plasma adiponectin depends more on visceral fat, it is possible that an abnormal fat repartition in patients with CKD may cause the difference we report here. Indeed, a recent report by Stenvinkel et al. in ESRD patients before dialysis (GFR: 6–7 ml/min/1.73m2) found a negative correlation between adiponectin and truncal fat mass, although no correlation was found between adiponectin and arm and leg fat mass. A further possible explanation could be that in the present study we did not include obese patients, whereas some of Zoccali‘s patients had a BMI of 45 kg/m2 [9]. The fact that obesity induces hyperinsulinaemia and alters plasma adiponectin might partly explain these discrepancies. In addition, we excluded diabetic patients in order to avoid confounding factors with possible impacts on adiponectin levels, a limitation not imposed in other studies of CKD. Finally, there is virtually no information on the potential effects of dialysis membranes and biocompatibility on adiponectin metabolism. Thus, dialysis characteristics or differences among patients’ body composition and metabolic status may partly explain these observations. Recent data in CKD patients indicate that plasma adiponectin is associated with several risk factors, such as hypercholesterolaemia or hyperinsulinaemia. Zoccali et al. have reported that plasma adiponectin is an inverse predictor of incident cardiovascular events in MHD patients, despite their adiponectin values being higher than those of controls. It should be noted that cardiovascular risk was still higher in patients with lesser elevations of adiponectin. Thus, in maintenance dialysis, adiponectin seems to remain protective, although this protection may occur in the presence of higher plasma adiponectin levels. We did not find a relationship between plasma adiponectin and CRP here, possibly because of the absence of any true inflammatory process. This observation is in accordance with the report by Zoccali et al. Two recent studies, however, showed an inverse relationship between adiponectin and CRP among peritoneal dialysis and ESRD patients before dialysis. Nevertheless, this point seems important enough to strongly encourage longitudinal prospective studies that examine the relationship between adiponectin and inflammation in CRF patients. In conclusion, we have shown that plasma adiponectin is elevated when renal function is impaired – as early as CKD stage III – and particularly in proteinuric patients. This increase is associated mainly with body composition (e.g. BMI) and plasma leptin, which is known to increase when renal function deteriorates. In our non-obese and nondiabetic patients, no relationship was found between adiponectin and serum insulin or CRP, these latter parameters being in their normal ranges. Thus, the plasma adiponectin rise that occurs when renal function deteriorates may represent an adaptive response to the altered metabolic profile associated with a high cardiovascular risk in CKD patients. No relationship was found between adiponectin and insulin or adiponectin and CRP. F. Mallamaci, G. Tripepi, C. Zoccali. Leptin in end stage renal disease (ESRD): A link between fat mass, bone and the cardiovascular system.J NEPHROL 2005; 18: 464-468 Regulation of the plasma leptin concentration is sex-dependent because leptin is at least twice higher in females than in males and this sex-dependent difference in plasma concentration is also maintained in ESRD patients. The strong relationship between leptin and body fat indicates that leptin is involved in the control of fat mass. Bjoern Becker, Florian Kronenberg, Jan T. Kielstein, Hermann Haller, Christian Morath, Eberhard Ritz, Danilo Fliser; Renal Insulin Resistance Syndrome, Adiponectin and Cardiovascular Events in Patients with Kidney Disease: The Mild and Moderate Kidney Disease Study. J Am Soc Nephrol 16: 1091-1098, 2005 A syndrome of IR is present in the earliest stages of kidney disease even before GFR is decreased. In renal patients, IR is associated with low adiponectin blood levels similar to what is found in patients with the metabolic syndrome. In the latter, the link between IR and related metabolic derangements, and CV morbidity and mortality has been well documented. This relationship also holds true in patients with mild and moderate renal dysfunction. In addition, hypoadiponectinemia is a novel putative CV risk factor in patients with early stages of chronic kidney disease. Fitsum Guebre-Egziabher, Jacques Bernhard, Tohru Funahashi, Aoumeur HadjAissa Denis Fouque. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant (2005) 20: 129–134. Despite an adverse metabolic environment in chronic renal insufficiency, serum adiponectin increases in non-obese patients when renal function deteriorates. Adiponectin is only weakly affected by renal function per se, but appears influenced by proteinuria, and more significantly by body mass index and the change in serum leptin that accompanies decline in renal function. Plasma ADPN levels are markedly increased among patients with ESRD and are related to several risk factors, such as insulin levels, serum triglyceride levels, HDL cholesterol levels, and von Willebrand factor levels, in a way consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system. More importantly, ADPN seems to be a strong and independent (inverse) predictor of cardiovascular outcomes among these patients. For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P=0.05) among patients who experienced new cardiovascular events (13.7±7.3 μg/ml) than among event-free patients (15.8±7.8 μg/ml). There was a 3% risk reduction for each 1 μg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors. The kidney is the principal site of elimination of circulating leptin, which in part explains why levels of this substance are increased among patients with ESRD. Among these patients, the relationships between leptin levels and BMI and fat mass are well maintained but seem steeper and upwardly displaced. Furthermore, leptin levels are directly related to plasma insulin levels, and hyperinsulinemia likely contributes to increases in plasma leptin levels among dialysis patients; this possibility is in line with the observed effect of insulin growth factor-1 . Interestingly, there seems to be a link between erythropoietin and leptin, because erythropoietin treatment induces a significant decline of leptinemia among hemodialysis patients, whereas erythropoietin doses and plasma leptin levels are inversely related among patients with moderate-to-severe renal failure. Independently of diabetes mellitus, ADPN plasma concentrations are markedly increased among dialysis patients and seem to be related to metabolic risk factors such as insulin levels and insulin sensitivity (HOMA-R index), triglyceride levels, and HDL cholesterol levels. Furthermore, our data demonstrate that the gender dependence of plasma ADPN levels is maintained in advanced renal failure. ADPN levels are inversely related to BMI, which is again in line with data for healthy subjects and diabetic patients, but, because of the increased plasma concentrations, this relationship is shifted upward in renal failure. Although ADPN and leptin levels were both increased among dialysis patients, the two hormones were inversely correlated. This phenomenon suggests that, in addition to renal failure, other factors play a role (perhaps an important one) in the regulation of the plasma concentrations of these substances in uraemia. A recent longitudinal study elegantly demonstrated that leptin behaves as a negative acute-phase reactant among dialysis patients. The fact that ADPN levels were unrelated to serum CRP levels suggests that inflammatory processes do not play a major role in the increased plasma levels of this substance. However, the crosssectional nature of our observations does not allow us to draw firm conclusions regarding the relationship between ADPN and inflammation. Hyperinsulinemia, which is a well known metabolic complication of chronic renal failure and a potential cause of hyperleptinemia, might down regulate plasma ADPN levels among dialysis patients, as suggested by the inverse correlation between levels of this cytokine and insulin levels. Our finding that plasma ADPN levels were higher among patients who were receiving erythropoietin treatment, which again mirrors the behaviour of leptin, suggests the possible involvement of this substance in hematopoiesis. Undoubtedly the most stimulating finding of our study is the independent association between ADPN levels and cardiovascular events in a comprehensive analysis including both traditional and non-traditional risk factors. Relatively higher ADPN levels were associated with better cardiovascular outcomes among dialysis patients. However, it must be noted that, on average, ADPN levels were increased, in comparison with healthy subjects, not only among patients who experienced relatively few cardiovascular events but also (albeit to a much lesser extent) among those who developed cardiovascular complications in large proportions (first ADPN tertile). It can be hypothesized that in ESRD the biologic phenomena underlying the cardiovascular protective role of ADPN must be down regulated, perhaps at the receptor level, thus resetting at a higher plasma concentration the relationship between this protein and cardiovascular damage and clinical complications. This hypothesis must be fully tested in in vitro and in vivo experiments, to better elucidate the role of this most interesting cytokine in human diseases. Andrzej Wiecek, Marcin Adamczak and Jerzy Chudek. Adiponectin—an adipokine with unique metabolic properties. Nephrol Dial Transplant (2007) 22: 981–988 An inverse relationship was found between plasma adiponectin concentrations and kidney function assessed by glomerular filtration rate (GFR) in apparently healthy individuals, patients with essential hypertension, renovascular hypertension, mild or moderate non-diabetic CKD, diabetes mellitus type 1 with nephropathy and kidney transplant subjects. In haemodialysis patients, plasma adiponectin concentration is almost three times higher than in healthy subjects. However, it remains unknown which fraction of adiponectin, i.e. globular or full-length protein, HMW, MMW or LMW adiponectin, mainly accumulates in subjects with impaired kidney function. The increased plasma adiponectin concentration in CKD patients cannot be explained by its over-secretion by adipose tissue. The adiponectin gene (ApM1) expression in adipocytes is even decreased in patients with advanced CKD. The kidney is certainly the main organ participating in the biodegradation and elimination of adiponectin from circulation. Thus, as expected, successful kidney transplantation is accompanied by a prompt reduction, but not normalization, of plasma adiponectin concentration. Moreover, measurement of plasma adiponectin concentration in the renal veins and aorta of patients with haemodynamically significant renal artery stenosis (>70%) further supports the kidney’s role in the elimination of adiponectin from circulation. Lower adiponectin gene expression in CKD patients may be partially explained by the micro-inflammation, frequently present in these patients. In the general population, as well as in haemodialysis patients, an inverse relationship was found between plasma concentrations of adiponectin and C-reactive protein (CRP). This clinical observation was confirmed by experimental studies indicating that TNFa and IL-6 inhibit adiponectin gene expression in cultured adipocytes. Expression of receptors for adiponectin in CKD patients has not yet been studied. Therefore, it is not possible to exclude the notion that reduction of adiponectin receptors expression in CKD patients, followed by decreased tissue adiponectin sensitivity, remains similar to other states of low adiponectin gene expression, i.e. obesity and diabetes mellitus type 2. Plasma adiponectin concentration and cardiovascular morbidity in patients with CKD. In the pioneer and seminal study by Zoccali et al., low plasma adiponectin concentration was recognized as a new risk factor for cardiovascular morbidity. They studied 227 haemodialysis patients without heart failure. During the mean follow-up period of 31 months, 95 fatal or non-fatal cardiovascular events occurred. Plasma adiponectin concentration in patients with cardiovascular events was significantly lower than in event-free patients (13.7 vs 15.8 mg/ml). Recently, Maeda et al. found, in a small cohort of haemodialysis patients, a significant negative relationship between plasma adiponectin concentration and left ventricular mass and a significant positive relationship between plasma adiponectin concentration and diastolic function index (E/A mitral valve). It seems that low plasma adiponectin concentration is a new risk factor for left ventricular hypertrophy and diastolic dysfunction in haemodialysis patients. However, in kidney transplant patients, such a relationship between plasma adiponectin concentration and left ventricular mass was not found. The observation of Zoccali et al. was further confirmed by Becker et al., in a group (n=227) of patients with mild or moderate nondiabetic CKD (measured GFR between 38 and 96 ml/min). They found that CKD patients with a history of cardiovascular events are characterized by significantly lower plasma adiponectin concentration, in comparison with those without cardiovascular complications PETER STENVINKEL, ALICIA MARCHLEWSKA, ROBERTO PECOITS-FILHO, OLOF HEIMBU RGER, ZHENGZHONG ZHANG, CATHERINE HOFF, CLIFF HOLMES, JONAS AXELSSON, SIVONNE ARVIDSSON, MARTIN SCHALLING, PETER BARANY, BENGT LINDHOLM, LOUISE NORDFORS. Adiponectin in renal disease: Relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney International, Vol. 65 (2004), pp. 274–281 Markedly (P<0.0001) elevated median plasma adiponectin levels were observed in ESRD patients (22.2 lg/mL), especially type 1 diabetic patients (36.8 lg/mL), compared to control subjects (12.2 lg/mL). Log plasma adiponectin correlated to visceral fat mass (R = −0.29; P < 0.01) and Log hs-CRP (R = −0.26; P < 0.01). In a stepwise (forward followed by backward) multiple regression model only type-1 diabetes (P<0.001) and visceral fat mass (P < 0.05) were independently associated with plasma adiponectin levels. The adiponectin gene –11377 C/C genotype was associated with a lower prevalence of CVD (25 vs. 42%) compared to the G/C genotype. lower visceral fat mass and the presence of IDDM both are independently associated with elevated plasma adiponectin levels in patients with ESRD. The present study also demonstrates that low levels of adiponectin are associated with inflammation in ESRD. ALICIA MARCHLEWSKA, PETER STENVINKEL, BENGT LINDHOLM, ANDERS DANIELSSON, ROBERTO PECOITS-FILHO, FREDRIK LONNQVIST, MARTIN SCHALLING, OLOF HEIMBURGER, LOUISE NORDFORS. Reduced gene expression of adiponectin in fat tissue from patients with end-stage renal disease Kidney International, Vol. 66 (2004), pp. 46–50 The present study demonstrates a significant downregulation of the ApM1 gene in fat tissue from ESRD patients compared with control patients. Because the down-regulation of the gene expression seems to be proportional to elevated plasma levels of adiponectin, we propose that a negative feedback mechanism down regulates the ApM1 gene expression in ESRD patients. DANIEL TETA, ALAN BEVINGTON, JEREMY BROWN,IZABELLA PAWLUCZYK, KEVIN HARRIS, JOHN WALLS. Acidosis Downregulates Leptin Production from Cultured Adipocytes through a Glucose Transport–dependent Post-transcriptional Mechanism.J Am Soc Nephrol 14: 2248–2254, 2003 Several studies have therefore suggested that serum leptin rises because of a reduced renal clearance (11). However, nearly one-third of patients with end-stage renal disease (ESRD) maintain normal plasma leptin, and uremic hyperleptinemia is not fully explained. Typical factors associated with ESRD, such as chronic inflammation, hyperinsulinemia, and endotoxemia, have all been shown to increase leptin gene expression (11–13). In contrast, Nordfors et al. (11) have demonstrated that in patients with advanced chronic renal failure, leptin mRNA levels from adipose tissue appeared to be decreased when compared with healthy subjects. The authors speculated that hyperleptinemia per se directly downregulates leptin gene expression. Whether other factors associated with uremia, conceivably acidosis, contribute to low leptin mRNA levels in these patients is unknown. Robert H Mak, Wai Cheung, Roger D Cone, Daniel L Marks. Mechanisms of Disease: cytokine and adipokine signaling in uremic cachexia. Nat Clin Practice Nephrology 2006;9:527-534 Preliminary observations show that markedly elevated plasma ghrelin concentrations are a feature of advanced CKD and correlate with the BMI, fat mass, plasma levels of insulin, and serum leptin levels. Plasma ghrelin concentrations did not differ between ESRD patients, with or without signs of wasting. Change in the plasma ghrelin level during the course of peritoneal dialysis is associated with change in body composition. Wynne et al. examined the effect of ghrelin on food intake in CKD patients. Nine peritoneal dialysis patients with mild-to-moderate malnutrition were given subcutaneous ghrelin or saline placebo. Administration of sub cutaneous ghrelin significantly increased mean absolute energy intake in these patients, compared with placebo. When expressed as the proportional energy increase for each individual, ghrelin administration resulted in immediate doubling of the energy intake. Hence, these results indicate that subcutaneous ghrelin administration might improve shortterm food intake in dialysis patients with mild-to-moderate malnutrition.. Chia-Chu Chang1,5, Ching-Hui Hung2, Chaun-Shu Yen4, Kai-Lin Hwang6 and Ching-Yuang Lin. The relationship of plasma ghrelin level to energy regulation, feeding and left ventricular function in non-diabetic haemodialysis patients Nephrol Dial Transplant (2005) 20: 2172–2177 We suggest that the role of ghrelin elevation in ESRD patients with anorexia may be only a compensatory pathway rather than a causative factor ghrelin is a hormone that signals the need to conserve energy to prevent cachexia or starvation. The AUC of 24 h ghrelin values in HD patients correlated significantly with ghrelin levels between 4 a.m. and 10 a.m., as reported in healthy volunteers [8]. This implies, as shown by Cummings et al. [7], which single measurements during that interval, can be performed for future studies in ESRD patients, instead of 24 h blood sampling. In conclusion, anorexia, instead of hyperphagia, was found in our patients with higher AUC of plasma ghrelin levels. These observations suggest that there is resistance to ghrelin action in ESRD patients, either peripheral or central, or both. Due to its significant correlation with the composition of body fat, ghrelin could modulate the metabolic substrate and reduce fat utilization to maintain energy balance. There was a significant correlation between the AUC of plasma ghrelin levels and most time-specific ghrelin levels. Schmidt A, Fabrizii V,Maier C, Riedl M,Schmidt A,Kotzmann H,Geyer G,Luger A. Normal regulation of elevated plasma ghrelin concentrations in dialysis patients Wien Klin Wochenschr. 2004 Apr 30;116(7-8):235-9 Plasma ghrelin concentrations are elevated in HD. The fact that ghrelin concentrations are higher in normal-weight than in overweight or obese HD patients and suppressed after ingestion of a meal suggests that the regulation of ghrelin release is retained in HD patients, albeit shifted to a higher level. Methods of adipokines estimation Anderson PD, Mehta NN, Wolfe ML, Hinkle CC, Pruscino L, Comiskey LL, TabitaMartinez J, Sellers KF, Rickels MR, Ahima RS, Reilly MP.Innate immunity modulates adipokines in humans.J Clin Endocrinol Metab. 2007 Jun;92(6):2272-9 Plasma leptin, adiponectin, resistin, insulin (RIA and ELISA from Linco Research, St Charles, MO), tumor necrosis factor alpha (TNF), IL6 (Linco Multiplex ELISAs on Luminex IS100, Austin, TX), soluble tumor necrosis factor receptor superfamily, member 1B (sTNFRSF1B) (ELISA, R+D Systems, Minneapolis, MN), and soluble leptin receptor (sLEPR) (ELISA, Biovender Laboratory Medicine, Brno, Czech Republic) were measured according to the manufacturers‘ guidelines. All samples were assayed in duplicate, and pooled human plasma samples were included to assess variability. The intra- and inter-assay CVs of pooled human plasma were: adiponectin, 5.65%, 9.9%; leptin, 5.5%, 12.4%; resistin, 4.6%, 4.3%; insulin, 4.1%, 11.6%; TNF, 8.66%, 20.4%; IL6, 8.7%, 10.9%; sTNF, 5.3%, 12.1%; and sLEPR, 4.0%, 10.6%, respectively. Anthropometry Anthropometric data were obtained once for each subject, at enrolment into the study. They included measured body weight and body fat mass calculated from the Durnin and Womersley tables [13], and were based on skinfold thickness measurements performed in triplicate at four different sites (biccipital, tricipital, subscapular and suprailiac). Fitsum Guebre-Egziabher, Jacques Bernhard, Tohru Funahashi, Aoumeur HadjAissa,Denis Fouque. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function.Nephrol Dial Transplant (2005) 20: 129–134 CRP levels were measured by using a commercially available kit (Behring Scoppito, l’Aquila, Italy). Serum insulin levels were measured by using a RIA kit (Sorin Saluggia, Vercelli, Italy). Insulin sensitivity was estimated by using the homeostatic model assessment (HOMA-R) index [i.e., plasma glucose level (plasma insulin level/22.5)], which was validated with the euglycemichyperinsulinemic clamp method (11). Plasma leptin measurements were made in a single assay, using a sensitive RIA developed at Linco Research Laboratories (St. Louis, MO). The assay was based on a polyclonal antibody raised in rabbits against highly purified recombinant human leptin. The recovery of leptin with the RIA ranged from 99 to 105% in the range of 0.5 to 100 μg/L. The intra-assay coefficient of variation ranged from 3.4 to 8.3%. Plasma ADPN concentrations were measured by using a sensitive enzyme linked immunosorbent assay Diabetes Care 30:280-285, 2007 Total and High–Molecular Weight Adiponectin in Relation to Metabolic Variables at Baseline and in Response to an Exercise Treatment Program Comparative evaluation of three assays Adiponectin assays. Serum adiponectin levels were measured using radioimmunoassay (LINCO Research, St. Charles, MO) (ADIPOL) with a sensitivity of 1 ng/ml and an intra-assay coefficient of variation (CV) of 6.6% and also using ELISA (Mediagnost, Reutlingen, Germany) (ADIPOM), as previously described. In addition, serum levels of total adiponectin, as well as HMW adiponectin, were determined using a novel ELISA (ALPCO Diagnostics, Salem, NH) (ADIPOA). The sensitivity of this assay was 0.04 ng/ml. The recovery rate was 99–103% for total adiponectin and 97–105% for HMW adiponectin. The effect of serial dilutions has been tested on human serum samples, and linearity and specificity of the assay has been documented. Total and HMW adiponectin values per subject time point were obtained together in the same assay, and the ratio of HMW to total adiponectin per subject time point was calculated by dividing the respective values. All respective samples before and after exercise were measured together in the same assay.