Adipose tissue and adipokines: for better or worse

It is now recognized that the white adipose tIssue (WAT) produces a variety of bioactive peptIdes, collectively termed "adipokines". Alteration of WAT mass in obesity or lipoatrophy, affects the production of most adipose secreted factors. Since both conditions are associated with multiple metabolic disorders and increased risk of cardiovascular diseases, the Idea has emerged that WAT could be instrumental in these complications, by virtue of its secreted factors. Several adipokines are increased in the obese state and have been implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (ASP, TNFalpha, IL-6, resistin). Conversely, leptin and adiponectin both exert an insulin-sensitizing effect, at least in part, by favoring tIssue fatty-acId oxIdation through activation of AMP-activated kinase. In obesity, insulin resistance has been linked to leptin resistance and decreased plasma adiponectin. In lipoatrophic mice, where leptin and adiponectin circulating levels are low, administration of the two adipokines synergistically reverses insulin resistance. Leptin and adiponectin also have distinct properties: leptin, as a long-term integrative signal of energy store and adiponectin, as a potent anti-atherogenic agent. The thiazolIdinedione anti-diabetic drugs increase endogenous adiponectin production in rodents and humans, supporting the Idea that the development of new drugs targeting adipokines might represent a promising therapeutic approach to protect obese patients from insulin resistance and atherosclerosis.     

Short-term beta-adrenergic regulation of leptin, adiponectin and interleukin-6 secretion in vivo in lean and obese subjects

Aim: Adipose tissue and skeletal muscle are endocrine organs, secreting substances that have been implicated in obesity‐related disorders. This study examined short‐term β‐adrenergic regulation of circulating leptin, adiponectin and interleukin‐6 (IL‐6) concentrations and secretion from abdominal subcutaneous adipose tissue and muscle (IL‐6) in vivo in lean and obese subjects. Methods: Systemic concentrations and net fluxes of leptin, adiponectin and IL‐6 across abdominal subcutaneous adipose tissue and forearm skeletal muscle (IL‐6) were assessed before and during β‐adrenergic stimulation (intravenous isoprenaline infusion) in 13 lean and 10 obese men. Results: Basal circulating leptin concentrations were higher in the obese (p < 0.001), while circulating adiponectin (p = 0.45) and IL‐6 concentrations (p = 0.41) were not different between groups. β‐Adrenergic stimulation decreased leptin concentrations in both groups (p < 0.01), but did not reduce net abdominal subcutaneous adipose tissue leptin release. Increased leptin clearance and/or decreased leptin secretion from other fat depots may explain the reduction in leptin concentrations. Adiponectin concentrations remained unchanged during β‐adrenergic stimulation in both groups. β‐Adrenergic stimulation increased IL‐6 concentration, which was more pronounced in the obese (p = 0.01 vs. lean). This cannot be explained by increased IL‐6 release per unit abdominal subcutaneous adipose tissue and muscle but might be because of the increased fat mass and fat‐free mass at whole‐body level. Conclusions: Short‐term β‐adrenergic stimulation decreases leptin concentrations, which cannot be explained by reduced net leptin release from abdominal subcutaneous adipose tissue, while it elevates IL‐6 concentration partly by increased release from this fat depot and muscle. Finally, β‐adrenergic stimulation has no short‐term regulatory role in adiponectin secretion.     

Adipose tissue: a regulator of inflammation

Adipose tissue is a highly active organ. In addition to storing calories as triglycerides, it also secretes a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. Intriguingly, many, if not most, of these adipose-derived proteins have dual actions; cytokines have both immunomodulatory functions and act as systemic or auto-/paracrine regulators of metabolism, while proteins such as leptin and adiponectin are regulators of both metabolism and inflammation. The production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications.     

Atrial natriuretic peptide inhibits the production of adipokines and cytokines linked to inflammation and insulin resistance in human subcutaneous adipose tissue

Aims/hypothesis Increased adipose tissue secretion of adipokines and cytokines has been implicated in the chronic low-grade inflammation state and insulin resistance associated with obesity. We tested here whether the cardiovascular and metabolic hormone atrial natriuretic peptide (ANP) was able to modulate adipose tissue secretion of several adipokines (derived from adipocytes) and cytokines (derived from adipose tissue macrophages). Subjects and methods We used protein array to measure the secretion of adipokines and cytokines after a 24-h culture of human subcutaneous adipose tissue pieces treated or not with a physiological concentration of ANP. The effect of ANP on protein secretion was also directly studied on isolated adipocytes and macrophages. Gene expression was measured by real-time RT-quantitative PCR. Results ANP decreased the secretion of the pro-inflammatory cytokines IL-6 and TNF-α, of several chemokines, and of the adipokines leptin and retinol-binding protein-4 (RBP-4). The secretion of the anti-inflammatory molecules IL-10 and adiponectin remained unaffected. The cytokines were mainly expressed in macrophages that expressed all components of the ANP-dependent signalling pathway. The adipokines, leptin, adiponectin and RBP-4 were specifically expressed in mature adipocytes. ANP directly inhibited the secretion of IL-6 and monocyte chemoattractant protein-1 by macrophages. The inhibitory effects of ANP on leptin and growth-related oncogene-α secretions were not seen under selective hormone-sensitive lipase inhibition. Conclusions/interpretation We suggest that ANP, either by direct action on adipocytes and macrophages or through activation of adipocyte hormone-sensitive lipase, inhibits the secretion of factors involved in inflammation and insulin resistance.     

Adipokines and aging

Dysregulation of adipose tissue-derived bioactive molecules, termed adipokines, is recognized as common ground for insulin resistance and metabolic syndrome associated with obesity. However, adipokine dysregulation is paradoxically associated with lipodystrophy and lipoatrophy with aging. In familial partial lipodystrophic syndromes and Hutchinson-Gilford progeria syndrome, both of which are caused by mutations in the LMNA gene, loss of adipose tissue is associated with adipokine dysregulation, insulin resistance, and atherosclerosis, suggesting a critical role of adipose tissue function in controlling whole body energy metabolism, age-related pathologies, and longevity. Centenarians, a model of healthy aging and longevity, are reported to exhibit preserved insulin sensitivity as well as favorable adipokine profiles, particularly high levels of circulating adiponectin. Furthermore, adipose tissue dysfunction indicated by dysregulation of leptin, tumor necrosis factor-α, and adiponectin is associated with poor prognosis in centenarians. In contrast to results obtained for obesity, adipokine dysregulation in centenarians is associated with very low leptin levels, suggesting that age-related lipoatrophy is the major factor for adipose tissue dysfunction at an advanced age. These observations suggest that adipose tissue excess as well as its aging is implicated in the regulation of adipokines, insulin sensitivity, and lifespan in humans.     

Adipokines and dietary interventions in human obesity

Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low‐grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5–10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules.     

Adipose tissue as an endocrine organ

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFα and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.     

Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction

There is a close anatomical and functional relationship between adipose tissue and blood vessels. The crosstalk between these two organs is vital to both metabolic and vascular homeostasis. On the one hand, adipose tissue is highly vascularized, and maintenance of ample supply of blood flow is essential for both expansion and metabolic functions of adipose tissue. Vascular endothelium also secretes many factors to regulate adipogenesis and adipose tissue remodeling. On the other hand, almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates vascular function by producing a large number of “vasocrine” molecules. Under the normal conditions, PVAT exerts its anti-contractile effects by release of vasorelaxants (such as adipocyte-derived relaxation factors and adiponectin) that promote both endothelium-dependent and –independent relaxations of blood vessels. However, PVAT in obesity becomes highly inflamed and induces vascular dysfunction by augmented secretion of vasoconstriction factors (such as the major components of renin-angiotensinogen-aldosterone system and superoxide) and pro-inflammatory adipokines (such as TNF-α and adipocyte fatty acid binding protein), the latter of which are important contributors to endothelial activation, vascular inflammation and neointimal formation. Furthermore, several adipocyte-derived adipokines impair vascular function indirectly, by acting in the brain to activate sympathetic nerve system (such as leptin) or by exerting their actions in major metabolic organs to induce vascular insulin resistance, which in turn aggravates endothelial dysfunction. Aberrant secretion of adipokines and other vasoactive factors in adipose tissue is a major contributor to the onset and progression of obesity-related metabolic and vascular complications.     

Chronobiology,endocrinology, and energy‐ and food‐reward homeostasis

Energy‐ and food‐reward homeostasis is the essential component for maintaining energy balance and its disruption may lead to metabolic disorders, including obesity and diabetes. Circadian alignment, quality sleep and sleep architecture in relation to energy‐ and food‐reward homeostasis are crucial. A reduced sleep duration, quality sleep and rapid‐eye movement sleep affect substrate oxidation, leptin and ghrelin concentrations, sleeping metabolic rate, appetite, food reward, hypothalamic‐pituitary‐adrenal (HPA)‐axis activity, and gut‐peptide concentrations, enhancing a positive energy balance. Circadian misalignment affects sleep architecture and the glucose‐insulin metabolism, substrate oxidation, homeostasis model assessment of insulin resistance (HOMA‐IR) index, leptin concentrations and HPA‐axis activity. Mood disorders such as depression occur; reduced dopaminergic neuronal signaling shows decreased food reward. A good sleep hygiene, together with circadian alignment of food intake, a regular meal frequency, and attention for protein intake or diets, contributes in curing sleep abnormalities and overweight/obesity features by preventing overeating; normalizing substrate oxidation, stress, insulin and glucose metabolism including HOMA‐IR index, and leptin, GLP‐1 concentrations, lipid metabolism, appetite, energy expenditure and substrate oxidation; and normalizing food reward. Synchrony between circadian and metabolic processes including meal patterns plays an important role in the regulation of energy balance and body‐weight control. Additive effects of circadian alignment including meal patterns, sleep restoration, and protein diets in the treatment of overweight and obesity are suggested.     

Leptin as a link between the immune system and kidney‐related diseases: leading actor or just a coadjuvant?

Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune‐related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue‐derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney‐related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune‐ and metabolic‐related kidney diseases.     

Splanchnic concentrations and postprandial release of visceral adipokines

No detailed data are available on hepatic clearance, postprandial release, and distribution profile of metabolically active adipokines in splanchnic blood compartments such as portal and hepatic veins. This would be a prerequisite for understanding the role of visceral adipose tissue-derived adipokines in metabolism. Adiponectin, resistin, leptin, and visfatin concentrations were measured by enzyme-linked immunosorbent assay in peripheral veins, arterial blood, hepatic veins, and portal veins in 50 patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic shunt implantation, in 6 patients with normal liver function, and in fasted and fed rats. Adiponectin, leptin, resistin, and visfatin did not differ among blood compartments in normal-weight probands in the fasted state. Adiponectin and leptin levels were similar in patients with and without liver cirrhosis. Systemic visfatin levels were decreased and resistin levels were increased in liver cirrhosis. Visfatin secretion was higher from visceral than from peripheral subcutaneous adipose tissue in liver cirrhosis. There was no hepatic clearance of visfatin. Leptin secretion was higher from peripheral than from visceral adipose tissue. Leptin did not undergo hepatic clearance. Resistin and adiponectin did not differ between blood compartments in liver cirrhosis. Resistin concentrations increased upon feeding in rats, and there was an increase in the postprandial clearance of adiponectin by the liver. A postprandial increase of leptin concentrations was restricted to peripheral adipose tissue in rats. The results give insight into the dynamics of splanchnic adipokine concentrations and help critically interpret data derived from messenger RNA expression studies.     

Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management

Elevated plasma triglyceride levels, as often seen in obese subjects, are independently associated with an increased risk of cardiovascular diseases. By secreting adipokines (such as adiponectin and leptin) and other proteins (such as lipoprotein lipase and cholesteryl ester transferase protein), adipose tissue affects triglyceride metabolism. In obesity, adipocyte hypertrophy leads to many changes in adipocyte function and production of anti‐ and pro‐inflammatory cytokines. Furthermore, free fatty acids are released into the circulation contributing to insulin resistance. Adipose tissue dysfunction will eventually lead to abnormalities in lipid metabolism, such as hypertriglyceridemia (due to increased hepatic very‐low‐density lipoprotein production and decreased triglyceride hydrolysis), small dense low‐density lipoprotein particles, remnant lipoproteins and low high‐density lipoprotein cholesterol levels, all associated with a higher risk for the development of cardiovascular diseases. The clinical implications of elevated plasma triglycerides are still a matter of debate. Understanding the pathophysiology of adipose tissue dysfunction in obesity, which is becoming a pandemic condition, is essential for designing appropriate therapeutic interventions. Lifestyle changes are important to improve adipose tissue function in obese patients. Pharmacological interventions to improve adipose tissue function need further evaluation. Although statins are not very potent in reducing plasma triglycerides, they remain the mainstay of therapy for cardiovascular risk reduction in high‐risk patients.     

Melatonin,energy metabolism,and obesity: a review

Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti‐obesogen and the weight‐reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G‐protein‐coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin‐signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin‐resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift‐work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.     

Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.     

Independent circadian and sleep/wake regulation of adipokines and glucose in humans

Leptin and adiponectin play important physiological roles in regulating appetite, food intake, and energy balance and have pathophysiological roles in obesity and anorexia nervosa. To assess the relative contributions of day/night patterns in behaviors (sleep/wake cycle and food intake) and of the endogenous circadian pacemaker on observed day/night patterns of adipokines, in six healthy subjects we measured circulating leptin, soluble leptin receptor, adiponectin, glucose, and insulin levels throughout a constant routine protocol (38 h of wakefulness with constant posture, temperature, and dim light, as well as identical snacks every 2 h) and throughout sleep and fasting periods before and after the constant routine. There were significant endogenous circadian rhythms in leptin, glucose, and insulin, with peaks around the usual time of awakening. Sleep/fasting resulted in additional systematic decreases in leptin, glucose, and insulin, whereas wakefulness/food intake resulted in a systematic increase in leptin. Thus, the day/night pattern in leptin is likely caused by combined effects from the endogenous circadian pacemaker and day/night patterns in behaviors. Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening, which, by influencing food intake and energy balance, could be implicated in the increased prevalence of obesity in the shift work population.     

Alcohol intake modulates hormonal activity of adipose tissue

White adipose tissue (WAT) is now recognized as a highly active metabolic tissue and important endocrine organ producing numerous peptides and proteins with broad biological activity. The term adipokines has been coined to refer to a series of adipocyte-derived biologically active molecules, which may influence the function as well as the structural integrity of other tissues. Adipokines are implicated in control of food intake, energy balance and body weight (leptin), glucose homeostasis (e.g., adiponectin, resistin, adiponutrin), lipid metabolism (e.g., retinol-binding protein, cholesterolester transfer protein), angiogenesis (vascular endothelial growth factor VEGF), fibrinolytic system (plasminogen activator inhibitor-1 PAI-1), pro- and anti-inflammatory effects (e.g., tumor necrosis factor-alpha TNF-alpha, interleukin-6 IL-6) or sexual development and reproduction (leptin). Alterations of WAT mass in obesity or lipoatrophy effect the production of most adipose secreted factors. Besides others, alcohol consumption affects also hormonal system leading to non-physiological increase/decrease of hormone gene expression and plasma hormone concentrations appearing as final poor or stronger effects on target tissues. As mentioned above, white adipose tissue is important endocrine organ, so alcohol intake can alter also adipokines expression in WAT and adipokines plasma levels and in this way it can affect the adipokine-targeted tissues and their functions.     

Leptin and gastro‐intestinal malignancies

Obesity is a well‐established risk factor for the development and mortality from several cancers, including adenocarcinoma of the oesophagus, oesophago‐gastric junction and colorectum. Despite a large body of epidemiological evidence describing this relationship, the mechanisms relating obesity and cancer are only starting to be uncovered. The altered secretion of metabolically active, pro‐inflammatory adipocytokines from adipose tissue is believed to play a key role, and leptin is believed to be a key player in obesity‐related carcinogenesis, as well as being the most extensively studied of the adipokines. In this literature review, we aim to examine the association between leptin and cancers of the gastro‐intestinal tract. For each individual cancer, we examine and present the published data examining the role of leptin in both cell and animal models, the association between circulating leptin levels and cancer risk, and finally the expression of the leptin system in human gastro‐intestinal tract tumours, in relation to tumour biology, stage and patient outcome.     

New adipokines

Adipose tissue is now widely recognized as “an organ” able to synthesize and secrete hundred factors collectively called adipokines. These secreted molecules exert pleiotropic actions, notably on the regulation of glucose and lipid metabolism, inflammation, reproduction, or angiogenesis. Over the past two decades, a considerable amount of work was performed on the two “star” adipokines, leptin and adiponectin, particularly because of their involvement in energy metabolism. The present review is focused on the three most recently discovered adipokines that are clearly emerging as important actors in metabolism: apelin, fibroblast growth factor-21, and neuroregulin-4. Moreover, given a number of clinical and experimental data, these three adipokines represent promising targets in the context of metabolic disorders associated with obesity.     

Intra-abdominal adiposity,inflammation, and cardiovascular risk: New insight into global cardiometabolic risk

Increasing evidence supports the role of adipose tissue in the development of a systemic inflammatory state, which contributes to obesity-associated vasculopathy and cardiovascular risk. In addition to storing calories as triglycerides, adipocytes secrete a large variety of proteins, including cytokines, chemokines, and hormone-like factors (eg, leptin, adiponectin, resistin). This production of pro chemokines by adipose tissue is of particular interest, because their local secretion by perivascular adipose depots may provide a new mechanistic link between obesity and its associated vascular complications. Insulin resistance, in subjects with or without diabetes, is frequently associated with obesity, particularly with an excess of intra-abdominal fat. Recently, the endocannabinoid system, among others, has been shown to be involved in the pathophysiology of visceral obesity and global cardiometabolic risk, as represented by the overall risk of developing type 2 diabetes or cardiovascular diseases.