Adipose tissue: an endocrine organ playing a role in metabolic regulation

Introduction

Excessive weight gain and subsequent obesity are becoming a world-wide problem [1, 2]. Weight increases following excess energy intake are primarily due to increases in adipose tissue deposition. Previously thought to function exclusively as insulation and an energy reservoir, adipose tissue is now characterized to be a complex organ with central nervous system (CNS) innervation and fundamental endocrine and immune roles (For review see [3]). The adipose depot is a multifaceted structure that is comprised of adipocytes as well as pre-adipocytes, endothelial cells, fibroblast and immune cell types that include, but are not limited to, macrophages, dendritic cells, and T cells. All these cells together contribute to the tissues effluent release of metabolites, lipids, cytokines and adipokines. Under standard conditions, adipose tissue plays a role in whole body homeostasis by storing lipids that are used as an energy source during fasting, thus preserving protein, regulating metabolism and food intake (balances energy homeostasis), reproduction, and fueling immune response to pathogen invasion. Excessive adiposity, which occurs with obesity causes balance of the adipose organ to become dysregulated and subsequently produces a negative effect on health. Hence, obesity is causally linked to a cluster of chronic and complex diseases such as cardiovascular disease [4], metabolic syndrome [5] and type 2 diabetes [6]. The complicated association between excessive adiposity, insulin resistance and metabolic diseases has become and remains a subject of prevalent investigation.

The metabolic and endocrine functions of adipose tissue have been extensively investigated over the last two decades. It is well established that adipose tissue secreted factors play a role in whole body glucose homeostasis, but the specifics of how this regulation occur are still being elucidated. Current proposed regulators of this link include both adipose depot derived hormones and cytokines. Adipocyte secreted factors, “adipokines”, are signaling molecules that regulate numerous biological processes by autocrine, paracrine and endocrine mechanisms. Adipokines are essential in the balance between appetite and satiety, regulation of body fat stores and energy expenditure, glucose tolerance, insulin release and sensitivity, cell growth, inflammation, angiogenesis and reproduction. Target organs/systems of adipose tissue include, but are not limited to, the brain, liver, muscle, heart, pancreas, thymus, spleen and lymph nodes. Cytokines released from the adipose depot also influence both local and systemic metabolism, but are slightly different than adipokines. First, cytokines can be secreted directly from adipose tissue, but are also released from other cell populations in the stromal vascular cells of the adipose depot such as preadipocytes, fibroblast and immune cells (macrophages, dendritic cells, and T cells). Second, cytokines are involved in cell signaling but primarily play a role in immune regulation and are generally not growth factors for non-immune cell populations. Overall, in both standard and dysregulated conditions it is valuable to specifically understand in what manner adipocyte released factors can affect within depot cellular events as well as those systemic events regulated through endocrine exchanges.

Diet-induced obesity alters adipose tissue beyond just increases in depot size. This rapid and persisting adipose growth alters cell composition and leads to depot dysregulation and subsequently altered adipocyte biology and function. Inflammation within adipose tissue is proposed to link obesity with the cluster of metabolic associated diseases [7]. A proposed trigger of this inflammation is hypoxia, which occurs in response to adipocytes that do not have access to depot vasculature [8]. Indeed, increases in adipocyte number increase circulating adipokine concentration while hypoxia independently exacerbates this adipokine release from individual adipocytes [9, 10]. Hypoxia is proposed to initiate obesity-induced inflammation and this together with enhanced adipokine release is fundamental in the loss of insulin sensitivity leading to elevated increases in glucose concentration. Taken together, excessive adipose deposition increases adipokine release and causes hypoxia among adipocytes, leading to increases in cytokines and recruitment of immune cells. This process is associated with insulin resistance and glucose intolerance. Here we will highlight the role of adipose depot released factors in glucose homeostasis and dysregulation events that occur with obesity. Figure 1 is a simplified representation of the insulin-signaling pathway. This figure summarizes where the below discussed adipokines are characterized to alter the insulin-signaling pathway.

Figure 1:

Adipokines and the insulin-signaling pathway.

Adipokines that are demonstrated to directly alter the insulin-signaling pathway. This is a simplified depiction of the insulin-signaling pathway that includes specific steps modulated by adipokines. The depiction is limited to what occurs under standard conditions. Certain steps, such as increases in AMPK or enhanced AKT phosphorylation, are increased by numerous adipokines. Arrows next to adipokine name indicates if process is increased or decreased by that particular factor. During obesity insulin resistance occurs because beneficial adipokines are either decreased or become inefficient by way of resistance, degradation or conversion to an inactive form.

Leptin

In a series of experiments, Zhang et al. [11] cloned and subsequently demonstrated an obesity gene, ob, fundamental to adipose tissue autocrine and paracrine signaling. The ob gene, which is highly conserved among all vertebrates including humans, is recognized to play a role in adipose tissue regulation since deficiency of the ob gene produces obesity. This gene was identified as an adiposity indicator because increases in ob gene expression are positively associated with increased adiposity. It was further demonstrated by Halaas et al. [12] that the proposed secretory protein encoded by the ob gene, identified as leptin, regulated adiposity by modulating food intake and energy expenditure. Hence, peritoneal leptin injections reduce body weight in both lean and leptin deficient ob/ob mice [12]. Leptin injections in the central nervous system (CNS), e.g. arcuate nucleus, also dose dependently reduces food intake and body weight, hence the CNS is a fundamental site for leptin regulation [13]. Leptin can therefore be defined as a lipostatic signal that functions in regulating energy balance through control of food intake.

Obesity is a factor well characterized to increase risk for type 2 diabetes and increased leptin levels are a direct indicator of obesity. Hence, numerous epidemiologic studies demonstrate a positive association between leptin and type 2 diabetes in adults. In a 6 year clinical investigation, individuals with high plasma leptin concentration at study initiation had a greater risk for the development of type 2 diabetes over the duration of the study [14]. In support of this a meta-analysis reported higher plasma leptin to be associated with the occurrence of type 2 diabetes in men [15]. Another study, in both men and women, associating β cell function, insulin levels, C-reactive peptide, intact pro-insulin, and Des-31,32 pro-insulin levels to leptin concentration reported a positive relation among leptin concentration with insulin and beta cell function [16]. Specifically, insulin assessment via tertiles (low insulin levels (<72 pmol/L), normal insulin levels (72–108 pmol/L) and hyperinsulinemia (>108 pmol/L)) while adjusting for age and fat mass revealed that higher insulin levels were associated with higher leptin levels. Beta cell function measured by homeostatic model assessment (HOMA) is also positively associated with leptin levels but is dependent upon fat mass. With groups separated according to beta cell function, as more or <100%, there is a positive association with increased leptin in those categorized as hyperinsulinemic even when adjusted for gender and fat mass. This led the authors to postulate that insulin resistance as measured by HOMA was positively correlated with increased leptin levels in both males and females [16]. Similarly, in moderately overweight men [mean body mass index (BMI) of 26.8] with type 2 diabetes, higher fasting leptin concentration is positively correlated with BMI and fasting insulin while negatively correlated with glucose clearance rates [17]. These correlations remained significant when adjusted for fat mass or BMI. With insulin sensitivity tertile separation, the highest fasting leptin levels are in patients with the greatest insulin resistance. This indicates a functional relationship between leptin and insulin resistance in patients with type 2 diabetes, with increased insulin resistance being associated with increased leptin levels [17]. In opposition of data collected from adults, a study in adolescents demonstrates that the development of type 2 diabetes is associated with hypoleptinemia [18]. The authors suggest contradictory findings are likely due to subjects being juveniles, BMI matched control group, and/or varying ethnic backgrounds among leptin studies.

The molecular mechanisms that link leptin to the development of type 2 diabetes are not completely understood and are currently being elucidated. Here we will highlight findings by first discussing exogenous leptin administration in an obese model and then extrapolate what occurs during leptin dysregulation. Under standard conditions leptin enhances insulin sensitivity via alterations in muscle metabolism. In rats, three mechanisms involved in muscle insulin regulation, including phosphorylation of AS160, ceramide and diacylglycerol (DAG) content, and distribution of fatty acid translocase/cluster of differentiation 36 (FAT/CD36) to the subsarcolemma and intramyofibrillar mitochondria, were investigated with regard to leptin-induced alterations [19]. Briefly, leptin administration to diet-induced obese rats reverses impaired glucose uptake, via enhanced insulin signaling. In the muscle of obese rats leptin treatment increases AS160 and AKT phosphorylation and concomitantly decreases concentration of harmful lipid intermediates, DAG and ceramide. Decreases in lipid deposition, however, are not due to alterations in the fatty acid transport proteins (FAT/CD36) but rather an increase in the oxidative capacity of the mitochondria. This increased oxidative capacity is due to an increase in phosphorylation of the alpha2 subunit of 5′AMP-activated protein kinase (AMPK) and inhibition of acetyl-CoA carboxylase (ACC) which allows transport of fatty acids (FAs) into the mitochondria by carnitine palmitoyltransferase 1 (CPT-1) [20]. AMPK is also a known activator of AS160 in the insulin-signaling cascade, thus is also linked to insulin sensitivity [21]. Overall, this study indicates leptin improves glucose uptake and insulin sensitivity in high fat diet (HFD) fed rats by several concurrent mechanisms; increased AS160 and AMPK phosphorylation, decreased of dangerous lipid intermediates in the muscle, and increased mitochondrial oxidative capacity [19]. Leptin also alters insulin regulation through insulin-like growth factor binding protein-2 (IGFBP-2) mechanisms. Leptin regulation of muscle metabolism occurs by central and peripheral nervous system regulation and direct muscle stimulation. This was investigated through a series of experiments in sheep and human myotubes that addressed leptin mediated central nervous system control of metabolism, leptin mediated release of IGFBP-2 via the sympathetic nervous system (SNS), and direct action of leptin on muscle [22]. Intracerebroventricular (icv) administration of leptin lowers plasma glucose levels, hence leptin mediates glucose levels via the central nervous system. Central administration of leptin also dose-dependently increases concentration of IGFBP-2 in muscle, but not circulating plasma, demonstrating SNS stimulation of muscle. This was associated with an increase in phosphorylated AKT, a key protein in phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-induced glucose uptake pathway, and a decrease in the levels of phosphatase and tension homologue (PTEN), inhibitor of PI3K/AKT. Leptin also dose dependently increases IGFBP-2 mRNA and protein directly in muscle. Leptin-induced increases in muscle IGFBP-2 production are dependent upon STAT-3 and PI3K signaling. Taken together, leptin has a direct and indirect effect on increasing IGFBP-2 mRNA expression and protein concentration that subsequently mediates enhanced glucose uptake via increased phosphorylated AKT and decreased levels of PTEN in the insulin-signaling pathway. Leptin exerts insulin sensitizing effects centrally through the SNS, as well as directly through STAT-3 and PI3K/AKT [22]. Overall, these studies suggest that leptin enhances insulin sensitivity in muscle and high circulating levels of leptin may help spare muscle tissue from the negative aspects of harmful lipid deposition while protecting insulin sensitivity.

At the onset of adiposity, increases in leptin directly enhance muscle glucose regulation while decreasing food intake and body weight through CNS alterations, however this signaling cascade can become dysregulated if obesity is not alleviated. As a lipostatic indicator, leptin serves as an afferent signal in a negative feedback loop that functions to maintain suitable fat storage. However, obesity is associated with exceedingly high leptin levels without counteractive feedback, hence resistance to adipose reducing effects of leptin develops [23]. Knight et al. [24] demonstrated that leptin resistance only developed when preceded by hyperleptinemia. This was accomplished by clamping leptin levels in ob/ob mice to that of normal weight mice. In comparison to obese wild-type controls the clamped ob/ob mice remained sensitive to exogenous leptin even after extended exposure to a HFD and obesity [24]. Hence, in chronic obesity, the ability of leptin to exert insulin-sensitizing effects may be decreased due to the development of leptin resistance.

Contradictory to the positive insulin sensitizing effects in muscle, leptin is involved in inflammatory processes that are associated with obesity and the development of type 2 diabetes. Leptin has been linked to inflammation but the mechanisms are not completely clear. This is of interest as inflammation is associated with and demonstrated to induce insulin resistance [25–27]. Leptin is involved in cell-mediated immunity. First indications of immune regulation by leptin was observed in ob/ob mice which had decreased levels of immune cell types needed for pathogen clearance, hence leptin deficiency impaired immune response [28]. Indeed, leptin not only regulates the proliferation of naïve T-cells but also influences cell polarization towards Th1 (pro-inflammatory) while suppressing Th2 (anti-inflammatory) cytokine response [29]. Leptin also stimulates pro-inflammatory cytokine release from B cells. Specifically, in this cell group leptin activates janus activator kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen activated protein kinase (p38MAPK), and extracellular signal-regulated kinase (ERK1/2), resulting in release of pro-inflammatory cytokines IL-6 and TNF-alpha. This was confirmed by showing that blocking any one of the previously mentioned pathways inhibited the release of IL-6 and TNFα [30]. Together, these studies demonstrate functional interactions between leptin, immunity and pro-inflammation, and thus provide mechanisms by which high leptin levels could exacerbate chronic inflammation and disturb insulin regulation.

Leptin is best characterized as being pro-inflammatory in nature, but emerging studies suggest anti-inflammatory roles as well. Leptin treatment in ob/ob mice increases production of cAMP in macrophages located within the adipose depot, this subsequently inhibits NF-κβ mediated expression of pro-inflammatory cytokines by activation of class IIa histone deacetlyases (HDAC) while increasing expression and production of IL-10, an anti-inflammatory cytokine [31]. The previous changes, however, are inversely associated with leptin resistance. This pathway also interacts with insulin signaling. Specifically, diet-induced obese mice with macrophage specific HDAC4 knock-out have higher plasma glucose, free fatty acids, insulin and macrophage infiltration in white adipose tissue compared with wild-type obese [31]. Consistent with this, administration of rolipram, an insulin sensitizing drug, improved glucose tolerance and insulin sensitivity in wild type but not HDAC4 macrophage knockout mice on HFD [31]. In total, these experiments demonstrated that induction of the cAMP-HDAC4 pathway in macrophages may promote insulin sensitivity in obesity by inhibiting the translocation of NF-κβ and subsequent production of pro-inflammatory cytokines. In humans single nucleotide polymorphisms (SNPs) in the HDAC4 gene are positively associated with high BMI and/or waist circumference, thus the previous discussed pathway may be conversed across species [31].

Overall, leptin is a hormone that modulates glucose homeostasis through both central and peripheral mechanisms. Centrally leptin plays a role in integrating metabolic signals that balance energy intake and expenditure. Peripherally this adipokine regulates lipid and glucose homeostasis in numerous tissues. Although leptin is demonstrated to have a positive effect on the previous factors deleteriously high levels cause desensitization and resistance which leads to overall dysregulation of the leptin axis and worsening of obesity-related co-morbidities including diabetes.

Adiponectin

Adiponectin, encoded by the gene AdipoQ, is the highest circulating adipokine with plasma concentrations ranging from 3–10 μg/mL [32, 33], this is ~40-fold higher than levels of circulating leptin [34]. Blood levels are commonly higher in women than men and have an inverse relationship with weight status for both genders, hence unlike most adipokines, higher BMI is associated with lower adiponectin concentration [32]. Adiponectin is associated with many metabolic processes, including lipid trafficking and glucose homeostasis [35–37], as such it is proposed to play a role in the pathogenesis of insulin resistance and diabetes.

Adiponectin exerts its effects through two receptors, AdipoR1 and AdipoR2, which have similar form and function but differential expression among various tissues. Both receptors consist of seven transmembrane domains similar to that of G-protein coupled receptors with the exception of orientation within the membrane which is opposite in terminus direction. Both adiponectin receptors associate only with isoforms of the adiponectin protein [38]. AdipoR1 is found primarily on the outer membrane of skeletal muscle myocytes whereas AdipoR2 resides mostly on the outer membrane of hepatocytes within the liver [39]. Intracellular signaling cascades that occur after ligand binding involve increased AMPK and peroxisome proliferator-activated receptor α (PPARα) activity [39], with subsequent increases in mitochondrial biogenesis and fatty acid oxidation. Adiponectin receptor stimulation also increases the activity of the enzyme ceramidase that cleaves and lowers cellular ceramide molecules and simultaneously increases the concentration of sphingosine 1-phosphate [40]. High ceramide levels are detrimental to the cell and have been implicated in apoptosis and cell growth arrest [41].

The hormone adiponectin is unique in that it is positively correlates with lean body types and is linked to insulin sensitivity and high density lipoprotein (HDL-C) levels [35, 37]. Accordingly, adiponectin and its receptors are decreased in individuals who are either obese or non-obese but pre-diabetic [42]. Through its AMPK stimulatory activities, adiponectin has similar effects of exercise with respect to increased glucose uptake and suppression of hepatic glucose output. While adiponectin does not affect the rate of glucose uptake, it down-regulates endogenous glucose production through reduced expression of key gluconeogenic enzymes [43]. Overall, this hormone is considered an insulin-sensitizing agent by means of increasing phosphorylation events in the insulin-signaling cascade and inhibition of muscle and liver triglyceride deposition by enhancement of β-oxidation and fatty acid combustion pathways [44, 45].

Studies demonstrate an inverse relation between circulating adiponectin concentration and fasting glucose concentrations. Insulin-sensitizing effects of adiponectin are predominantly a product of altered liver metabolism. In wild-type, ob/ob, and non-obese diabetic (NOD) mice, a single physiologic injection of purified adiponectin decreases circulating fasting glucose levels by approximately 30% and is associated with decreases in hepatic glucose output [46]. The greatest suppression of circulating glucose was 4 h post-injection and was associated with enhanced insulin sensitivity [46]. Another study demonstrates a 65% decrease in hepatic glucose production following adiponectin infusion and suggests it is due to a reduction in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression, key enzymes in the gluconeogenic pathway [43]. Furthermore, adiponectin-induced glucose alterations are primarily mediated in the liver because alterations to peripheral glucose uptake are minimal, hence endogenous glucose production is reduced without affecting glucose utilization in peripheral tissues. Consistent with rodent studies, there is a negative correlation between plasma adiponectin levels and endogenous glucose production in humans [47].

Adiponectin is also proposed to alter glucose metabolism and insulin sensitivity via phosphorylation and activation of AMPK in both liver and skeletal muscle. Overall, this pathway begins with adiponectin receptor binding and initiation of a series of phosphorylation steps that results in increased glucose uptake by myocytes or decreased glucose production by hepatocytes [48]. Furthermore, this pathway increases phosphorylation of ACC, which subsequently increases fatty acid oxidation [48]. In support of this, the lack of adiponectin in HFD fed mice causes rapid development of glucose intolerance and inhibits response to PPARγ agonist, a robust stimulator of AMPK activity [49]. This suggests that adiponectin is required for improving insulin sensitivity through the AMPK pathway.

Others demonstrate via adiponectin knockout models that this hormone is associated with the insulin-signaling pathway, with its removal impairing phosphorylation of insulin receptor substrate 1 (IRS-1) and AKT [50]. These impairments decreased insulin response resulting in diminished glucose uptake and hepatic insulin resistance [50]. In humans, fasting plasma adiponectin is positively correlated with insulin receptor tyrosine phosphorylation, a key step in the insulin-signaling cascade and vital for maintaining insulin sensitivity [51]. These data indicate a separate but related connection of adiponectin to phosphorylation events in the insulin-signaling cascade.

Visceral adiposity, a highly associated risk factor for metabolic disease, is linked with low adiponectin levels [52]. Chronic low grade inflammation, driven by enhanced visceral adiposity, is exacerbated by decreasing adiponectin. It is unclear, however, which is casual or consequence, hence it is yet to be determined if pro-inflammatory factors suppress adiponectin release or if decreased adiponectin permits increased release of inflammatory cytokines. Regardless, low adiponectin concentration is associated with increased circulation levels of inflammatory markers such as TNFα, C-reactive protein, IL-6, and reactive oxygen species [53].

Overall, adiponectin is an adipocyte secretory molecule that defends against obesity-related diseases such as type 2 diabetes. Its inverse relationship with insulin resistance, visceral adiposity, and inflammatory markers support its role as a protective adipokine. Adiponectin concentrations remain a significant indicator of glucose tolerance and metabolic homeostasis.

Resistin

Named for resistance to insulin, resistin is an adipocyte produced and released hormone that was discovered in a mouse model [54]. Resistin was originally discovered as a gene that is upregulated during adipocyte differentiation, but later was identified to be secreted [55]. Circulating resistin increases with increasing adiposity in both genetic and diet-induced obese mouse models [55, 56], though some suggest resistin mRNA is reduced in obesity [57, 58]. Differences among studies were later confirmed to be assay methods [56], hence it is now well established that resistin alters insulin sensitivity. Mouse models demonstrate resistin is associated with insulin resistance. First, exogenous injections of resistin in lean mice reduce insulin sensitivity and induce glucose intolerance [55]. Second, ob/ob obese mice that are resistin deficient have improved fasting glucose levels compared with ob/ob mice with resistin [59]. Humans also produce and secrete resistin from adipose tissue depots, but production is not from adipocytes. Adipocyte resistin mRNA expression has no correlation with obesity in humans for it is undetectable in adipocytes in obese individuals [60]. In humans RETN is responsible for the production of resistin [55] which is produced and secreted from monocytes and macrophages [61] rather than adipocytes. This implies that resistin in humans plays a role in immune/inflammatory responses that is reminiscent of those prompted by TNFα [60]. Despite the species differences, humanized-resistin mice are more susceptible to insulin resistance [62]. Overall, elevated resistin is associated with glucose intolerance, reduced insulin sensitivity, hyperglycemia, and increased levels of circulating free fatty acids in rodents [55, 56, 59, 62]; whereas in humans it is associated with atherosclerosis and cardiometabolic disease [63, 64].

Receptors with the affinity for resistin have been identified in mice. These thus far include an isoform of decorin on adipose progenitor cells [65] and tyrosine kinase-like orphan receptor (ROR) 1 on adipocytes [66]. Resistin through these receptors is proposed to regulate adipogenesis, white adipose tissue expansion, and glucose homeostasis. Though resistin-specific receptors have not been confirmed in humans, it is suggested that resistin may bind to toll-like receptor 4 (TLR4) [67]. Consistent with its release from immune cells within adipose tissue in humans, resistin further plays a role in pro-inflammation through TLR4-mediated events. In support of this, recent studies demonstrate human resistin to be a cytokine that induces low-grade inflammation via monocytes [68]. In particular, adenylyl cyclase-asssociated protein 1 (CAP1) is the resistin receptor responsible for mediating the inflammatory action of monocytes [68]. CAP1 is detected on the cellular membrane of promonocytic THP-1 cells (human monocytic cell line) but primarily resides in the cytosol until induced by resistin to translocation to the membrane, the mechanisms of these events, however, are currently unknown [68]. Binding of resistin to CAP1 upregulates cAMP concentration, protein kinase activity and NF-κβ related transcription of inflammatory cytokines [68]. Specifically, in humans resistin binds directly to the proline-rich Src homology 3 (SH3) domain on CAP1. This leads to adenylyl cyclase activation, which converts ATP into cAMP, which then promotes activity of cAMP-dependent protein kinase A (PKA) and results in NF-κβ activity in monocytes. Likewise, the activation of NF-κβ upregulates mRNA expression and protein levels of pro-inflammatory cytokines such as IL-6, TNFα, and IL1β. The previous effects are amplified when CAP1 is overexpressed, but lessened when PKA is inhibited because of subsequent decreases in NF-κβ activity [68]. Knockout of CAP1 blocks resistin-induced increases in intracellular cAMP concentrations and subsequent inflammatory reactions [68]. Because human resistin is secreted from monocytes and its receptor translocates to the cellular membrane of monocytes, it is proposed to be an autocrine and paracrine signal that is enhanced during obesity [68]. Overall, in humans resistin via CAP1 induces inflammation, which if unresolved, can result in exacerbating chronic low-grade inflammation associated with metabolic disease and type 2 diabetes.

Apelin

Apelin has two predominate isoforms and is the primary endogenous ligand of the APJ G-protein coupled receptor that is expressed in a variety of tissues, most notably the lung, heart, adipose tissue, kidney, spleen and brain [69]. Functions of apelin are dependent on the site of receptor binding, some examples include stimulation of angiogenesis and hypotensive vessel outcomes [70], cardiac contractions in the heart [71], fluid homeostasis [72], and inhibiting glucose-stimulated insulin secretion by the pancreas [73]. As a ubiquitous peptide, apelin is secreted by neurons, cardiomyocytes, and endothelial cells, however it is considered an adipokine because it is produced and secreted by adipocytes [74].

Apelin is proposed to be anti-obesigenic and anti-diabetic. The peptide is highly expressed in the central nervous system (CNS), specifically the hypothalamus and regulates food intake and drinking behavior [75]. In support of this, icv injection of apelin-13 in rats causes a decrease in food intake in both fed and fasted conditions [76, 77]. Icv injection of apelin-13 is also demonstrated to increase water intake, hence apelin also plays a role in fluid homeostasis [78]. In addition to food and fluid balance, apelin is proposed to reverse insulin resistance and development of diabetes by diminishing insulin response to increases in blood glucose concentrations. Specifically, apelin inhibits insulin production from INS-1 cells (insulin secreting cell line) by activating a PI3K-dependent protein, which suppresses cAMP levels, an amplifier of glucose-induced insulin secretion [79]. As apelin has been found in pancreatic juices secreted from rats, it also appears to be involved in exocrine processes as well as endocrine [80]. Last, apelin increases glucose uptake in isolated myocytes by activation of AMPK, which phosphorylates AKT and facilitates glucose transport [81].

Overall the positive effects of apelin on food and fluid regulation, control of insulin secretion, and glucose utilization, make the peptide a viable target for obesity and pre-diabetic therapies. However, apelin concentrations are elevated in individuals who are obese, have type 2 diabetes with and without obesity, and/or hyperinsulinemic [82], whereas those who are lean, dieting or received bariatric surgery have diminished levels [82]. This indicates that high circulating levels of apelin are not protective and, at best, high levels of apelin at the onset of obesity may initially protect against the development of insulin resistance. However after prolonged obesity the hormone signaling becomes deficient or ineffective. This may occur by multiple mechanisms such as enzymatic degradation of apelin to an inactive form Pyr1 apelin [83], which has a lower binding affinity to the respective receptor [84] or apelin resistance via decreased AJP receptors [85]. Despite these two circumstances, exogenous apelin in obesity is still demonstrated to be an effective treatment [81]. Mechanisms that regulate endogenous dysregulation of the apelin-signaling pathway remain to be elucidated.

Visfatin

Previously known as both nicotinamide phosphoribosyltransferase (Nampt) [86] and pre-B-cell colony-enhancing factor (PBEF) [87], visfatin is an adipokine with several physiological roles involved in the regulation of immune cells, insulin mimicking regulation and cellular energetics via NAD-dependent enzymes and nicotinamide adenine dinucleotide (NAD) biosynthesis [88–90]. First recognized in large amounts mainly in bone marrow, liver, muscle and brown adipose tissue [87], visfatin was further described to be released from white adipose tissue [91]. Although originally characterized to be produced and release from adipose tissue depots, visfatin is produced and secreted by immune cells (leukocytes, in particular macrophages, monocytes and neutrophils) located among the adipocytes [92]. Visfatin is further characterized to be more abundant in the visceral adipose depot than the subcutaneous depot [91], likely because of the higher prevalence of macrophages within the visceral depot [92].

Visfatin is involved in immune cell signaling. In vitro, visfatin promotes expansion of B-cell colonies in bone marrow when in the presence of both IL-7 and stem cell factor (SCF) [87]. Visfatin actions are also cytokine-like with promotion of pro-inflammatory molecule transcription and translation from monocytes, which include TNFα, interleukin-1β (IL-1β), and IL-6 [90, 93]. Via a MAPK inhibitor method, visfatin is determined to promote innate immune response through the MEK1 pathway, further activating NF-κβ [94].

In adipocytes, visfatin treatment upregulates expression of PPAR-γ, CCAAT-enhancer binding protein-α (C/EBP-α), fatty acid synthase (FAS), DGAT-1, adipose P2 (aP2) and adiponectin, hence increases adipocyte differentiation and maturation markers [93]. Therefore a paracrine function of visfatin is adipocyte growth and expansion, but this adipokine also plays an endocrine role. Visfatin is proposed to activate the insulin receptor inducing insulin-like effects. Indeed, compared with wild type, transgenic mice with lower circulating visfatin have increases in fasting and postprandial glucose concentrations without altered insulin sensitivity [93]. Insulin-like functions of visfatin include increases in preadipocyte triglyceride accumulation and adipocyte glucose uptake, suppression of hepatocyte glucose uptake, increases in triglyceride accumulation in preadipocytes and triglyceride synthesis from glucose [93].

Despite these effects on insulin action, Jacques et al. determined in chondrocytes that visfatin does not directly interact with either the insulin receptor or insulin growth-like factor 1 receptor (IGF-1R) [95]. The authors speculate that visfatin may interact with the growth hormone receptor and/or induce elevated insulin growth-like factor 1 (IGF-1) [95]. Subsequently it is proposed that activation of IGF-1R induces the AKT or Erk1/2 pathway via MAPK signaling [95]. Another study, however, determined that IGF-1 signaling in chondroytes was inhibited by administration of visfatin [96]. The authors here conclude that visfatin signals the activation of ERK pathway via an unknown receptor which then inhibits the activation of AKT by IGF-1 [96]. These specific mechanisms of visfatin are yet to be determined on other insulin sensitive tissues that greatly contribute to homeostasis of glucose concentration.

Two meta analyses support an association between visfatin and metabolic diseases specifically demonstrating increased visfatin concentration is positively related to obesity, adiposity, cardiovascular disease, insulin resistance and type 2 diabetes [97, 98]. In clinical studies, some demonstrate visfatin concentration increases are positively associated with obesity [99] and diabetes [100], whereas others demonstrate only a positive correlation with circulating inflammatory markers such as C reactive protein [101]. Therefore, general opinion indicates that visfatin increases with increasing adiposity and markers of inflammation. Overall despite the insulin mimicking effect of visfatin, it is postulated that during obesity the functions on immunity as an inflammatory cytokine dominates and subsequently exacerbates inflammation.

Omentin

Omentin is an adipocyte hormone identified to be primarily released from visceral adipose tissue; hence it is nearly undetectable in subcutaneous adipose tissue. The amino acid sequence was original identified as a protein called intelectin that plays a protective role against bacterial translocation in the gut and is proposed to be a defense mechanism for intestinal inflammation [102]. Within the abdomen omentin, released from stromal vascular cells of the omental adipose depot and not adipocytes, stimulates glucose uptake via enhancement of insulin signaling [103].

Omentin plays a protective role in glucose homeostasis and insulin signaling by modulating systemic metabolism in an autocrine and paracrine fashion. In human embryonic kidney (HEK-293T) cells, omentin treatment does not affect basal glucose uptake, but does increase insulin-stimulated glucose uptake by 50% [103]. Similar to adiponectin and apelin, omentin is proposed to enhance glucose utilization via phosphorylation of AMPK and AKT proteins [104]. Nonetheless, plasma omentin levels and mRNA are significantly higher in lean, but not overweight and obese, subjects and plasma levels are negatively correlated with BMI [105]. Omentin concentrations are increased following decreases in BMI and associated with improved insulin sensitivity [106]. Omentin levels are higher in women than men and low in morbid obesity, hence low circulating omentin is strongly associated with metabolic syndrome [105, 107].

Omentin is inversely correlated with inflammatory factors like IL-6 and TNFα, and has been shown to suppress the inflammatory response in cultured endothelial cells [108]. Inflammatory suppression is accomplished through the AMPK/eNOS signaling pathway by blocking Jun amino-terminal kinase (JNK) activation [109]. These favorable inflammatory factors may play a role in hampering systemic insulin resistance.

Omentin is yet another beneficial adipokine identified to enhance the effects of insulin on glucose metabolism in the body. As such, the release of omentin from visceral adipose depot, but not subcutaneous, is advantageous because of the depots proximal location with direct effluent to the insulin-sensitive liver. Omentin is predictive of metabolic consequences and co-morbidities of obesity because lower circulating amounts are predictive of insulin resistance and decreased glucose utilization.

Vaspin

Visceral adipose tissue-derived serpin, shortened to vaspin, is an adipokine characterized to play a role in insulin regulation and glucose homeostasis [110]. First recognized as a member of the serpin protease inhibitor family, vapsin is a gene associated with visceral adiposity and type 2 diabetes as determined by representational difference analysis between Otsuka Long-Evans Tokushima fatty (OLETF) type-2 diabetes rat and Long-Evans Tokushima Otsuka (LETO), the diabetes-resistant counterpart [111]. Transcribed by the gene Serpina12, vaspin in humans is not detectable in lean subjects (BMI<25), but is detected in obese individuals as well as those with type 2 diabetes [110]. This adipokine in humans is regulated in a depot specific manner with higher detection in the visceral depot compared with the subcutaneous [110]. Vaspin mRNA expression and serum concentrations are increased in both human and rodent obesity [110, 112–114], although in humans it tends to be higher in women [115]. It is proposed that vaspin may be a beneficial adipokine that protects or attenuates co-morbidities associated with metabolic disease as a compensatory factor against insulin-resistance.

The role of vaspin as an insulin-sensitizing adipokine was demonstrated in two rodent models; a genetic obesity model (OLETF rats) and a high-fat and high-sucrose (HFHS) obese model (CRL:CD-1 mice) (ICR) [116]. In the OLETF rats, treatment with insulin or pioglitazone, an insulin-like molecule, upregulates adipocyte vaspin mRNA and circulating protein concentrations, suggesting vaspin increases may be a feedback response to alleviate insulin resistance [116]. In support of this, vaspin treatment reversed HFHS-induced hyperglycemia, while also decreasing circulating leptin, resistin and TNFα concentration, but did not change hyperinsulinemia [116].

Vaspin is also demonstrated to regulate insulin sensitivity through adipose depot growth. Specifically, vaspin in 3T3-L1 cultured cells is proposed to promote the differentiation of preadipocytes [117]. This occurs by an increase in differentiation factors including PPARY, C/EBP, and free fatty acid-binding protein 4 (FABP4) [117]. The downstream effects are smaller differentiated adipocytes expressing decreased IL-6 mRNA and increased glucoe transporter type 4 (GLUT4) mRNA, contributing to reduced inflammation and increased insulin sensitivity, respectively. From these results, the authors suggest that vaspin induces phosphorylation of AKT and AMPK, improving glucose regulation while reducing inflammation. Overall, vaspin is a beneficial adipokine that currently is characterized to ameliorate metabolic dysregulation in type 2 diabetes and metabolic disease via enhancement of insulin sensitivity.

Retinol binding protein

A family of proteins, known as retinol binding proteins (RBP), function to bind and carry retinol (vitamin A) through cells, plasma, or interstitial fluid to its target, where it acts to modulate gene expression. The gene RBP4 encodes for a specific isoform secreted by adipocytes that functions as a plasma indicator for decreases in blood glucose levels [118]. A study performed in children show a relation between RBP4, obesity, and insulin resistance, suggesting that RBP4 is related to adiposity and weight status [119]. Furthermore, high plasma RBP4 is associated with impaired glucose tolerance and type 2 diabetes in adults and in general is higher in women and seniors [120]. Protein levels of this adipokine are elevated in abdominal adipose tissue, the omentum, of obese subjects with and without type 2 diabetes [121]. Thus, visceral adiposity is a better predictor of both RBP4 levels and insulin resistance than general measures of obesity like BMI [122, 123].

GLUT4, the primary transporter for glucose uptake in myocytes and adipocytes, is decreased in insulin resistant states and is inversely correlated with RBP4 levels [124]. Serum RBP4 levels are 2.5-fold higher in mice with lower adipose-GLUT4 compared with control mice, suggesting a possible contributing role of RBP4 in systemic insulin resistance [124]. Consistent with this, RBP4 interferes with insulin signaling in human adipocytes by inhibiting serine phosphylation of IRS-1, which attenuates availability of the GLUT4 transporter [125]. In addition, RBP4 increases expression of the gluconeogenic enzyme PEPCK which leads to higher levels of blood glucose [124]. In obese humans, GLUT4 is also decreased in visceral adipose tissue [121].

Although the link between RBP4 and insulin resistance has been demonstrated in vivo, it is not clear if dietary intake of vitamin A has an effect on plasma RBP4 levels in humans. Vitamin A deficiency in a rodent model increases adiposity [126] and vitamin A supplementation prompts weight loss and increases in insulin sensitivity [127]. Thus, the relation between RBP4 and vitamin A with insulin resistance are incongruent. Overall, the exact mechanism linking RBP4 with insulin resistance is still unknown.

WISP-1

Research continues to identify a number of novel adipokines that play a potential role in the pathogenesis of type 2 diabetes. Recently characterized is adipokine Wnt 1 inducible signaling pathway protein 1 (WISP-1). WISP-1 is an extracellular matrix associated protein of the connective tissue growth factor, cysteine rich protein and nephroblastoma overexpressed gene (CCN) family and is involved in the WNT signaling pathway [128]. The WNT signaling pathway is classically associated with mechanisms involving cell proliferation, cell fate determination and cell polarity during both embryonic development and tissue homeostasis [129].

Human adipocytes, but not monocytes or monocyte-derived macrophages, express WISP-1, which plays a role in adipose depot expansion via adipocyte differentiation [128]. WISP-1, dose dependently increases mRNA expression of IL-6, TNF-α, IL-1β and IL-10 in macrophages but not in adipocytes [128]. This is paralleled by increases in the expression of M1 (pro-inflammatory) macrophage markers (CCR7 and COX2) and a reduction of M2 (anti-inflammatory) macrophage markers (CD36 and CD136). These increases in WISP-1 mRNA in adipose tissue samples from humans are also positively associated with high fasting insulin levels and macrophage infiltration and negatively with insulin sensitivity [128]. Although much remains to be elucidated this study generally demonstrates WISP-1, released from fully differentiated adipocytes stimulates pro-inflammatory cytokines release from macrophages and plays an unidentified role in increasing insulin concentration.

Adipolin

Enomoto et al. [130] identified the adipokine CTRP12, C1q/TNF-related Protein-12, also known as adipolin, in a mouse model of obesity, where adipolin mRNA and circulating protein were decreased. Systemic administration of adipolin in diet-induced obese mice reduces adipose tissue macrophage (ATM) infiltration and pro-inflammatory gene expression in the adipose depot [130]. These alterations are associated with an attenuation of obesity-induced insulin resistance and glucose intolerance. In addition, macrophage pro-inflammatory cytokine production stimulated by lipopolysaccharide (LPS) or TNF-α is decreases when immune cells are pretreated with conditioned media from kidney cells (COS-7) transfected with adenovirus vectors for adipolin [130]. Together these data suggest that adipolin functions as an anti-inflammatory adipokine and exerts beneficial effects on glucose tolerance and insulin sensitivity [130]. In support of this others demonstrate adipolin recombinant protein administration lowers blood glucose levels in wild type lean and ob/ob and diet-induced obese mice [131]. In hepatocyte and adipocyte cultures adipolin treatment directly (independent of insulin) activates the PI3K/AKT signaling pathway improving insulin sensitivity by promoting glucose uptake and reducing gluconeogenesis in the liver [131].

Bell-Anderson et al. [132] further demonstrated adipolin as a potential target for the treatment of type 2 diabetes. The beneficial actions of adipolin are also demonstrated in Kruppel-like factor 3 (KLF3) null mice. These mice are characterized as resistant to diet-induced obesity with lower adiposity in the abdominal and subcutaneous adipose depots [132]. When compared to wild type controls KLF3-null mice were more insulin sensitive. Epididymal white adipose tissue, red skeletal muscle and liver microarray analysis identified that fam132a, the gene that codes for adipolin, was significantly upregulated in KLF3-null mice [132]. This was further confirmed with RT-PCR in multiple tissues from the KLF3-null mice including heart, lung, bone marrow and epididymal white adipose tissue. Consistent with this plasma adipolin concentration is increased in the KLF3-null mice. Overall, KLF3 binds directly to the promoter for fam132a and represses promoter activity and production of adipolin. Others demonstrate that adipolin expression in adipocytes is also regulated by Kruppel-like factor 15 (KLF15). Unlike KLF3, KLF15 is positively associated with adipolin [133]. As such, diet-induced obese mice have decreased expression of KLF15 and adipolin. Targeted ablation of KLF15 reduces expression of adipolin, hence adipolon expression is dependent upon KLF15 [133]. In 3T3L1 adipocytes obesity-associated inflammatory factors such as TNFα reduce mRNA expression of KLF15 and adipolin [133]. This, however, does not occur if cells are KLF15 adenovirus transfected or if JNK signaling is inhibited blocking subsequent TNFα production. Taken together obesity-induced inflammation increases JNK signaling which decreases expression of KLF15 and subsequently decreases promoter activity of adipolin, in the adipocyte [133]. Combined, the two previous studies identified both the inhibitor (KLF3) and the promoter (KLF15) for the adipolin gene (fam132a).

Overall adipolin influences glucose homeostasis by two paths; as an insulin sensitizing adipokine that can act directly on insulin signaling or by inflammatory mechanisms that may enhance the insulin-signaling cascade.

Subfatin

Subfatin, also known as Metrnl, was discovered in a gene array analysis seeking identification of novel adipokines stimulated by caloric restriction in diet-induced obese rats, hence the exploration of a metabolically beneficial adipokine [134]. Subfatin mRNA and protein is highly expressed in white adipose tissue and annotated as “Meteorin-like” [134]. Subfatin was first recognized for its similar transcription to Meteorin, a glial cell differentiation regulator expressed exclusively in the brain [135], however expression of subfatin has not been detected in the brain [134]. Additionally, its expression is higher in white adipose than brown adipose tissue of both mice and humans[134], and is higher in subcutaneous adipose tissue than abdominal [136]. Subfatin expression increases during the differentiation of preadipocytes and in obese mice fed a high-fat diet [134, 137].

Another study in mice reported increases of subfatin in muscle after exercise and in adipose tissue upon cold exposure to increase whole-body energy expenditure [137]. Rao et al. [137] determined that the presence of subfatin stimulates the infiltration of immune cytokines, specifically IL4 and IL 13, into adipose tissue where they trigger pro-thermogenic actions. These immune cytokines, following recruitment by subfatin, also shift the monocyte population towards M2 macrophages, thus inducing a repair and wound healing response [137]. Subfatin is also characterized to regulate insulin sensitivity. Specifically, diet-induced obese mice, but not chow, deficient in subfatin are insulin resistant [136]. When overexpressed, however, subfatin enhanced insulin sensitivity in diet-induced obese mice, but again not chow fed [136]. Hence, subfatin restores insulin sensitivity in obese mice, but does not further enhance insulin regulation in lean mice. Overexpression of subfatin also restores insulin sensitivity in genetic models of obesity such as leptin knockouts [136].

Subfatin enhances insulin sensitivity by increases in AKT phosphorylation [136], hence this factor is enhanced in subfatin overexpressing mice. In addition, this adipokine likely regulates insulin sensitivity via regulation of inflammation. As such, subfatin deficiency is also linked to an increase in TNFα expression, hence overexpression of subfatin decreases this inflammatory factor [136]. Lastly, subfatin promotes adipocyte growth with upregulation of PPARγ and subsequent increases adipocyte lipid accumulation and maturation [136].

Cytokines

Obesity is now defined as a state of chronic low-grade inflammation. This inflammation theory is gaining support as a fundamental link between obesity and the development of type 2 diabetes. As such, type 2 diabetes in lean or obese children is positively associated with an increase in plasma pro-inflammatory cytokines, specifically TNFα and MCP-1 [25]. This relation is consistent in adults where insulin sensitivity is inversely associated with adipose tissue TNFα protein and plasma IL-6 concentration [26]. Another study demonstrates that elevated plasma IL-6 and TNFα concentrations are indicative of the development of type 2 diabetes over a 2 year period [27]. After adjusting for confounding factors, BMI, age and sex, IL-6 remained a predictive factor [27]. Overall, this supports a relation between inflammation and the subsequent development of type 2 diabetes.

Mechanistic evidence, thus far, supports the inflammation-diabetes link. In vitro adipocyte studies demonstrate that TNFα greatly suppresses the transcription and mRNA stability of C/EBPα and subsequently transcribed GLUT4 [138]. As a result, cellular protein content of C/EBPα and GLUT4 are also decreased. In addition, continuous exposure of adipocytes to TNFα decreases insulin receptor mRNA by ~50% [138]. Overall loss of TNFα in a mouse model, both genetic and diet induced, is associated with lower levels of fasting glucose and insulin and increased insulin sensitivity as well as lower levels of circulating free fatty acids [139]. Lack of TNFα function via targeted mutation of the gene or its receptors increases insulin mediated autophosphorylation of the insulin receptor [140]. In total these data in mice demonstrate that lack of TNFα in an obese state serves to protect from insulin resistance [139, 140]. Immune cells that infiltrate adipose tissue also play a role in glucose homeostasis. Adipose tissue from obese humans contains CD4 T cells that produce 3–7.5 times more IL-17 and IL-22 than non-obese subjects [141]. These cytokines, IL-17 and IL-22, inhibit glucose uptake in skeletal muscle isolated from rats, as measured by 2-deoxyglucose uptake, and induced insulin resistance in cultured human hepatocytes as measured by total phosphorylated AKT protein [141].

Clinical investigations demonstrate that calorie restriction, increased physical activity and subsequent weight loss are effective at reducing inflammation that likely contributes to insulin resistance and type 2 diabetes. In particular, weight loss reduces expression of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in adipose tissue, which reduces caspase-1 activation and subsequent secretion of the pro-inflammatory factors IL-1β and of IL-18 [142]. The relation between this inflammasome and insulin resistance was further explored in the mouse. Specifically, ablation of NLRP3 in mice increases insulin sensitivity in liver and adipose tissue and is associated with decreases in IL-18 and interferon gamma (INFγ) expression [142]. In addition, naïve CD4 T-cells are increased while CD4-effector T cells were decreased, suggesting a decrease in pro-inflammatory signaling. In NLRP3 knock out mice there is an increase in PI3K/AKT activity, hence improved insulin signaling, and a reduction of serine phosphorylation of the IRS-1 substrate that is commonly associated with insulin resistance [142]. Excess lipids in obesity are proposed to activate this NLRP3 inflammasome in macrophages via the production and build-up of harmful lipid intermediates, such as ceramides, leading to a proinflammatory cell that releases IL-1β [142]. This progression potentiates insulin resistance, however is inhibited in NLRP3 knock out mice with attenuation of macrophage IL-1β activation and secretion.

Overall these studies suggest that adipose tissue is the nexus of immunity and metabolism. Adipose tissue disorders encountered in obesity cause alterations in cytokine release and composition of adipose-resident immune cell populations. The resulting changes appear to induce profound consequences for basal systemic inflammation. As such insulin resistance and type 2 diabetes are regulated by inflammation, hence are driven by the metabolic consequences of excess adiposity. Figure 2 illustrates associations between inflammation and insulin regulation with the contributions of adipokines known to play a role in immunity.

Figure 2:

Adipokines, inflammation and insulin sensitivity.

Inflammation is described to be the fundamental link between obesity and the development of type 2 diabetes. Insulin sensitivity is influenced by the balance between pro- and anti-inflammatory cytokines. Certain adipokines alter insulin sensitivity indirectly by interactions with adipose depot immune cells such as monocytes and macrophages. Leptin, resistin, WISP-1 and visfatin induce pro-inflammatory immune cell types, whereas adiponectin prompts immune cells to secrete anti-inflammatory cytokines. Omentin and adipolin are demonstrated to inhibit production of harmful cytokines from pro-inflammatory cells.

Concluding remarks

The understanding of the pathogenesis of obesity and associated co-morbidities has advanced rapidly over the past two decades. New adipokines are continuously being identified and categorized relative to their ability to promote or reduce obesity associated disease risk. Adipokines discussed in this review change glucose regulation by way of directly altering the insulin-signaling pathway (Figure 1) or indirectly by altering immune response and subsequent inflammation which then alters components of the insulin-signaling pathway (Figure 2). Overall, most adipokines are demonstrated to play a beneficial role towards the enhancement of insulin sensitivity and glucose uptake and utilization. Others, however, are primarily detrimental and drive inflammation and insulin resistance. Leptin, is considerably characterized and demonstrated to have multiple functions including the enhancement of insulin sensitivity, and exacerbation of inflammation and insulin resistance (Figure 3). These functions, however are specific to cell types involved and environmental cues.

Figure 3:

Adipokine classification and relation to insulin regulation.

General postulated role of adipokines in regard to insulin regulation as traditionally classified by inflammation, insulin regulation and insulin mimicking effects.

Glucose homeostasis is dependent upon the appropriate balance of circulating adipokines. One can postulate these differential adipokines create a coordinated response to fluctuating energy storage. As such decreases in adiposity would augment this response to increase food intake and energy storage, whereas increases in adiposity would decrease food intake while increasing oxidation of lipid stores. Leptin, adiponectin, apelin, omentin, vaspin, adipolin subfatin and visfatin are all characterized to improve insulin sensitivity in rodent models, however epidemiological studies suggests obesity is associated with insulin resistance. Perhaps these insulin sensitizing factors are only effective during acute periods of rapid adipose tissue growth in an effort to maintain glucose homeostasis despite the intake of excessive calories. The beneficial effects, however, are lost with chronic obesity because helpful adipokines either decrease, e.g. adiponectin and omentin, or increase, e.g. leptin and apelin, but become less efficient via resistance, lower binding affinity or increased degradation.