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Review

Adipokines and insulin action

A sensitive issue

, , , &
Pages 88-96 | Received 14 Oct 2013, Accepted 16 Dec 2013, Published online: 08 Jan 2014

Abstract

Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease.

Introduction

The last several decades have seen a worrying increase in the prevalence of obesity worldwide, presenting a public health concern hard to ignore.Citation1 The World Health Organization defines obesity as abnormal or excessive fat accumulation that may impair health. It is often associated with a low-grade state of chronic inflammation, and is causally linked to metabolic disorders such as insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease.Citation2,Citation3 The inextricable link between adiposity, insulin resistance, and the metabolic syndrome has been the subject of extensive investigation, paralleling the rising prevalence of obesity and related metabolic disease in society. Visceral adiposity in particular is a major risk factor for the development of insulin resistance and approximately 80% of T2DM are overweight or obese. The estimated prevalence of diabetes in Australia is 8.1% and it is one of the fastest growing chronic conditions in Australia and globally.Citation4,Citation5 The prevalence of T2DM in China has risen from less than 1% in 1980 to 11.6% and is now comparable to the United States (1980: 2.5%, 2013: 11.3%).Citation6,Citation7 Obesity and related cardiometabolic disorders are posing a monumental strain on the global health system.

Research over the past 20 y has provided new insight into the metabolic and endocrine functions of adipose tissue in the body. While previously white adipose tissue (WAT) was regarded as a passive site for energy storage, identification of WAT secreted factors and their signaling effects on various tissues implicate a role for adipose in whole body glucose and lipid metabolism, insulin action, hemostasis, reproduction, and immunity.Citation8-Citation14 These factors of hormones and cytokines, collectively coined “adipokines” due to their secretory and signaling nature, derive from either adipocytes or the stromal vascular cells within the adipose tissue matrix, including preadipocytes, fibroblasts, and macrophages.Citation10,Citation15 The diverse systemic functions of adipose tissue are likely to be mediated by adipokines.

Several adipokines have been associated with the development of insulin resistance, and thus by extension have importance in the pathophysiology of obesity and its link to T2DM. Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine derived mainly from macrophagesCitation16 and associated with insulin resistance in rodents and humans. Dysregulation of insulin signaling and fatty acid metabolism are key underlying mechanisms of TNF-α-induced insulin resistance.Citation17-Citation20 Resistin is a hormone associated with increased blood glucose concentrations and enhanced glucose output from the liver in mice.Citation21,Citation22 Furthermore, recombinant resistin administration in normal mice impairs insulin sensitivity.Citation23 It also has a role in inducing inflammation and secretion of other cytokines, such as IL-6,Citation24 which itself is an adipokine capable of inducing insulin resistance in vitro and in vivo.Citation25,Citation26 The discovery of resistin was thought to provide a link between adiposity and insulin resistance as resistin is increased in obesity in rodents. However, the role of resistin in humans is controversial as some cross-sectional and intervention studies have failed to show an association of circulating resistin levels with insulin resistance.Citation27,Citation28 While these pro-inflammatory adipokines may be upregulated in obese, insulin-resistant subjects,Citation29 several novel adipokines are dysregulated in obesity and positively associated with insulin sensitization—namely leptin, adiponectin, and adipolin.

Debate continues over the role of leptin (LEP gene) in metabolic disorders; however studies have connected leptin to stimulation of fatty acid oxidation and amelioration of insulin resistance.Citation30,Citation31 Adiponectin (ADIPOQ gene) is the most highly expressed protein in adipose tissue and constitutes up to 0.01% of plasma protein.Citation32 It is significantly downregulated in obesity, and has been shown to directly improve insulin sensitivity in rodent models.Citation32-Citation34 More recently, adipolin (FAM132A/CTRP12 gene) has been associated with improvements in insulin sensitivity and glycaemic control in mouse models of obesity and diabetes.Citation35-Citation37 A summary of the metabolic effects of these adipokines is presented in .

Table 1. The effects and metabolic implications of adipokines with respect to energy metabolism and insulin action

The precise pathways underpinning the mechanisms of these insulin-sensitizing adipokines have yet to be fully elucidated. This review will explore what is known about these factors in their modulation of insulin sensitization and glucose homeostasis. A clearer and broader understanding of the interactions between adipokines and blood glucose regulation has great potential to aid in the development of therapeutic tools for insulin resistance in metabolic disorders such as obesity, metabolic syndrome, and T2DM.

Insulin Resistance

Insulin plays a part in most metabolic processes, but its main role is in glucose homeostasis. Insulin is secreted from pancreatic β cells in response to elevated blood glucose levels and it acts to stimulate uptake of glucose into target tissues (muscle, liver, adipose) and suppress hepatic glucose output into the bloodstream, re-establishing normal blood glucose levels. In the normal physiological state, insulin binds and activates insulin receptors at the cell surface, resulting in tyrosine phosphorylation of insulin receptor substrates (IRS1/2).Citation38 Phosphorylated IRS proteins associate and activate phosphatidylinositol 3-kinase (PI3K) allowing the catalytic subunit of the kinase to convert phosphatidylinositol (4,5)-bisphosphate (PIP2) to PIP3.Citation39,Citation40 PIP3 is a bioactive lipid that potently activates 3-phosphoinositide-dependent protein kinase-1/2 (PDK1/2), localizing this protein with Akt to initiate downstream PI3K-dependent Akt signaling, ultimately facilitating the uptake of glucose into the cell via translocation of glucose transporter 4 (GLUT4) to the plasma membrane.

Insulin resistance is characterized by the impaired capacity of muscle, liver and adipose tissue to respond to insulin, resulting in sustained high blood glucose levels. Defects in insulin signal transduction, and its downstream effects on transport and metabolism of cellular glucose have all been closely associated with the progression of insulin resistance.Citation41,Citation42

The presence of insulin resistance in an individual conveys susceptibility to further conditions such as dyslipidemia, glucose intolerance, and cardiovascular disease and is the primary characteristic of T2DM. Skeletal muscle insulin resistance is an early event contributing to the ultimate failure of insulin-secreting pancreatic β-cells and progression to T2DM.Citation43,Citation44 Studies performed in muscle specific insulin receptor-deficient mice indicate that glucose tolerance may be maintained despite muscle insulin resistance, highlighting the complexity of the inter-organ pathophysiology of diabetes.Citation38,Citation45 It is widely regarded that increasing amounts of abdominal or visceral fat is strongly associated with the onset of insulin resistance. Visceral fat, as compared with subcutaneous fat, has greater lipolytic activity that is less sensitive to suppression by insulin. The anatomical position and proximity of this depot to the liver exposes the portal vein to a greater concentration of perpetually released free fatty acids (FFA). It has long been suggested that elevated circulating FFAs are causal to the development of insulin resistance. This hypothesis might be expanded to include a detrimental effect of dysregulated adipokine release from visceral fat resulting in overproduction of pro-inflammatory cytokines and decreased amounts of anti-inflammatory counterparts.

Despite concerns over a rising incidence of obesity and T2DM in the 21st century, the precise pathophysiological mechanisms underlying causative factors such as insulin resistance continue to be the subject of intense scientific investigation.

Adipokine Dysregulation in Insulin Resistance

Leptin and adiponectin are adipokines dysregulated in obese and insulin resistant subjects.Citation32,Citation46-Citation49 Adipolin is a recently discovered adipokine and little studied in the human context.Citation35 Studies in rodents and humans have demonstrated a role for these adipokines in the amelioration of insulin resistance.

Leptin

The obese (Ob), or leptin (LEP) gene which heralds from the Greek for “thin” (leptos), was first cloned in 1994.Citation50 Friedman and colleagues showed that the product, leptin, a 16-kDa protein, is a hormone secreted by adipocytes that regulates food intake and energy expenditure in addition to effects on reproduction, immune regulation and other endocrine systems.Citation51-Citation53 Mice that lack the ob gene (ob/ob) are massively obese, weighing three times as much as their normal littermates. Injection of leptin into normal and ob/ob mice causes reduced food intake, weight loss, increased physical activity and thermogenesis.Citation50,Citation54 Leptin is thus thought to serve as an “adipostat”, as circulating levels reflect the degree of adiposity and its release from adipocytes signals to the brain to trigger the suppression of food intake and to boost energy expenditure.Citation11,Citation55 These initial studies filled the field with promise of a powerful hormone that could facilitate weight loss, but it became quickly apparent that leptin was not going to be the solution for the majority because circulating leptin levels were already elevated in the overweight and obese population.Citation56,Citation57 Falling leptin levels may act as an excellent signal of diminishing energy stores in starvation, but in the obese state increased circulating leptin offers little protection against adiposity, with the development of leptin resistance facilitating further weight gain.

The precise relationship between leptin and insulin sensitivity remains uncertain; however some headway has been made in the past decade. Insulin and leptin signaling constitute the adipo-insular axis, which contributes to the regulation of nutrient and energy balance in the body. Leptin suppresses insulin secretion in a negative feedback loop where insulin stimulates the release of leptin.Citation58,Citation59 Perhaps dysregulation of the adipo-insular axis may contribute to the progression of insulin resistance. Leptin exerts positive, insulin-like effects on glucose metabolism and is being considered as potential treatment to attenuate hyperglycemia in type 1 diabetes and lipodystrophy syndromes,Citation60 but the role of leptin as an insulin-sensitizing adipokine per se still needs clarification.

Leptin acts centrally as a potent appetite suppressant and results in considerable weight loss in rodent studies.Citation54,Citation61 Weight loss itself is highly likely to alter hormonal-metabolic homeostasis making it important to include a pair-fed control group in in vivo experiments to help dissect the effects of leptin independent of loss of body weight. Several studies have demonstrated that acute administration of leptin in mice improves glucose metabolism and insulin sensitivity under various conditions, including fasting and hyperinsulinemia, regardless of body weight.Citation62,Citation63 Continuous systemic infusion of leptin can reverse insulin resistance in mice with congenital lipodystrophy, characterized by lack of adipose tissue and very low leptin levels.Citation31 Chronic leptin therapy in humans with severe lipodystrophy and insulin resistance also results in restoration of insulin action associated with marked reductions in intracellular lipid in liver and muscle.Citation64 How much of the leptin effect on insulin sensitization is centrally mediated? Insulin sensitivity also improves following adenoviral-mediated rescue of the leptin receptor (LepR) in the hypothalamus of LepR-deficient obese rats.Citation65 This study reported that alteration in hypothalamic PI3K signaling could be the underlying mechanism of the effect of leptin on insulin sensitization, suggesting that the brain is integral to leptin’s insulin-sensitizing effects.

Leptin activation of AMP-activated protein kinase (AMPK), particularly in muscle, is likely to significantly contribute to the mechanisms of insulin sensitization.Citation30 Leptin’s strong central effects on energy balance are also associated with hypothalamic AMPK activation.Citation66 AMPK is a metabolic fuel gauge in the cell that acts to maintain cellular energy stores. AMPK activation is stimulated in the fasting state by high AMP:ATP levels and turns on fatty acid oxidation. The resulting reduction in plasma and non-adipose tissue lipid stores in response to leptin, implicates a role for leptin in the prevention of ectopic lipid accumulation which may also be involved in the mechanism of improved insulin sensitivity.Citation67,Citation68

There is a strong case for the involvement of leptin in ameliorating insulin resistance via its effects on fat oxidation and the adipo-insular axis, however the precise mechanisms and contribution of central vs. peripheral effects that underlie this phenomenon need further investigation.

Adiponectin

Adiponectin is encoded by the ADIPOQ gene, and the high molecular weight (HMW) form is widely regarded as an important insulin-sensitizing hormone, acting via two distinct adiponectin receptors, AdipoR1 and AdipoR2, and associated downstream signaling pathways.Citation69,Citation70 Rodent studies have revealed distinct anti-atherogenic, anti-inflammatory and insulin-sensitizing functions of adiponectin.Citation14,Citation34,Citation71,Citation72 Adiponectin is the most highly expressed adipose-derived hormone in the plasma, however rather than exhibiting higher plasma concentrations, obese individuals (with more adipose tissue) in fact have a considerable curtailing of adiponectin levels.Citation32 This presented a paradox to researchers; it would be expected that a hormone secreted solely by fat would increase with greater fat tissue mass; however, adiponectin is clearly downregulated in the overweight and obese. From this, it was suggested that adiponectin was dysregulated in obese states, potentially linking the hormone to a role in insulin resistance.

Hypoadiponectinaemia is closely correlated with incidence of insulin resistance, T2DM, and dyslipidemia.Citation73,Citation74 However, there are some reports in the literature that fail to show improvements in circulating total or high molecular weight adiponectin levels in response to weight loss despite improvements in insulin sensitivity.Citation75,Citation76 The reasons for this are unclear, but given that circulating adiponectin levels are so high, regulation of adiponectin action may be at the level of receptor expression and function. Adiponectin functions in a feedback loop with pro-inflammatory cytokines such as TNF-α and IL-6, with each regulating the expression of the others. Stimuli such as overnutrition and hyperglycemia may result in the activation of inflammatory signaling, thus altering the delicate regulation of pro- and anti-inflammatory molecules. Increased TNF-α and IL-6 can critically downregulate adiponectin, generating greater susceptibility to the development of insulin resistance.Citation77-Citation79

Adiponectin gene expression, processing, and secretion is upregulated via peroxisome proliferator activating receptor γ (PPARγ) agonists, such as the anti-diabetic drugs, thiazolidinediones (TZDs).Citation80,Citation81 PPARγ-mediated adiponectin upregulation is a likely mechanism contributing to improved insulin sensitivity shown in both rodents and human subjects treated with TZDs.Citation70,Citation82 Like leptin, adiponectin has also been shown to stimulate AMPK activity and fatty acid oxidation.Citation83 Adiponectin upregulates proteins involved in fatty acid oxidation and transport resulting in decreased muscle and hepatic triglycerides and improved insulin sensitivity in obese mice.Citation34,Citation84,Citation85 Loss of adiponectin in vivo in mice is associated with a reduction in fatty acid oxidation and consequently increased levels of plasma and tissue ceramide and diacylglycerol both postulated to inhibit insulin signaling.Citation33,Citation86,Citation87 Rats fed high-fat diets rapidly develop adiponectin resistance, measured as a reduction in adiponectin induced fatty acid oxidation, and show impaired phosphorylation of the crucial insulin signaling proteins Akt and AS160 in muscle resulting in impaired GLUT4 vesicular translocation in skeletal muscle, characteristic of insulin resistance.Citation88

Besides having clear beneficial effects on insulin action in peripheral tissues, most notably in liver, adiponectin also targets the β cells of the pancreas. Adiponectin promotes β-cell function and survival, and can boost glucose-stimulated insulin secretion in diet-induced obese mice.Citation89,Citation90 While acknowledging that the development of adiponectin resistance remains an issue in any therapeutic strategy, current research still points toward the value of targeting adiponectin, the adiponectin receptors and downstream signaling pathways in efforts to ameliorate glucose intolerance and insulin resistance in obese, diabetic subjects.

Interestingly, combination treatment with leptin and adiponectin yields complete reversal of insulin resistance in lipoatrophic mice, compared with only partial improvement with adiponectin or leptin alone.Citation34 This complementary action makes sense, suggesting an integrated interplay between insulin-sensitizing adipokines in the improvement of insulin action.

Adipolin

Adipolin (FAM132A/CTRP12 gene) is a novel, recently characterized adipokine associated with roles in glycaemic control and insulin sensitization.Citation35,Citation36 It is a hormone secreted from adipose tissue, hence the derivation of its name (adipose-derived insulin-sensitizing factor). Similar to adiponectin, circulating adipolin is considerably diminished in obese mice and administration of adipolin results in improved insulin-sensitivity and glucose tolerance, and reduced adiposity and inflammation in obese and diabetic animal models.Citation35,Citation36 Although not extensive, primary literature on adipolin is highly topical in the field of diabetes and obesity research due its potential for therapeutic use. To date, there has been only limited study of adipolin levels in humans. A microarray analysis of adipose tissue from pre-pubertal children indicated a reduction in FAM132A expression associated with obesity, although numbers were limited and insulin resistance was not assessed.Citation35 A second study reveals decreased adipolin expression in adipose tissue and reduced circulating adipolin in women with polycystic ovary syndrome, an insulin resistant and inflammatory condition associated with obesity and T2DM.Citation91

Obesity and its physiological stresses are major risk factors for insulin resistance and subsequently, T2DM. In vitro simulation of endoplasmic reticulum stress and inflammation in 3T3-L1 adipocytes reduce adipolin expression, reminiscent of the effect on adiponectin.Citation36 Diet-induced obese (DIO) mice fed a high-fat diet demonstrate significant improvements in glucose tolerance and insulin action upon adipolin administration.Citation36 In addition, adipolin reduces macrophage accumulation in adipose tissue, and presumably an associated decrease in the presence of pro-inflammatory cytokines implicated in the development of insulin resistance. This suggests an anti-inflammatory role of adipolin, countering the chronic inflammation that often accompanies the obese and insulin resistant state. A similar study by Wei et al. in 2012 observed improvements in glucose tolerance and insulin sensitivity following recombinant/adenovirus-mediated administration of adipolin in wild-type, DIO, and leptin-deficient mice.Citation35 Enhancement of PI3K-dependent insulin signaling by adipolin was also noted through increased phosphorylation of the well-characterized insulin signaling proteins (IRS, Akt, MAPK), in addition to downregulation of hepatic gluconeogenic enzymes such as glucose-6-phosphatase. The same study demonstrated a direct negative correlation between adipolin levels and the pro-inflammatory factor, resistin, which is upregulated in insulin resistant individuals.

Treatment of human primary adipose tissue explants with glucose reduces adipolin expressionCitation91 and functional regulation of the adipolin protein in obesity in mice has also been reported.Citation92 DIO mice exhibit raised levels of the proprotein convertase, furin, associated with an inflammatory setting reminiscent of chronic low-grade inflammation in obesity. Upregulation of furin in adipose tissue of obese mice results in a higher proportion of the cleaved form of adipolin, presumably less effective at enhancing insulin signaling and thus less insulin sensitizing.Citation93 Coincidentally, the pro-inflammatory cytokine TNF-α is processed by TNF-α converting enzyme (TACE), which is dependent upon furin for maturation.Citation94 Increased furin levels under obese conditions could facilitate an increase in TACE-mediated TNF-α production, leading to a chronic inflammatory state and downregulation of insulin-sensitizing adipokines such as adipolin and adiponectin.Citation11,Citation29 This may help explain the surprising downregulation of adipose-derived hormones in obese individuals where increased fat mass would typically be associated with an enhanced level of hormonal output from adipocytes.

While the signaling pathways that mediate adipolin action are becoming clearer, less is known about the control of systemic adipolin levels. However, in a recent study, Bell-Anderson et al. have elucidated a novel regulatory pathway controlling FAM132A gene expression.Citation37 In this, and previous work, they describe how mice deficient in the transcriptional repressor Krüppel-like Factor 3 (KLF3/BKLF) are lean due to reduced adiposity, and also demonstrate that loss of KLF3 leads to a favorable metabolic phenotype on a high fat diet, associated with resistance to obesity, improved insulin sensitivity and glucose tolerance.Citation37,Citation95,Citation96 Importantly, they demonstrate that the FAM132A promoter is bound and regulated in vivo by KLF3 and show that in Klf3−/− mice, adipolin levels are significantly elevated.Citation37 Interestingly, KLF3 recruits the NAD+/NADH-dependent metabolic sensor C-terminal binding protein to regulate gene expression, suggesting a possible mechanism allowing this pathway to respond to metabolic stimuli and energy levels intracellularly.Citation97,Citation98

While the extent to which the KLF3-adipolin pathway underlies the favorable metabolic phenotype of KLF3 null mice remains to be fully resolved, this discovery provides novel therapeutic potential, perhaps via targeting of signaling molecules that regulate KLF3 activity. A recent study of interest in this area has shown that the anti-diabetic drug metformin is capable of elevating adipolin production and secretion from human subcutaneous tissue explants, thought to be via activation of the AMPK signaling pathway.Citation91 That both AMPK and KLF3 activity are strongly regulated by the redox state of the cell and stimulate adipolin expression and secretion may not be coincidental.

Future Directions

Clearly, the known actions of these insulin-sensitizing adipokines suggest that they confer a healthy metabolic phenotype when effectively acting in the body. While originally touted as the master obesity gene, leptin has a complex systemic role in the body. Studies in rodent and humans demonstrate that leptin can function as an effective insulin sensitizer.Citation62,Citation64 Chronic leptin treatment may be clinically relevant in type 1 diabetes and lipodystrophic conditions to help steady glucose homeostasis.Citation60,Citation64 The development of leptin resistance in the overweight and obese limits its use as an effective weight loss and insulin-sensitizing drug in this population.

Adiponectin is a therapeutic candidate for improvement of insulin sensitivity in peripheral tissues and regulation of energy balance in the CNS, although little is known about adiponectin signaling and direct actions in the brain. There are several positive side effects of adiponectin administration, including reported anti-atherogenic and anti-inflammatory actions.Citation71,Citation113 Given the extraordinarily high levels of circulating adiponectin, it is likely that adiponectin effects are mediated by oligomerization of adiponectin and the expression of adiponectin receptors. The potential development of adiponectin resistance also presents a serious challenge to adiponectin–based therapies.Citation88

The widely-used anti-diabetic drugs metformin and TZDs are effective insulin-sensitizing drugs; however they can be associated with a number of side effects including weight gain and heart failure.Citation114 Both classes of drugs also activate AMPK, the downstream target of both leptin and adiponectin. Metformin activates AMPK in the liver and reduces hepatic steatosis.Citation115 Metformin has other AMPK-independent effects that also contribute to the control of glucose metabolism.Citation116 Mediation of AMPK activity, and downstream pathways, are promising sites for intervention as dysregulation of these systems is associated with insulin resistance.Citation66,Citation82,Citation117 AMPK, as a metabolic sensor, is regulated through the redox state of the cell and switched on in response to high AMP and low ATP levels, as typically occurs with exercise and cellular stress such as nutrient depletion. AMPK acts to counter falling ATP levels by switching on catabolic pathways and inhibiting anabolic, ATP consuming pathways. It achieves these effects by phosphorylation of metabolic enzymes and regulation of protein and gene expression.

Very recent studies report that glucose inhibits, and metformin stimulates, adipolin gene expression directly in human adipose tissue explants.Citation91 Future research should address the coordination of adipolin gene regulation with respect to AMPK, metabolic stimuli, and indirect mediation of the transcription factor KLF3. Adipolin is a novel adipokine that might be of use in prevention and treatment of obesity-associated metabolic disorders, due to its effects on adiposity, insulin resistance, glucose tolerance, and chronic inflammation.Citation35-Citation37 However, while these data are encouraging, our current understanding of adipolin remains in its infancy. Future research, directed toward defining and characterizing adipolin’s receptors, signaling pathway, and physiological effects will ultimately determine the extent to which adipolin can influence insulin sensitivity in both healthy and diseased individuals.

Conclusions

The prevalence of obesity in society continues to rise despite the concerted efforts of medical research and health education. Its many associated risk factors, including insulin resistance, T2DM, and cardiovascular disease, present a demanding public health concern. Fundamental understanding of the mechanisms underlying the development of insulin resistance, and the involvement of adipokines, will place us in a better position to address the molecular links between obesity and related metabolic disorders. The roles and actions of adipokines such as leptin, adiponectin, and adipolin are still being fully elucidated; however their capacity for improving insulin sensitivity in obese insulin-resistant settings validates their potential use for therapeutic purposes.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/adip.27552

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