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Fetuin-A: a novel link between obesity and related complications

Subjects

Abstract

Fetuin-A (FetA) is a 64-kDa glycoprotein that is secreted from both the liver and adipose tissue. Circulating FetA is elevated in obesity and related disorders including type 2 diabetes mellitus, nonalcoholic fatty liver disease and the metabolic syndrome; and a FetA-related parameter, caliciprotein particle, is highly relevant to vascular calcification in overweight/obese patients with chronic kidney disease. FetA level is also associated with impaired insulin sensitivity and glucose tolerance. Accumulating evidence suggests that elevated FetA level causes impaired glycemic control, as FetA has been implicated in impairment of insulin receptor signaling, toll-like receptor 4 activation, macrophage migration and polarization, adipocyte dysfunction, hepatocyte triacylglycerol accumulation and liver inflammation and fibrosis. Weight loss, aerobic exercise, metformin and pioglitazone have each been shown to be effective for reducing FetA level.

Introduction

Fetuin-A (FetA) is a 64-kDa glycoprotein that is found in relatively high concentrations in human serum (300–1000 μg ml−1).1, 2, 3 Fetuin was first discovered in 1944 in bovine calves, and it derived its name from ‘fetus’ to reflect the observation that fetal serum contained the highest concentration of this protein.4 Fetuin was renamed ‘fetuin-A’ in 2000 upon the discovery of a fetuin-like molecule termed ‘fetuin-B’.5 Human FetA is also known as α2-Heremans-Schmid glycoprotein (AHSG);6 this naming honors the (independent) discoverers of the human homolog of FetA, Heremans7 along with Bürgi and Schmid.8

In human adults, FetA is mainly expressed and secreted from the liver and adipose tissue. Epidemiologic research consistently observes elevated circulating FetA in obesity9 and related complications, such as type 2 diabetes mellitus (T2DM),1 the metabolic syndrome10 and nonalcoholic fatty liver disease (NAFLD).11 Moreover, FetA level is associated with many parameters related to metabolic health, such as insulin sensitivity,3 glucose tolerance,11 circulating lipid levels10 and circulating levels of both pro- and anti-inflammatory proteins.12 FetA also has an important role in calcification inhibition,13 particularly in patients with chronic kidney disease (CKD).14

Recent research is the uncovering mechanisms that underlie the relationship between FetA and obesity-related complications. Much of this research can be categorized as explaining either (1) how glucolipotoxicity induces FetA expression or (2) how FetA promotes metabolic dysfunction.

Intervention trials demonstrate that diet,15 aerobic exercise,16 gastric bypass surgery,9 metformin17 and pioglitazone18 can each be employed to reduce circulating FetA. Reductions in FetA level are often associated with improvements in insulin-related parameters and/or circulating adiponectin.15, 16

This is the first comprehensive review to exclusively focus on the relationship between FetA and obesity. To expound on this relationship, epidemiologic, mechanistic (cell, animal and human models) and interventional research are each summarized. Although all relevant research is discussed, special emphasis is given to studies that have been published as the most recent reviews of FetA and obesity.19, 20

Search strategy

A PubMed search was conducted through October 2014 of publications in English. The following input was used for the search: (FetA or AHSG) and (obesity or diabetes or metabolic syndrome or NAFLD or cardiovascular disease (CVD) or kidney disease or nephropathy or glucose or palmitate or insulin receptor or inflammation or toll-like receptor 4 or adipocyte or diet or exercise or metformin). This search yielded 599 potentially relevant articles. Additional articles were identified using the references listed in these manuscripts. Intervention studies were considered for review only if they: (1) included a subject population that was overweight/obese (body mass index (BMI) 25.0 kg m2) and/or presented with T2DM and/or presented with NAFLD; and (2) examined an intervention that typically reduces body weight and/or improves insulin sensitivity. Articles were selected for inclusion in this review if they provided evidence for an association between FetA level and obesity or related metabolic conditions. A total of 87 articles were finally selected.

Epidemiologic data

Obesity

Associations between FetA level and obesity-related parameters are widely reported in the epidemiologic literature. BMI,21 visceral adipose tissue (VAT)1 and leptin concentration22 are each positively associated with FetA concentration. Furthermore, change in FetA level is associated with the change in visceral adipose tissue over a 5-year period.23 Circulating FetA is elevated in insulin-resistant obesity compared with insulin-sensitive obesity.24

The relationship between FetA and obesity appears to be mediated at least in part by genetics. A variant of the AHSG gene that is associated with lower FetA level is more common among normal weight men compared with overweight and obese men.25 In addition, bi-directional Mendelian randomization shows evidence of a casual association from circulating FetA to BMI, along with no evidence of reverse causality from BMI to FetA.26

Type 2 diabetes mellitus

Incident diabetes risk increases in individuals with higher FetA concentrations even after adjustment for potential mediators, including: body weight, BMI, waist circumference, blood pressure, blood lipid levels, race, fasting glucose level, HbA1C level, C-reactive protein level, adipocytokine levels and liver enzyme levels.1, 2, 27 A recent investigation found that a positive association between FetA concentration and incident diabetes risk existed only in female participants.21 However, previous research found that this association applied similarly to both genders.1, 2, 28 Gestational diabetes patients have elevated FetA level compared with healthy pregnant women and non-pregnant controls.29 Moreover, FetA concentration is positively associated with both fasting C-peptide concentration and C-peptide/blood glucose ratio in both gestational diabetes patients and healthy pregnant women.29 Isolated impaired glucose tolerance, but not isolated impaired fasting glucose, is associated with higher FetA concentration when compared with normal glucose tolerance.11 The reason for this is currently unclear but may be related to the greater degree of peripheral insulin resistance that is typically observed in isolated impaired glucose tolerance.30 In individuals with impaired glucose tolerance, but not normal glucose tolerance, FetA concentration is negatively associated with insulin secretion during an oral glucose tolerance test (OGTT).31

AHSG gene single-nucleotide polymorphisms have been associated with prevalent type 2 diabetes.32, 33 Yet, a recent Mendelian randomization study observed that genetically predicted FetA level was not associated with prevalent diabetes, incident diabetes or fasting glucose.34 This suggests that FetA level may not be causally related to diabetes risk. However, this study did not measure non-esterified fatty acid (NEFA) level, which has been recently shown to interact with FetA level to predict the degree of insulin resistance.35 Future Mendelian randomization studies and interventional studies should measure NEFA concentration along with FetA concentration to better determine whether the latter is causally related to diabetes risk.

The relationship between circulating FetA and CVD risk appears to be modified by the diabetes status. Non-diabetics with higher FetA level have decreased risks of incident CVD36 and CVD-related mortality;37 this is likely due to the vascular calcification inhibitory ability of FetA.13 On the other hand, type 2 diabetics with higher FetA level have increased risks of incident CVD36 and CVD-related mortality.37 Two studies have examined the association between circulating FetA and prevalent peripheral arterial disease among type 2 diabetics, with one study reporting a positive association,38 and another study reporting a negative association.39 Methodological issues in the latter study (specifically very selective study inclusion criteria) may explain these discrepant findings.40

Metabolic syndrome

Relationships between FetA level and parameters related to the metabolic syndrome have been researched. FetA level has been found to be positively associated with the following: total cholesterol level, low-density lipoprotein cholesterol level, non-high-density lipoprotein cholesterol level, triacylglycerol level, waist circumference, systolic blood pressure, diastolic blood pressure, fasting glucose level, fasting insulin level, the homeostasis model of insulin resistance, OGTT-derived 2-h glucose level and OGTT-derived 2-h insulin level.3, 11, 37, 41, 42 FetA concentration has been found to be negatively associated with high-density lipoprotein cholesterol level, adiponectin level and insulin sensitivity measured with the euglycemic clamp.3, 11 The AHSG gene is located on chromosome 3q27, a region that has been identified as a metabolic syndrome susceptibility locus.43

Nonalcoholic fatty liver disease

Circulating FetA is elevated in NAFLD (even when patients with the same glycemic status are compared),11 and is positively associated with liver fat.3 FetA concentration is also positively associated with the rs738409 I148M variant of patatin-like phospholipase domain-containing 3,44 which is the major determinant of liver fat content in the general population. A positive association between FetA level and the liver fibrosis score index has been observed.45 However, other studies have reported no association between FetA level and liver histology.17, 44, 46 A negative association between FetA concentration and the calculated NAFLD fibrosis score was also reported,47 although this calculation does not involve measurements derived from liver biopsy or liver imaging. Among NAFLD patients, FetA level has been reported to be positively associated with carotid artery intima-media thickness in one investigation,46 and negatively associated in another.47 Differences in NAFLD diagnosis methodology (liver biopsy for the study reporting a positive association, abdominal ultrasonography for the study reporting a negative association) may explain these discrepant findings.

Chronic kidney disease

Vascular calcification is a prominent feature of CKD and an established risk factor for cardiovascular events and cardiovascular mortality.48 FetA is a potent extraosseous calcification inhibitor,13 and in studies examining CKD patients (typically with a mean BMI of ~25 kg m2), FetA level is inversely associated with calcification scores, cardiovascular events and cardiovascular mortality (see Evrard et al.49 for a review). On the other hand, the number of studies that have examined the relationship between FetA level and vascular calcification (and related parameters) in a predominately overweight/obese population is very small, and highlights the need for more work in this area. Mehrotra et al.50 observed a paradoxical positive association between FetA level and coronary artery calcification score in patients with diabetic nephropathy who were not receiving dialysis. However, the researchers also found a positive association between FetA level and glomerular filtration rate (which was a mean of 30 ml min−1 per 1.73 m), suggesting that the patients’ average renal function was ‘too healthy’ to observe the expected relationship between FetA level and coronary artery calcification score.50 Another limitation of this study is its measurement of total FetA concentration as a putative marker of extraosseous calcification stress, because research has shown that measurement of total FetA concentration often fails to yield the expected results in studies examining CKD.14 Rather, the more effective method that is now employed involves measuring the fraction of total circulating FetA that is incorporated into calciprotein particles.14 Calciprotein particles have been positively associated with coronary artery calcification scores, aortic stiffness and procalcific cytokine production in (predominately) overweight/obese CKD patients.14, 51 Furthermore, the time to transformation from spherical primary calciprotein particles to spindle-shaped secondary calciprotein particles (reflecting serum calcification propensity)52 was significantly associated with all-cause mortality in (predominately) overweight/obese patients with stages 3 and 4 CKD.53

So far, we are unaware of any human studies that have examined the relationship between circulating FetA and extraosseous calcification outside of the cardiovascular system. However, the recent discovery that FetA protects the kidney from nephrocalcinosis in rats54 provides promise for future research in humans.

Mechanistic data

Glucolipotoxicity induces FetA expression

Positive energy balance in mice has been shown to increase FetA mRNA,55 and in humans, positive energy balance was recently shown to elevate circulating FetA.56 Experiments have examined mechanisms that underlie these phenomena, specifically examining glucolipotoxic conditions. Figure 1 illustrates the main findings and explains how FetA can link glucolipotoxicity to hepatic steatosis.

Figure 1
figure1

Proposed model: glucolipotoxic-mediated upregulation of fetuin-A leads to hepatic steatosis. Excess glucose and fatty acids impose endoplasmic reticulum stress and activate ERK 1/2, which subsequently upregulates NF-κB. Reduction of NF-κB activity by AMPK is limited due to the inhibition by palmitate and under-stimulation by APN (as a consequence of fetuin-A-induced hypoadiponectinemia). Signal transduction through NF-κB promotes fetuin-A upregulation, which in turn induces mTOR phosphorylation and SREBP-1C expression. Upregulated lipogenic enzymes by SREBP-1C favor triacylglycerol accumulation. AMPK, adenosine monophosphate-activated protein kinase; APN, adiponectin; ER, endoplasmic reticulum; ERK 1/2, extracellular signal-regulated kinases 1 and 2; FA, fatty acid; G, glucose; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor-κB; SREBP-1C, sterol regulatory element-binding protein-1c.

Incubation of HepG2 cells or rat hepatocytes with palmitate stimulates nuclear factor-κB binding to the FetA promoter, thereby augmenting FetA mRNA expression, protein synthesis and secretion.57 Palmitate-induced FetA subsequently stimulates triacylglycerol accumulation in hepatocytes through the mammalian target of rapamycin-sterol and regulatory element-binding protein-1c pathway.58 Adiponectin inhibits palmitate-induced hepatic FetA expression through the adenosine monophosphate-activated protein kinase pathway.58 Thus, hypoadiponectinemia, which is frequently observed in obesity,59 may be another cause of elevated FetA. In lean, healthy humans, a trend was observed for increased circulating FetA in response to low-dose infusion of Intralipid (30 ml per hour) for 48 h.60

Incubation of HepG2 cells with glucose increases FetA protein expression and enhances the AHSG gene promoter activity.61 These effects are mediated through the ERK 1/2 signaling pathway.61 Endoplasmic reticulum stress appears to mediate both glucose- and lipid-induced elevations in FetA expression.62 The ERK 1/2 signaling pathway is involved in the FetA response to endoplasmic reticulum stress.62

It was believed until recently that the liver was the only major secretory organ of FetA. This paradigm changed with the discovery that adipocytes can also synthesize FetA. Incubation of mouse adipocytes with palmitate dose-dependently increased FetA mRNA expression, protein expression and secretion; these effects are mediated by nuclear factor-κB.63

FetA promotes metabolic dysfunction

Interference with insulin receptor signaling

Srinivas et al.64 first provided evidence two decades ago that human FetA interferes with insulin-receptor signaling at the tyrosine kinase level. Their research corroborated similar reports that rat FetA65, 66 and bovine FetA67 also inhibit insulin receptor tyrosine kinase activity. Other work demonstrated that Fetuin-null mice were protected from age-induced68 and obesity-induced insulin resistance.69 Early investigations suggested that although FetA interferes with the mitogenic effects of insulin signaling, it had no effect on insulin’s metabolic actions.64, 65, 70, 71 However, recent evidence that FetA blocks insulin-stimulated glucose transporter 4 translocation and protein kinase B activation demonstrates the metabolic-interfering effects of this protein.72 This study also clarified that FetA interferes with downstream phosphorylation events in insulin receptor signaling without affecting the binding of insulin to the α-subunit of the receptor72 (Figure 2).

Figure 2
figure2

Fetuin-A interferes with the metabolic arm of insulin receptor signaling. Left, insulin binds to the α-subunit of the insulin receptor, which initiates a cascade of phosphorylation events that ultimately promotes GLUT4 translocation and enhances glucose uptake. Right, fetuin-A binds to the ectodomain of the β-subunit. This does not affect binding of insulin to the α-subunit, but it does interfere with downstream phosphorylation events. GLUT4 translocation is inhibited, and glucose uptake is impaired. α, α-subunit of insulin receptor; β, β-subunit of insulin receptor; Akt, protein kinase B; G, glucose; GLUT4, glucose transporter type 4; IRS1, insulin receptor substrate 1; P, phosphate group (PO4); PI3K, phosphatidylinositide 3-kinase.

Inflammatory stimulation

Apart from its direct effects on the insulin receptor, FetA may also promote insulin resistance by propagating a pro-inflammatory state. In both adipocytes and monocytes, FetA treatment augments pro-inflammatory cytokine mRNA and protein expression while reducing adiponectin mRNA and protein expression.12, 57 Furthermore, intraperitoneal bolus delivery of FetA in C57BL/6 mice induces adipose tissue expression of IL-6 and TNF while reducing ADIPOQ mRNA and circulating adiponectin.12 These findings may help to explain the inverse association between circulating FetA and adiponectin that is frequently observed.59

Pal et al.73 recently reported that FetA is necessary for NEFAs to induce inflammation and insulin resistance via toll-like receptor 4 (TLR4) signaling in both adipocytes and macrophages. The researchers also found that FetA forms a ternary complex with NEFAs and TLR4, indicating that FetA serves as an endogenous ligand for TLR4 signaling.73 Building on these findings, Stefan and Häring35 indirectly assessed whether FetA mediates lipid-induced insulin resistance in humans in vivo. The researchers observed an interaction effect between NEFA level and FetA level on OGTT-derived insulin sensitivity: NEFA level was only significantly associated with insulin sensitivity in individuals with high FetA levels, and FetA level was only significantly associated with insulin sensitivity in individuals with high NEFA levels.35 FetA activation of TLR4 recently was observed to promote nonalcoholic steatohepatitis and liver fibrosis independently of toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β.74

Macrophage migration into adipose tissue and polarization from an anti-inflammatory M2 subtype to a pro-inflammatory M1 subtype are important events that promote the low-grade inflammatory state observed in obesity.75 Adipocyte-derived FetA was recently found to signal both of these events.63 Figure 3 represents a putative model to explain how FetA promotes a pro-inflammatory state in adipose tissue.

Figure 3
figure3

Proposed model: fetuin-A promotes adipose tissue inflammation. Fetuin-A originating from hepatocytes and adipocytes sends chemoattractant signals that induce macrophage infiltration into adipose tissue and subsequent conversion to a classically activated M1 subtype. Fetuin-A then presents fatty acids to the TLR4 receptors on both M1 macrophages and adipocytes, thereby propagating the release of pro-inflammatory cytokines. FA, fatty acid; TLR4, toll-like receptor 4.

Impairment of adipocyte function

FetA may attenuate lipogenesis and accelerate lipolysis in adipocytes, thereby promoting obesity and insulin resistance. Treatment of mouse 3T3L1 adipocytes and human pre-adipocytes with FetA was found to lower the lipid droplet size and numbers while reducing total lipid content.57 FetA treatment also lowered the protein and mRNA expressions of the adipogenic factor peroxisome proliferator-activated receptor-γ, as well as downstream molecules of the peroxisome proliferator-activated receptor-γ signaling pathway, including adiponectin, adipocyte protein 2 and fatty acid translocase.57 Relationships between AHSG gene single-nucleotide polymorphisms and adipocyte function have also been reported. One study found that the rs2077119 single-nucleotide polymorphism had strong associations with insulin inhibition of lipolysis, as well as 8-bromocyclic AMP stimulation of lipolysis, and weak associations with insulin stimulation of lipogenesis and basal lipolysis.76 Another study found that the rs4917 single-nucleotide polymorphism was associated with lipolytic sensitivity to terbutaline.77

Intervetional data

Interventions that produce weight loss are effective at lowering FetA3, 9, 15, 16, 17, 78, 79 (Table 1). Gastric bypass surgery improves FetA level, albeit not as effectively as its improvements in some components of the metabolic syndrome (that is, systolic blood pressure, triacylglycerol level and fasting glucose level).9 A recent investigation observed that gastric bypass reduced circulating FetA to a greater extent compared with sleeve gastrectomy 3 days following surgery and before improvements in homeostasis model of insulin resistance could be observed;80 the mechanism explaining this greater reduction awaits discovery. Aerobic exercise can reduce FetA in the absence of either weight loss or even reduction in hepatic steatosis provided that the exercise intensity is sufficient: whereas exercising at the anaerobic threshold,18 60% volume of oxygenpeak (ref. 81) and 60–75% heart rate (HR)max (ref. 82) were all unable to reduce circulating FetA, exercising at 85% HRmax was able to achieve this in only 7 days.83 A low dose of metformin (500 or 750 mg per day for 3 months) was ineffective at reducing FetA level,18 but higher dosing (2500 or 3000 mg per day for 6 months) was successful.17 Pioglitazone (15 or 30 mg per day for 3 months) has also been observed to lower circulating FetA.18

Table 1 Interventions for reducing fetuin-A

As has been previously observed elsewhere,84 each of these interventions is capable of activating adenosine monophosphate-activated protein kinase, which itself has been shown to inhibit hepatic FetA expression.58 Future research should confirm whether adenosine monophosphate-activated protein kinase activation is an important factor in intervention-induced reduction of circulating FetA. Future work should also measure phosphorylated FetA, as phosphorylation is necessary for insulin receptor-tyrosine kinase inhibition by this protein.85 Interestingly, a single bout of treadmill walking that expended 350 kcal reduced serum phosphofetuin without affecting total circulating levels.86 Fasting insulin level and homeostasis model of insulin resistance were also reduced, and while the data are preliminary, they suggest that changes in phosphofetuin, and not total FetA, may be associated with these improvements.

Reduced FetA in response to intervention is often associated with improvement in insulin-related parameters. Indeed, reductions in FetA have been associated with improvements in fasting insulin,9 homeostasis model of insulin resistance,9, 79 OGTT-derived insulin sensitivity,83 hepatic insulin resistance (fasting insulin × fasting hepatic glucose production)16 and metabolic flexibility (insulin-stimulated respiratory exchange ratio−fasting respiratory exchange ratio).16 Also, reductions in FetA have been associated with increases in circulating adiponectin.15, 16

Conclusions

The evidence is clear that FetA is elevated in obesity and is associated with many obesity-related complications. Unfortunately, due to the different assay techniques that have been employed in the epidemiologic literature,14 along with the many confounders existing across studies (for example, insulin sensitivity, fat mass, gender, age and so on), clinically relevant cut points of FetA concentration in obesity and related disorders such as T2DM, NAFLD, the metabolic syndrome and CKD are currently unknown. A standardized assaying procedure will likely need to be widely adopted before such cut points emerge.

It is likely that FetA has a causal role in the development and progression of obesity-related complications, because FetA has been implicated in impairment of insulin receptor signaling, TLR4 activation, macrophage migration and polarization, adipocyte dysfunction, hepatocyte triacylglycerol accumulation and liver inflammation and fibrosis. Weight loss through diet or surgery, aerobic exercise, metformin and pioglitazone have each been shown to be effective for reducing FetA, provided that the intensity/dose of the intervention is sufficient.

Going forward, research should investigate whether FetA has a role in the progressive deterioration of β-cell function that occurs during the etiology of T2DM. Such a role is likely when considering the importance of TLR4 activation in lipid-induced β-cell dysfunction,87 the discovery that FetA serves as an endogenous ligand for TLR4, and the finding that OGTT-derived insulin secretion is negatively associated with FetA level in individuals with impaired glucose tolerance. Future research should additionally clarify whether adenosine monophosphate-activated protein kinase activation is involved in intervention-induced lowering of circulating FetA. Other areas in need of clarification include the relative contributions of the liver and adipose tissue to circulating FetA levels, the specific mechanism by which FetA promotes macrophage migration and polarization, the factors that underlie the association between CVD and FetA level in individuals with T2DM and the ability of FetA to protect against extraosseous calcification outside of the cardiovascular system.

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Trepanowski, J., Mey, J. & Varady, K. Fetuin-A: a novel link between obesity and related complications. Int J Obes 39, 734–741 (2015). https://doi.org/10.1038/ijo.2014.203

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