International Journal of Obesity (2015) 39, 734–741 © 2015 Macmillan Publishers Limited All rights reserved 0307-0565/15 www.nature.com/ijo REVIEW Fetuin-A: a novel link between obesity and related complications JF Trepanowski, J Mey and KA Varady 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. International Journal of Obesity (2015) 39, 734–741; doi:10.1038/ijo.2014.203 INTRODUCTION relationship, epidemiologic, mechanistic (cell, animal and human Fetuin-A (FetA) is a 64-kDa glycoprotein that is found in relatively models) and interventional research are each summarized. high concentrations in human serum (300–1000 μgml− 1).1–3 Although all relevant research is discussed, special emphasis is Fetuin was first discovered in 1944 in bovine calves, and it given to studies that have been published as the most recent 19,20 derived its name from ‘fetus’ to reflect the observation that fetal reviews of FetA and obesity. serum contained the highest concentration of this protein.4 Fetuin was renamed ‘fetuin-A’ in 2000 upon the discovery of a fetuin-like SEARCH STRATEGY molecule termed ‘fetuin-B’.5 Human FetA is also known as α2- Heremans-Schmid glycoprotein (AHSG);6 this naming honors the A PubMed search was conducted through October 2014 of (independent) discoverers of the human homolog of FetA, publications in English. The following input was used for the Heremans7 along with Bürgi and Schmid.8 search: (FetA or AHSG) and (obesity or diabetes or metabolic In human adults, FetA is mainly expressed and secreted from syndrome or NAFLD or cardiovascular disease (CVD) or kidney the liver and adipose tissue. Epidemiologic research consistently disease or nephropathy or glucose or palmitate or insulin receptor observes elevated circulating FetA in obesity9 and related or inflammation or toll-like receptor 4 or adipocyte or diet or complications, such as type 2 diabetes mellitus (T2DM),1 the exercise or metformin). This search yielded 599 potentially metabolic syndrome10 and nonalcoholic fatty liver disease relevant articles. Additional articles were identified using the (NAFLD).11 Moreover, FetA level is associated with many references listed in these manuscripts. Intervention studies were parameters related to metabolic health, such as insulin considered for review only if they: (1) included a subject sensitivity,3 glucose tolerance,11 circulating lipid levels10 and population that was overweight/obese (body mass index (BMI) ⩾ −2 circulating levels of both pro- and anti-inflammatory proteins.12 25.0 kg m ) and/or presented with T2DM and/or presented FetA also has an important role in calcification inhibition,13 with NAFLD; and (2) examined an intervention that typically particularly in patients with chronic kidney disease (CKD).14 reduces body weight and/or improves insulin sensitivity. Articles Recent research is the uncovering mechanisms that underlie the were selected for inclusion in this review if they provided evidence relationship between FetA and obesity-related complications. for an association between FetA level and obesity or related fi Much of this research can be categorized as explaining either metabolic conditions. A total of 87 articles were nally selected. (1) how glucolipotoxicity induces FetA expression or (2) how FetA promotes metabolic dysfunction. EPIDEMIOLOGIC DATA Intervention trials demonstrate that diet,15 aerobic exercise,16 gastric bypass surgery,9 metformin17 and pioglitazone18 can each Obesity be employed to reduce circulating FetA. Reductions in FetA level Associations between FetA level and obesity-related parameters are often associated with improvements in insulin-related para- are widely reported in the epidemiologic literature. BMI,21 visceral meters and/or circulating adiponectin.15,16 adipose tissue (VAT)1 and leptin concentration22 are each This is the first comprehensive review to exclusively focus on positively associated with FetA concentration. Furthermore, the relationship between FetA and obesity. To expound on this change in FetA level is associated with the change in visceral Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA. Correspondence: JF Trepanowski, Department of Kinesiology and Nutrition, University of Illinois at Chicago, 1919 West Taylor Street, Room 506F, Chicago, 60612, IL, USA. E-mail: [email protected] Received 19 June 2014; revised 4 October 2014; accepted 2 November 2014; accepted article preview online 3 December 2014; advance online publication, 6 January 2015 Fetuin-A in obesity and related complications JF Trepanowski et al 735 adipose tissue over a 5-year period.23 Circulating FetA is elevated pressure, fasting glucose level, fasting insulin level, the home- in insulin-resistant obesity compared with insulin-sensitive ostasis model of insulin resistance, OGTT-derived 2-h glucose level obesity.24 and OGTT-derived 2-h insulin level.3,11,37,41,42 FetA concentration The relationship between FetA and obesity appears to be has been found to be negatively associated with high-density mediated at least in part by genetics. A variant of the AHSG gene lipoprotein cholesterol level, adiponectin level and insulin that is associated with lower FetA level is more common among sensitivity measured with the euglycemic clamp.3,11 The AHSG normal weight men compared with overweight and obese men.25 gene is located on chromosome 3q27, a region that has been In addition, bi-directional Mendelian randomization shows evi- identified as a metabolic syndrome susceptibility locus.43 dence of a casual association from circulating FetA to BMI, along 26 with no evidence of reverse causality from BMI to FetA. Nonalcoholic fatty liver disease Circulating FetA is elevated in NAFLD (even when patients with Type 2 diabetes mellitus the same glycemic status are compared),11 and is positively Incident diabetes risk increases in individuals with higher FetA associated with liver fat.3 FetA concentration is also positively concentrations even after adjustment for potential mediators, associated with the rs738409 I148M variant of patatin-like including: body weight, BMI, waist circumference, blood pressure, phospholipase domain-containing 3,44 which is the major blood lipid levels, race, fasting glucose level, HbA1C level, determinant of liver fat content in the general population. C-reactive protein level, adipocytokine levels and liver enzyme A positive association between FetA level and the liver fibrosis levels.1,2,27 A recent investigation found that a positive association score index has been observed.45 However, other studies between FetA concentration and incident diabetes risk existed have reported no association between FetA level and liver only in female participants.21 However, previous research found histology.17,44,46 A negative association between FetA concentra- that this association applied similarly to both genders.1,2,28 tion and the calculated NAFLD fibrosis score was also reported,47 Gestational diabetes patients have elevated FetA level compared although this calculation does not involve measurements derived with healthy pregnant women and non-pregnant controls.29 from liver biopsy or liver imaging. Among NAFLD patients, FetA Moreover, FetA concentration is positively associated with both level has been reported to be positively associated with carotid fasting C-peptide concentration and C-peptide/blood glucose artery intima-media thickness in one investigation,46 and ratio in both gestational diabetes patients and healthy pregnant negatively associated in another.47 Differences in NAFLD diagnosis women.29 Isolated impaired glucose tolerance, but not isolated methodology (liver biopsy for the study reporting a positive impaired fasting glucose, is associated with higher FetA concen- association, abdominal ultrasonography for the study reporting a tration when compared with normal glucose tolerance.11 The negative association) may explain these discrepant findings. reason for this is currently unclear but may be related to the greater degree of peripheral insulin resistance that is typically Chronic kidney disease observed in isolated impaired glucose tolerance.30 In individuals Vascular calcification is a prominent feature of CKD and an with impaired glucose tolerance, but not normal glucose established risk factor for cardiovascular events and cardiovascular tolerance, FetA concentration is negatively associated with insulin mortality.48 FetA is a potent extraosseous calcification inhibitor,13 secretion during an oral glucose tolerance test (OGTT).31 and in studies examining CKD patients (typically with a mean BMI AHSG gene single-nucleotide polymorphisms have been