Fetuin-A: a novel marker for obesity and associated comorbidities
Background: Obesity is a disease characterized by excess adiposity which complicates metabolism, mobility, and multiple systems in the body. Over a third of Americans have a body mass index (BMI) greater than 30 kg/m2 and therefore, are considered obese. Excess adiposity may be prevented or reduced through behavioral, pharmacological and surgical methods. Bariatric surgery results in significant and sustained loss of body weight and body fat. Many bariatric surgeries have also been termed metabolic surgeries as they result in significant improvements of metabolic abnormalities associated with obesity including dyslipidemia and insulin resistance. It is estimated that 80% of individuals with Type 2 Diabetes Mellitus (T2DM) will experience resolution after bariatric surgeries such as Roux-en-Y gastric bypass and sleeve gastrectomy (SG). Although individuals with morbid obesity have a greater risk of T2DM, 25% remain insulin-sensitive. To date, it is unclear why some develop insulin-sensitive obesity (Obsen) and others insulin-resistant obesity (Obres). A validated biomarker to distinguish these groups may aid in more targeted interventions and monitoring of at-risk populations. Fetuin-A (FetA) has shown promise as a potential marker of insulin resistance yet much about this hepatokine remains unknown. The overarching goal of this research is to understand whether FetA may be a novel marker of obesity and obesity-associated insulin resistance. Therefore, the objectives of this research were to 1) determine the role genetics play in circulating FetA and metabolic health, 2) investigate how circulating FetA responds to SG, a bariatric procedure known to markedly improve insulin sensitivity, and 3) compare FetA, adipocyte hypertrophy and weight loss trajectories between SG patients with Obsen and Obres. Methods: To determine the genetic influence of FetA, 717 college applicants to the Autonomous University of San Luis Potosi, Mexico (18-25 years old) were genotyped for single nucleotide polymorphisms (rs4917 and rs2518136) in the gene that codes for FetA, alpha2-Heremans-Schmid Glycoprotein (AHSG). Circulating lipids, glucose, insulin and FetA were measured in plasma. To investigate the role of FetA in obesity and interventions aiming to improve insulin sensitivity, forty SG patients were recruited and evaluated longitudinally. Participants met with research staff at baseline (T0) (prior to hypocaloric, low-fat preoperative diet), on the morning of surgery (T1) and six weeks following surgery (T2). At each visit, fasting blood and three-day food logs were collected. Body composition was measured via direct segmental multi-frequency bioelectrical impedance analysis. Circulating FetA, insulin, blood lipids and glucose were measured at each visit. Omental adipose tissue was collected at the time of surgery. Formalin-fixed and paraffin-embedded tissues were stained with hematoxylin and eosin, and adipocyte diameter was calculated. To compare individuals with Obres and Obsen, the cohort was divided into age- and BMI-matched groups based on homeostatic model assessment for insulin resistance (HOMA-IR) with consideration for diabetes diagnosis and use of anti-diabetic medications. Results: Individual genetic variation in AHSG SNPs rs4917 and rs2518136 explained 8% and 10% of the variability in FetA, respectively. Lower triglyceride values were observed in CC-rs4917 homozygotes than in T-allele carriers (p<0.05). In the SG cohort, FetA decreased 12% during the preoperative diet (p=0.007) and an additional 26% during the postoperative diet (p<0.0001). FetA was negatively associated with age (r= -0.52, p=0.004). Higher HOMA-IR at all time points was associated with lower FetA at T3 (HOMA-IR T0: p=0.002, T1: 0.003 and T2: 0.001). Obsen and Obres groups did not differ in baseline BMI or percent body fat. Age-adjusted FetA tended to be higher in Obsen at T0 and T1 (p=0.09 and p=0.10, respectively). At T2, age-adjusted FetA was higher in the Obsen group than the Obres group (p=0.004). The Obres group had significantly more excess body weight loss (adjusted for baseline BMI and time) (p=0.012) and larger adipocytes than the Obsen group (p=0.0099). Adipocyte size was positively correlated with preoperative change in FetA (r=0.64, p=0.007) but not with reported changes in caloric intake, macronutrient intake, PBF loss or BMI loss. Conclusions: Variations in the AHSG gene influence circulating FetA and are associated with altered triglycerides. The influence of genetic variation was exaggerated in those who were overweight or obese. Individuals with obesity have higher FetA which is significantly reduced by calorie and fat restriction as well as SG. Immediate post-bariatric improvements of FetA have been correlated with rapid improvements in insulin sensitivity. However, decreased FetA may be partially explained by preoperative calorie restriction. Greater reduction in FetA during the preoperative diet was associated with smaller adipocyte size on the day of surgery. Smaller adipocytes have been shown to be more insulin sensitive. Individuals with Obsen had smaller adipocytes than those with Obres. In contrast to previous reports, those with Obsen tended to have higher circulating FetA at all time points, lost less weight, and had no appreciable improvements in HOMA-IR. This research demonstrates the usefulness of FetA as a biomarker for weight loss and insulin sensitivity improvements following lifestyle and bariatric intervention.
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign