Omentin changes following bariatric surgery and predictive links with biomarkers for risk of cardiovascular disease

A recently described adipokine, Omentin, has gained interest lately following reports of associations with various comorbidities stemming from obesity such as cardiovascular disease, insulin resistance and metabolic syndrome (reviewed in [1]). Omentin expression varies throughout the body (heart, lungs, ovary and placenta) but its main tissue of production is now considered to be visceral adipose tissue [2],[3]. First identified in intestinal Paneth cells, Omentin demonstrates low affinity binding to bacterial cell wall carbohydrates and was thought to be part of early-defense mechanisms in the gut against pathogenic bacteria [4].

In obesity, Omentin levels are decreased and are inversely correlated to body mass index (BMI), waist circumference and leptin concentration [5]. Omentin levels correlate inversely with markers of metabolic syndrome [6]–[8] and is decreased in patients with heart disease. Omentin has been suggested to be an even better marker than adiponectin of patients at risk for coronary artery disease [9]. Other studies have also shown a significant decrease in Omentin in subjects with demonstrated carotid plaque in combination with type 2 diabetes vs patients with type 2 diabetes with no plaque vs glucose tolerant subjects [10]. This relationship with insulin resistance is further reported in many studies documenting that patients who showed impaired glucose tolerance or with diabetes also had decreased Omentin levels [11],[12]. During weight loss due to diet or an exercise regimen, Omentin levels increased over time [13],[14], further solidifying its link to obesity and body weight.

Omentin has also been linked to chronic inflammation, with reduced levels in rheumatoid arthritis, Crohn’s disease and asthma (reviewed in [1]). All these studies point towards a possible link between this visceral adipose tissue produced hormone and a diseased state.

In vitro, Omentin enhances insulin-stimulated glucose uptake in human adipocytes as well as activating Akt signaling pathways [3]. Pre-treatment of rat cells with Omentin significantly decreased TNF-α mediated phosphorylation of p38 and JNK, expression of VCAM-1, monocyte adhesion to smooth muscle cells, and NOX-derived superoxide production [4]. In adipose tissue explants, both insulin and glucose decrease Omentin mRNA expression and secretion [15]. To date, no receptor has been identified for intracellular transduction of these functions.

Severely obese patients have few options for weight loss and resolution of comorbidities that are as effective as bariatric surgery [16]. In fact, bariatric surgery was recently recognized as a valid treatment option for type 2 diabetes in obese patients by both the International Diabetes Federation and the American Diabetes Association. Further, long-term (6-year) remission rates post-gastric bypass reached up to 31% in a study by Brethauer et al. [17] and up to 72% in the Swedish Obese Subjects Study (SOS; with a follow-up of 2 years) [18], and result in improvements in cardiovascular function [19]. Biliopancreatic diversion (BPD) with or without duodenal switch (DS) is frequently used and has shown improvement in insulin and glucose metabolism in most patients [20]. As Omentin has demonstrated insulin-sensitizing effects and because patients undergoing BPD-DS become more insulin-sensitive mere days following surgery, even before any weight loss [21], Omentin levels were evaluated in a cohort of BPD-DS patients in the early stages post-surgery (1 day and 5 days, prior to weight loss) and over a longer period (6 months and 1 year, a period associated with weight loss). Specifically, we propose that Omentin levels will increase post-bariatric surgery and that this rise will precede gain of insulin sensitivity.

The adipokine Omentin has been increasingly implicated in metabolic dysfunctions. Pre-surgery values of Omentin positively correlated with both BMI and ASP levels. This contrasts with observations in previous studies, where Omentin decreases with weight increases [3],[5], however our correlations may be confounded by the subjects, which were all severely obese. In the present study, changes that occurred in Omentin levels following BPD-DS were evaluated both in the short-term as well as up to one year following surgery. As expected, subjects showed significant weight loss in the months following BPD-DS. In corroboration with other weight loss studies [14] we show that, in a large proportion of the patients, Omentin levels increase post-operatively. Interestingly, this change in Omentin occurred even before induction of weight loss, and these levels were maintained up to one-year post-bariatric intervention. Specifically, the Omentin increase occurred by one day post-surgery, even prior to resolution of the diabetic status, which occurred in many of these subjects by 5 days post-surgery [21]. However, not all patients demonstrated this Omentin increase following BPD-DS. In fact, 18% saw their levels decrease >10% by 24 hours after surgery but still demonstrated a resolution of their diabetic status in the short-term post-surgery. Further, these decreased levels were consistently maintained up to 1 year following the surgery.

Interesting differences could also be seen between the groups, Omentin_DEC and Omentin_INC, at various time points. Omentin_DEC group was characterized by elevation of markers related to heart disease (both short- and long-term). Homocysteine, bilirubin and red blood cell counts were significantly different between the two groups throughout the one-year follow-up period, while NT-proBNP showed an overall difference but a peak difference at day 5 post-surgery. Increases in NT-proBNP have been linked to increased mortality rates in patients and several studies have proposed this as a marker of left ventricular diastolic dysfunction and heart failure [23]–[26], although in the present study the patients have not been followed up long enough, or with these outcomes as study criteria.

In line with these results, homocysteine increases are also linked to left ventricular diastolic function as well as coronary artery disease [27],[28]. Levels of this non-protein α-amino acid can reflect vitamin intake, especially vitamin B6, which is needed as a cofactor for the transformation of homocysteine into cysteine [28],[29]. Thus, in a cohort of patients receiving not only restrictive but also malabsorptive surgery, vitamin intake could well play a significant role in homocysteine levels. Patients receive high doses of vitamins to curtail any negative impact of bariatric surgery and although patient compliance can never be fully assured, vitamin A, D, B12 and folate levels remained within normal healthy parameters up to 1 year post-surgery (data not shown).

Elevated bilirubin levels have been shown to correlate with increased heart failure and death and corroborate the observations made with the previously mentioned biomarkers [30],[25]. By contrast, other studies demonstrate that lower bilirubin levels correlate closely to coronary heart disease and metabolic syndrome components [31],[32]. Further, bilirubin is the end-product of heme degradation which would be consistent with the observation of lowered red blood cell count in the Omentin_DEC group. Interestingly, bilirubin levels are elevated before the surgery in this group of patients (as well homocysteine), suggesting that these patients are already more at risk, even before any changes in diabetic status or Omentin levels.

Other studies have reported a link between Omentin and heart disease. Moreno-Navarette et al. suggested that Omentin, after controlling for adiposity, age, and inflammation in patients with impaired glucose tolerance, contributed independently to endothelial dysfunction [13]. A very recent study [33] shows that patients with lower levels of Omentin had increased risk of heart failure and even suggest its use as a novel prognostic marker for risk stratification in heart failure patients. This is further reinforced mechanistically by a study from Kataoka and colleagues [34], where systemic injection of Omentin in mice that suffered sustained ischemic injury led to a reduction of myocardial infarct size and apoptosis. Further, studies have also shown lower Omentin levels in patients with type 2 diabetes compared to healthy controls and even lower Omentin levels when patients with diabetes presented with carotid plaque [10].

While the functions of Omentin are still being elucidated and its receptor is still unknown, a role as “insulin sensitizer” in adipocytes has already been demonstrated. However, recent evidence supports the potential for an as yet unidentified role in heart function based on the links to heart disease. Interestingly, pre-operative BMI (as well as weight and fat mass) correlated negatively with the acute (1 day) change in Omentin, as did IL-6 levels, perhaps indicating that a subgroup of these severely obese patients are already at-risk for the development of cardiovascular problems and this could be associated with Omentin (and other factors) in an as-yet-undiscovered function. Initial studies on Omentin (then known as Intelectin) focused on its microbial surface galactofuranose binding properties. Thus, it was suggested to participate in host early-defense against bacterial infections [35]. Literature in recent years has shown the importance of gut microbiota in the development of obesity as well as insulin resistance and other metabolism-related comorbidities (as reviewed in [36]). We would speculate that Omentin could be part of this link, being produced by visceral adipose tissue and acting as an “insulin sensitizer” yet also being able to interact with specific bacteria in the gut. BPD-DS also plays a role in post-surgery microbiota redistribution (reviewed in [37]) and this could possibly be evidenced through changes in Omentin levels. Further, Omentin has demonstrated anti-inflammatory properties, cementing its links with CVD and Metabolic Syndrome (reviewed in Jaikanth et al. [1]. Thus, lower levels of this adipokine could well be implicated in worsening of situations where immune activation is present, as is the case in obesity and diabetes. These proposed roles of Omentin, and correlations with ASP and lymphocytes, mesh with the concept of the contribution of various biomarkers to an enhanced pro-inflammatory state and autoimmune activation as pivotal in understanding chronic diseases, as reviewed in detail by Onat et al. [38].

The limitations of this present study are that all patients were severely obese, and as such interpretations cannot be generalized to other groups. Further, given the exploratory nature of Omentin physiology, with little known regarding regulation, signaling pathway, receptor target and broader functions in various tissues, the current correlations cannot be interpreted as causative. Further studies will be necessary to determine the possible links between Omentin and risk of heart failure and whether this novel adipokine could be used as an early biomarker to identify patients with increased risk, and whether special care or treatment should be administered.

Altogether, the present study suggests that a subgroup of patients (approximately 25%) following bariatric surgery may be at greater risk for heart-related complications, at least based on the presentation of known risk markers, both preoperatively and within the one year follow-up period following surgery. Further, Omentin levels 1 day following surgery may be a marker of this “higher risk” group, where lowered Omentin correlates with higher levels of risk factors overall, well before any weight loss or changes in adiposity and before insulin sensitivity is restored.