Thrombosis is a major comorbidity of obesity and type-2 diabetes mellitus (T2DM). Despite the development of numerous effective treatments and preventative strategies to address thrombotic disease in such individuals, the incidence of thrombotic complications remains high. This suggests that not all the pathophysiological mechanisms underlying these events have been identified or targeted. Non-esterified fatty acids (NEFAs) are increasingly regarded as a nexus between obesity, insulin resistance, and vascular disease. Notably, plasma NEFA levels are consistently elevated in obesity and T2DM and may impact hemostasis in several ways. A potentially unrecognized route of NEFA-mediated thrombotic activity is their ability to disturb Zn2+ speciation in the plasma. Zn2+ is a potent regulator of coagulation and its availability in the plasma is monitored carefully through buffering by human serum albumin (HSA). The binding of long-chain NEFAs such as palmitate and stearate, however, trigger a conformational change in HSA that reduces its ability to bind Zn2+, thus increasing the ion’s availability to bind and activate coagulation proteins. NEFA-mediated perturbation of HSA-Zn2+ binding is thus predicted to contribute to the prothrombotic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.

Obesity is a complex disease that increases an individual’s risk of developing other diseases and health-related problems. A common feature is dyslipidemia characterized by increased levels of plasma lipids, which include non-esterified fatty acids (NEFAs). The role of NEFAs in obesity-related morbidity is interesting as NEFAs constitute a reservoir of metabolic energy, are principal components of cell membranes and are precursors for signalling molecules. Bariatric surgery promotes sustained weight loss in severely obese patients, reducing the incidence and severity of co-morbidities. In this study we measure changes in circulating NEFA species in plasma samples taken from 25 obese individuals before and 9 months after Roux-en-Y gastric bypass surgery. The mean weight of the cohort reduced by 29.2% from 149.0 ± 25.1 kg pre-surgery to 105.5 ± 19.8 kg post-surgery and the BMI by 28.2% from 51.8 ± 6.3 kg/m2 pre-surgery to 37.2 ± 5.4 kg/m2. Mean glycated haemoglobin (HbA1c) reduced from 6.5 ± 1.3 to 5.5 ± 0.5%, consistent with the intervention leading to improved glycaemic control, particularly in those who were dysglycemic prior to surgery. Total and LDL cholesterol concentrations were markedly reduced following surgery. Concentrations of seven NEFAs were found to decrease 9 months after surgery compared to pre-surgery levels: myristate, palmitoleate, palmitate, linoleate, oleate, stearate and arachidonate. Bariatric surgery led to increased lipogenesis and elongase activity and decreased stearoyl-CoA desaturase 1 activity. This study therefore highlights metabolic changes that take place following gastric bypass surgery in severely obese patients.

Obesity enhances the risk of type-2 diabetes, cardiovascular disease and inflammatory conditions and often leads to metal dyshomeostasis, which contributes to the negative health aspects associated with the disease. In severe cases, bariatric surgery can be recommended to achieve sustained weight loss and improvement in health. Here, magnesium, zinc, copper and selenium concentrations were examined in 24 obese patients (7 males; 17 females) before and 9 months after undergoing Roux-en-Y gastric bypass surgery. All patients lost weight over this period, with the mean BMI reducing from 51.2±7.1 kg/m2 to 37.2±5.5 kg/m2. Moreover, whole-blood glycated haemoglobin (HbA1c), as a marker of average glycaemia, was also measured and a correlative analysis of this parameter with metal concentrations performed. Significant alterations in the plasma concentrations of magnesium, zinc (both increased by 13.2% and 25.2% respectively) and copper (decreased by 7.9%) were observed over this period (plasma selenium concentration was unchanged), with BMI values correlating with plasma magnesium (p = 0.004) and zinc (p = 0.022) concentrations. At 9 months post-surgery, an increase in mean zinc/copper ratio was observed (0.86±0.29 compared to 0.63±0.14 pre-surgery). Comparison of whole-blood HbA1c concentrations pre- and post-surgery revealed a reduction from 6.50±1.28% pre-surgery to 5.51±0.49% post-surgery. Differences in plasma HbA1c and magnesium at either pre- and post-surgery correlated significantly, as did HbA1c and magnesium levels when pre- and post-surgery values were analysed together. Collectively, this work reveals that bariatric surgery, in conjunction with lifestyle/dietary changes, lead to improvements in the nutritional status of magnesium, zinc and copper. Furthermore, the observed improvements in magnesium and zinc were associated with weight loss and in the case of magnesium, to better glycaemic control.

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70–85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.