Background: The prevalence of chronic obesity is increasing worldwide, resulting in more intervention with bariatric surgeries being performed each year. However, the variable success of surgical approaches in treating obesity and its co-morbidities varies between individuals and by the type of surgery, and is not readily explained by baseline clinical features. A better understanding is needed of the metabolic shifts, and their underpinning mechanisms, which result from different types of bariatric surgery. From this a better knowledge should emerge of biomarkers and causal pathways driving the development of obesity and its comorbidities.
Methods: We investigated the effects of bariatric surgery on miRNA profile before and after of either gastric bypass surgery (GBP) or sleeve gastrectomy (SG) in nine obese patients with T2DM. Recent work has identified an early reduction in post-operative circulating levels of the hepatokine fetuin-A (FetA) after GBP but not SG, as a putative candidate to monitor the efficacy of intervention. Therefore, we used FFA-induced HepG2 cells to indicate the underlying mechanism these miRNAs could lead to increased level of FetA.
Results: Here we extend these observations, and in plasma samples defined a specific set of miRNAs whose post-surgery expression among GBP patients correlated strongly with beneficial decreases in BMI and blood glucose (HbA1c) levels, demonstrated that particular miRNAs mediate signaling pathways that regulate FetA expression. Additionally, we reported that expression of both FetA and leukocyte cell-derived chemotaxin2 (LECT2; another major hepatokine) was dependent on intracellular signaling by metabolic regulator myostatin (MSTN). Finally, we linked the activity of a key miRNA in particular to FFA induced, MSTN-dependent regulation of FetA.
Conclusions: These data provide novel mechanistic insights into the metabolic stimulation of hepatokine expression, and the epigenetics role in mediating hepatocellular changes associated with greater weight loss and diabetes remission observed with GBP rather than SG.