Micro RNAs as Biomarkers of Bariatric Surgery Outcome and Putative Regulators of Hepatokines Selectively after Gastric Bypass, but not Sleeve Gastrectomy

The obesity prevalence is increasing worldwide, resulting in more bariatric surgeries interventions being performed. However, the success of surgical approaches in treating obesity and its co-morbidities varies between types of surgery and is not readily explained by baseline clinical features. Better understanding is needed of the metabolic shifts, and their underpinning mechanisms, which result from different types of surgery. We investigated 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 type 2 diabetes mellitus (T2DM). Recent work has identified 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 intervention efficacy. Therefore, we used FFA-induced HepG2 cells to indicate the underlying mechanism these miRNAs could lead to increased FetA level. Here we defined a specific set of miRNA species whose postsurgery expression among GBP patients correlated strongly with beneficial decreases in body mass index (BMI) and blood glucose (HbA1c) levels. 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 miR-335 activity in particular to FFA-induced, MSTN-dependent regulation of FetA. 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.