Abstract
Bariatric surgery provides significant and durable improvements in glycemic control and hepatic steatosis, but the underlying mechanisms that drive improvements in these metabolic parameters remain to be fully elucidated. Recently, alterations in mitochondrial morphology have shown a direct link to nutrient adaptations in obesity. Here, we evaluate the effects of Roux‐en‐Y gastric bypass (RYGB) surgery on markers of liver mitochondrial dynamics in a diet‐induced obesity Sprague‐Dawley (SD) rat model. Livers were harvested from adult male SD rats 90‐days after either Sham or RYGB surgery and continuous high‐fat feeding. We assessed expression of mitochondrial proteins involved in fusion, fission, mitochondrial autophagy (mitophagy) and biogenesis, as well as differences in citrate synthase activity and markers of oxidative stress. Gene expression for mitochondrial fusion genes, mitofusin 1 (Mfn1; P < 0.05), mitofusin 2 (Mfn2; P < 0.01), and optic atrophy 1 (OPA1; P < 0.05) increased following RYGB surgery. Biogenesis regulators, peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α; P < 0.01) and nuclear respiratory factor 1 (Nrf1; P < 0.05), also increased in the RYGB group, as well as mitophagy marker, BCL‐2 interacting protein 3 (Bnip3; P < 0.01). Protein expression for Mfn1 (P < 0.001), PGC1α (P < 0.05), BNIP3 (P < 0.0001), and mitochondrial complexes I‐V (P < 0.01) was also increased by RYGB, and Mfn1 expression negatively correlated with body weight, insulin resistance, and fasting plasma insulin. In the RYGB group, citrate synthase activity was increased (P < 0.02) and reactive oxygen species (ROS) was decreased compared to the Sham control group (P < 0.05), although total antioxidant capacity was unchanged between groups. These data are the first to show an association between RYGB surgery and improved markers of liver mitochondrial dynamics. These observed improvements may be related to weight loss and reduced energetic demand on the liver, which could facilitate normalization of glucose homeostasis and protect against hepatic steatosis.
Highlights
The chronic imbalance in nutrient supply and demand is a hallmark characteristic of obesity and type 2 diabetes (T2D) (Liesa and Shirihai 2013)
There was a significant increase in mRNA expression for fusion genes, mitofusin 1 (Mfn1) (P = 0.02), mitofusin 2 (Mfn2) (P = 0.003), and optic atrophy 1 (OPA1) (P = 0.01) in livers of Roux-en-Y gastric bypass (RYGB) animals compared to Sham (Fig. 1A–C)
We investigated the effect of RYGB surgery on liver mitochondrial dynamics in SD rats fed a high-fat diet known to induce obesity and hepatic steatosis
Summary
The chronic imbalance in nutrient supply and demand is a hallmark characteristic of obesity and type 2 diabetes (T2D) (Liesa and Shirihai 2013). Bariatric surgery is considerably more effective in restoring balance compared to medical therapy, and this is evidenced by several longterm prospective and randomized controlled trials showing sustained weight loss and glycemic control in obese patients In addition to striking improvements in body weight and insulin sensitivity, Roux-en-Y gastric bypass (RYGB) has been shown to reverse non-alcoholic fatty liver disease (NAFLD) and related steatosis, inflammation, and fibrosis (Sasaki et al 2014; Bower et al 2015). We have previously shown that bariatric surgery reduces insulin resistance and hepatic steatosis and inflammation from obese, non-diabetic Sprague-Dawley (SD) rats, and protects against endoplasmic reticulum (ER) stress and apoptosis (Mosinski et al 2016). The specific cellular and molecular mechanisms by which re-routing of the gut anatomy facilitates metabolic improvements in the liver is an area of active investigation
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