Gastric bypass surgery is protective from high-fat diet-induced non-alcoholic fatty liver disease and hepatic endoplasmic reticulum stress.

AIM: High-fat diets are known to contribute to the development of obesity and related co-morbidities including non-alcoholic fatty liver disease (NAFLD). The accumulation of hepatic lipid may increase endoplasmic reticulum (ER) stress and contribute to non-alcoholic steatohepatitis and metabolic disease. We hypothesized that bariatric surgery would counter the effects of a high-fat diet (HFD) on obesity-associated NAFLD. METHODS: Sixteen of 24 male Sprague Dawley rats were randomized to Sham (N = 8) or Roux-en-Y gastric bypass (RYGB) surgery (N = 8) and compared to Lean controls (N = 8). Obese rats were maintained on a HFD throughout the study. Insulin resistance (HOMA-IR), and hepatic steatosis, triglyceride accumulation, ER stress and apoptosis were assessed at 90 days post-surgery. RESULTS: Despite eating a HFD for 90 days post-surgery, the RYGB group lost weight (-20.7 ± 6%, P < 0.01) and improved insulin sensitivity (P < 0.05) compared to Sham. These results occurred with no change in food intake between groups. Hepatic steatosis and ER stress, specifically glucose-regulated protein-78 (Grp78, P < 0.001), X-box binding protein-1 (XBP-1) and spliced XBP-1 (P < 0.01), and fibroblast growth factor 21 (FGF21) gene expression, were normalized in the RYGB group compared to both Sham and Lean controls. Significant TUNEL staining in liver sections from the Obese Sham group, indicative of accelerated cell death, was absent in the RYGB and Lean control groups. Additionally, fasting plasma glucagon like peptide-1 was increased in RYGB compared to Sham (P < 0.02). CONCLUSION: These data suggest that in obese rats, RYGB surgery protects the liver against HFD-induced fatty liver disease by attenuating ER stress and excess apoptosis.

Exercise-induced lowering of chemerin is associated with reduced cardiometabolic risk and glucose-stimulated insulin secretion in older adults.

OBJECTIVE: To determine the effect of exercise on chemerin in relation to changes in fat loss, insulin action, and dyslipidemia in older adults. PARTICIPANTS: Thirty older (65.9±0.9yr) obese adults (BMI:34.5±0.7kg/m2). SETTING: Single-center, Cleveland Clinic. DESIGN: Prospective clinical trial. INTERVENTION: Twelve-weeks of exercise training (60minutes/day, 5day/week at ~85% HRmax). Subjects were instructed to maintain habitual nutrient intake. MEASUREMENTS: Plasma chemerin was analyzed using an enzyme-linked immunosorbent assay. Peripheral and hepatic insulin sensitivity was assessed using a euglycemic-hyperinsulinic clamp with glucose kinetics. First-phase and total glucose-stimulated insulin secretion (GSIS) was calculated from an oral glucose tolerance test. Fasting blood lipids (cholesterol, triglycerides), total/visceral fat (dual-x-ray absorptiometry and computerized tomography) and cardiorespiratory fitness (treadmill test) were also tested pre and post intervention. RESULTS: Exercise increased fitness and reduced total/visceral fat, blood lipids, and first-phase GSIS (P<0.05). Training also increased peripheral insulin sensitivity and lowered basal/insulin-related hepatic glucose production (P<0.01). The intervention reduced chemerin (87.1±6.0 vs. 78.1±5.8ng/ml; P=0.02), and the reduction correlated with decreased visceral fat (r=0.50, P=0.009), total body fat (r=0.42, P=0.02), cholesterol (r=0.38, P=0.04), triglycerides (r=0.36, P=0.05), and first-phase and total GSIS (r=0.39, P=0.03 and r=0.43, P=0.02, respectively). CONCLUSIONS: Lower chemerin appears to be an important hormone involved in cardiometabolic risk and GSIS reduction following exercise in older adults.