Huang Hazel, Aminian Ali, Hassan Monique, Dan Olivia, Axelrod Christopher L, Schauer Philip R, Brethauer Stacy A, Kirwan John P
Department of Pathobiology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
Cleveland Clinic, Bariatric and Metabolic Institute, Cleveland, OH, USA.
Obes Surg. 2019 Jul;29(7):2158-2165. doi: 10.1007/s11695-019-03800-z.
Roux-en-Y gastric bypass (RYGB) is associated with remission of type 2 diabetes. However, the cellular and molecular mechanisms remain unknown. We hypothesized that RYGB would increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (SIRT1), AMPK/pAMPK, and citrate synthase (CS) protein expression and decrease insulin resistance and these changes would be mediated by sphingolipids, including ceramides and the sphingolipid metabolite sphingosine-1 phosphate (S1P).
Male ZDF rats were randomized to RYGB (n = 7) or sham surgery (n = 7) and harvested after 28 days. Total tissue ceramide, ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), and S1P were quantified in the white gastrocnemius muscle using LC-ESI-MS/MS after separation with HPLC. Total SIRT1, AMPK, PGC-1α, and CS protein expression were measured by Western blot.
Body weight, fasting glucose, insulin, and HOMA-IR decreased significantly after RYGB compared with sham control. These changes were paralleled by lower total ceramide (483.7 ± 32.3 vs. 280.1 ± 38.8 nmol/g wwt), C18:0 ceramide subspecies (P < 0.05), higher S1P (0.83 ± 0.05 vs. 1.54 ± 0.21 nmol/g wwt, P < 0.05), and a lower ceramide/S1P ratio (P < 0.05) in the RYGB versus sham group. AMPK, pAMPK, SIRT1, PGC-1α, and CS protein expression was also higher after RYGB (P < 0.05). The ceramide/S1P ratio correlated with weight loss (r = 0.48, P = 0.08), insulin resistance (r = 0.61, P = 0.02), PGC-1α (r = - 0.51, P < 0.06), CS (r = - 0.63, P = 0.01), and SIRT1 (r = - 0.54, P < 0.04).
Our data demonstrate that sphingolipid balance, and increased AMPK, SIRT1, PGC-1α, and CS protein expression are part of the mechanism that contributes to the remission of diabetes after RYGB surgery.
Roux-en-Y胃旁路术（RYGB）与2型糖尿病缓解相关。然而，其细胞和分子机制仍不清楚。我们推测RYGB会增加过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、沉默调节蛋白1（SIRT1）、AMPK/pAMPK和柠檬酸合酶（CS）的蛋白表达，并降低胰岛素抵抗，且这些变化将由鞘脂介导，包括神经酰胺和鞘脂代谢物鞘氨醇-1-磷酸（S1P）。
将雄性ZDF大鼠随机分为RYGB组（n = 7）或假手术组（n = 7），28天后处死取材。用HPLC分离后，采用LC-ESI-MS/MS对白色腓肠肌中的总组织神经酰胺、神经酰胺亚类（C14:0、C16:0、C18:0、C18:1、C20:0、C24:0和C24:1）以及S1P进行定量分析。通过蛋白质免疫印迹法检测总SIRT1、AMPK、PGC-1α和CS的蛋白表达。
与假手术对照组相比，RYGB术后体重、空腹血糖、胰岛素和HOMA-IR显著降低。这些变化伴随着RYGB组总神经酰胺含量降低（483.7±32.3对280.1±38.8 nmol/g湿重）、C18:0神经酰胺亚类减少（P<0.05）、S1P升高（0.83±0.05对1.54±0.21 nmol/g湿重，P<0.05）以及神经酰胺/S1P比值降低（P<0.05）。RYGB术后AMPK、pAMPK、SIRT1、PGC-1α和CS的蛋白表达也更高（P<0.05）。神经酰胺/S1P比值与体重减轻（r = 0.48，P = 0.08）、胰岛素抵抗（r = 0.61，P = 0.02）、PGC-1α（r = -0.51，P<0.06）、CS（r = -0.63，P = 0.01）和SIRT1（r = -0.54，P<0.04）相关。
我们的数据表明，鞘脂平衡以及AMPK、SIRT1、PGC-1α和CS蛋白表达增加是RYGB手术后糖尿病缓解机制的一部分。
