Gastaldi G, Russell A, Golay A, Giacobino J-P, Habicht F, Barthassat V, Muzzin P, Bobbioni-Harsch E
Service of Therapeutic Education for Chronic Diseases, Geneva University Hospital, 24, Rue Micheli du Crest, 1211 Geneva, Switzerland.
Diabetologia. 2007 Nov;50(11):2348-55. doi: 10.1007/s00125-007-0782-1. Epub 2007 Sep 8.
AIMS/HYPOTHESIS: We investigated whether skeletal muscle peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1A; also known as PPARGC1A) and its target mitofusin-2 (MFN2), as well as carnitine palmitoyltransferase-1 (CPT1; also known as carnitine palmitoyltransferase 1A [liver] [CPT1A]) and uncoupling protein (UCP)3, are involved in the improvement of insulin resistance and/or in the modification of energy expenditure during surgically induced massive weight loss.
Seventeen morbidly obese women (mean BMI: 45.9 +/- 4 kg/m(2)) were investigated before, and 3 and 12 months after, Roux-en-Y gastric bypass (RYGB). We evaluated insulin sensitivity by the euglycaemic-hyperinsulinaemic clamp, energy expenditure and substrate oxidation by indirect calorimetry, and muscle mRNA expression by PCR.
Post-operatively, PGC1A was enhanced at 3 (p = 0.02) and 12 months (p = 0.03) as was MFN2 (p = 0.008 and p = 0.03 at 3 and 12 months respectively), whereas UCP3 was reduced (p = 0.03) at 12 months. CPT1 did not change. The expression of PGC1A and MFN2 were strongly (p < 0.0001) related. Insulin sensitivity, which increased after surgery (p = 0.002 at 3, p = 0.003 at 12 months), was significantly related to PGC1A and MFN2, but only MFN2 showed an independent influence in a multiple regression analysis. Energy expenditure was reduced at 3 months post-operatively (p = 0.001 vs before RYGB), remaining unchanged thereafter until 12 months. CPT1 and UCP3 were not significantly related to the modifications of energy expenditure or of lipid oxidation rate.
CONCLUSIONS/INTERPRETATION: Weight loss upregulates PGC1A, which in turn stimulates MFN2 expression. MFN2 expression significantly and independently contributes to the improvement of insulin sensitivity. UCP3 and CPT1 do not seem to influence energy expenditure after RYGB.
目的/假设：我们研究了骨骼肌过氧化物酶体增殖物激活受体γ共激活因子-1（PGC1A；也称为PPARGC1A）及其靶标线粒体融合蛋白2（MFN2），以及肉碱棕榈酰转移酶-1（CPT1；也称为肉碱棕榈酰转移酶1A[肝脏][CPT1A]）和解偶联蛋白（UCP）3是否参与手术诱导的大量体重减轻过程中胰岛素抵抗的改善和/或能量消耗的改变。
对17名病态肥胖女性（平均BMI：45.9±4kg/m²）在Roux-en-Y胃旁路术（RYGB）前、术后3个月和12个月进行研究。我们通过正常血糖高胰岛素钳夹评估胰岛素敏感性，通过间接量热法评估能量消耗和底物氧化，并通过PCR评估肌肉mRNA表达。
术后，PGC1A在3个月（p = 0.02）和12个月（p = 0.03）时增强，MFN2也是如此（3个月和12个月时分别为p = 0.008和p = 0.03），而UCP3在12个月时降低（p = 0.03）。CPT1没有变化。PGC1A和MFN2的表达密切相关（p < 0.0001）。胰岛素敏感性在术后增加（3个月时p = 0.002，12个月时p = 0.003），与PGC1A和MFN2显著相关，但在多元回归分析中只有MFN2显示出独立影响。术后3个月能量消耗降低（与RYGB术前相比p = 0.001），此后至12个月保持不变。CPT1和UCP3与能量消耗或脂质氧化率的改变无显著相关。
结论/解读：体重减轻上调PGC1A，进而刺激MFN2表达。MFN2表达对胰岛素敏感性的改善有显著且独立的作用。UCP3和CPT1似乎不影响RYGB术后的能量消耗。
