Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance.
Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance.
复制标题
DOI：
10.1016/j.molmet.2023.101703
复制
发表时间：
2023-05
影响因子：
8.1
通讯作者：
White, Morris F.
中科院分区：
文献类型：
--
作者：
Tao, Rongya;Stohr, Oliver;Wang, Caixia;Qiu, Wei;Copps, Kyle D.;White, Morris F.
体重变化和肥胖遵循与严格控制的EE（能量消耗）平衡的过量能量输入的方差。由于胰岛素抵抗可以减少能量储存，我们研究了肝脏胰岛素信号转导的遗传破坏是否会随着EE的增加而减少脂肪量。胰岛素信号转导被LDKO小鼠肝细胞中Irs 1（胰岛素受体底物1）和Irs 2的遗传失活破坏（Irs 1 L/L·Irs 2L/L·CreAlb），产生完全的肝脏胰岛素抵抗状态。我们通过将LDKO小鼠与FoxO 1 L/L或FstL/L小鼠杂交来灭活LDKO小鼠肝脏中的FoxO 1或FoxO 1调节的肝细胞因子Fst（Follistatin）。我们使用DEXA（双能X线吸收法）评估总瘦体重、脂肪量和脂肪百分比，并使用代谢笼测量EE（能量消耗）和估计基础代谢率（BMR）。采用高脂饮食诱导肥胖。Irs 1和Irs 2（LDKO小鼠）的肝脏破坏以FoxO 1依赖性方式减弱HFD（高脂饮食）诱导的肥胖并增加全身EE。肝脏破坏FoxO 1调节的肝细胞因子Fst使LDKO小鼠的EE正常化，并在HFD消耗期间恢复脂肪量;此外，肝脏Fst破坏单独增加脂肪量积累，而肝脏Fst过度表达减少HFD诱导的肥胖。在过度表达小鼠中过量的循环Fst中和了Mostatin（肌肉生长抑制素），激活了mTORC 1促进的骨骼肌营养摄取和EE途径。与Fst过表达类似，肌肉mTORC 1的直接激活也减少了脂肪量。因此，喂食HFD的LDKO小鼠中的完全肝脏胰岛素抵抗揭示了肝脏和肌肉之间的Fst介导的通信，这可能在普通肝脏胰岛素抵抗期间被忽视，作为增加肌肉EE和限制肥胖的机制。慢性肝脏胰岛素抵抗促进小鼠能量消耗。慢性肝脏胰岛素抵抗可预防高脂饮食引起的肥胖。肝脏FoxO 1或卵泡抑素的破坏降低了高代谢率，并恢复肝脏胰岛素抵抗期间的体重增加。肝脏卵泡抑素增加骨骼肌的能量消耗，减少胰岛素抵抗期间饮食诱导的肥胖。
Body weight change and obesity follow the variance of excess energy input balanced against tightly controlled EE (energy expenditure). Since insulin resistance can reduce energy storage, we investigated whether genetic disruption of hepatic insulin signaling reduced adipose mass with increased EE. Insulin signaling was disrupted by genetic inactivation of Irs1 (Insulin receptor substrate 1) and Irs2 in hepatocytes of LDKO mice (Irs1L/L·Irs2L/L·CreAlb), creating a state of complete hepatic insulin resistance. We inactivated FoxO1 or the FoxO1-regulated hepatokine Fst (Follistatin) in the liver of LDKO mice by intercrossing LDKO mice with FoxO1L/L or FstL/L mice. We used DEXA (dual-energy X-ray absorptiometry) to assess total lean mass, fat mass and fat percentage, and metabolic cages to measure EE (energy expenditure) and estimate basal metabolic rate (BMR). High-fat diet was used to induce obesity. Hepatic disruption of Irs1 and Irs2 (LDKO mice) attenuated HFD (high-fat diet)-induced obesity and increased whole-body EE in a FoxO1-dependent manner. Hepatic disruption of the FoxO1-regulated hepatokine Fst normalized EE in LDKO mice and restored adipose mass during HFD consumption; moreover, hepatic Fst disruption alone increased fat mass accumulation, whereas hepatic overexpression of Fst reduced HFD-induced obesity. Excess circulating Fst in overexpressing mice neutralized Mstn (Myostatin), activating mTORC1-promoted pathways of nutrient uptake and EE in skeletal muscle. Similar to Fst overexpression, direct activation of muscle mTORC1 also reduced adipose mass. Thus, complete hepatic insulin resistance in LDKO mice fed a HFD revealed Fst-mediated communication between the liver and muscle, which might go unnoticed during ordinary hepatic insulin resistance as a mechanism to increase muscle EE and constrain obesity. Chronic hepatic insulin resistance promotes energy expenditure in mice. Chronic hepatic insulin resistance prevents high-fat diet-induced obesity. Disruption of hepatic FoxO1 or Follistatin reduces the high metabolic rate and restores body weight gain during hepatic insulin resistance. Hepatic follistatin increases energy expenditure in skeletal muscle and reduces diet-induced obesity during insulin-resistance.
登录
查看更多内容
影响因子：
4.8
作者：
Davey, Jonathan R.;Estevez, Emma;Gregorevic, Paul
通讯作者：
Gregorevic, Paul
影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
10.9
作者：
Brown, Melissa L.;Schneyer, Alan L.
通讯作者：
Schneyer, Alan L.
影响因子：
5.3
作者：
DiPilato, Lisa M.;Ahmad, Faiyaz;Birnbaum, Morris J.
通讯作者：
Birnbaum, Morris J.
影响因子：
29
作者：
Hagiwara, Asami;Cornu, Marion;Hall, Michael N.
通讯作者：
Hall, Michael N.