Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice.
Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice.
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DOI：
10.1038/srep26442
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发表时间：
2016-05-25
影响因子：
4.6
通讯作者：
Narkar VA
中科院分区：
文献类型：
--
作者：
Badin PM;Vila IK;Sopariwala DH;Yadav V;Lorca S;Louche K;Kim ER;Tong Q;Song MS;Moro C;Narkar VA
解剖运动模拟途径，可以复制肥胖和糖尿病运动的好处，可能会导致有希望的治疗代谢紊乱。肌肉雌激素相关受体γ（Muscle estrogen-related receptor gamma，ERRγ）是运动诱导的，当ERR γ在瘦小鼠骨骼肌中过表达时，通过刺激糖酵解-氧化肌纤维转换、线粒体生物合成和血管生成来模拟运动。本研究的目的是测试肥胖小鼠的肌肉ERRγ是否减轻体重增加和胰岛素抵抗。为此，ERRγ在肥胖和糖尿病db/db小鼠的骨骼肌中选择性过表达。在db/db小鼠中，肌肉ERRγ过表达成功地触发了糖酵解到氧化肌纤维的转换，增加了功能性线粒体含量并促进了血管供应。尽管有氧重塑，ERRγ令人惊讶地未能改善db/db小鼠的全身能量消耗，阻断甘油三酯、毒性二酰基甘油（DAG）和神经酰胺的肌肉积累或抑制肌肉PKCε肌膜易位。因此，在这些小鼠中，肌肉ERRγ没有减轻受损的肌肉胰岛素信号传导或胰岛素抵抗。总之，db/db小鼠中的肥胖和糖尿病不适合骨骼肌中经典运动样效应的选择性ERRγ定向编程。其他生化途径或运动的综合全身效应可能对抵抗糖尿病和肥胖至关重要。
Dissecting exercise-mimicking pathways that can replicate the benefits of exercise in obesity and diabetes may lead to promising treatments for metabolic disorders. Muscle estrogen-related receptor gamma (ERRγ) is induced by exercise, and when over-expressed in the skeletal muscle mimics exercise by stimulating glycolytic-to-oxidative myofiber switch, mitochondrial biogenesis and angiogenesis in lean mice. The objective of this study was to test whether muscle ERRγ in obese mice mitigates weight gain and insulin resistance. To do so, ERRγ was selectively over-expressed in the skeletal muscle of obese and diabetic db/db mice. Muscle ERRγ over-expression successfully triggered glycolytic-to-oxidative myofiber switch, increased functional mitochondrial content and boosted vascular supply in the db/db mice. Despite aerobic remodeling, ERRγ surprisingly failed to improve whole-body energy expenditure, block muscle accumulation of triglycerides, toxic diacylglycerols (DAG) and ceramides or suppress muscle PKCε sarcolemmal translocation in db/db mice. Consequently, muscle ERRγ did not mitigate impaired muscle insulin signaling or insulin resistance in these mice. In conclusion, obesity and diabetes in db/db mice are not amenable to selective ERRγ-directed programming of classic exercise-like effects in the skeletal muscle. Other biochemical pathways or integrated whole-body effects of exercise may be critical for resisting diabetes and obesity.