Matsakas Antonios, Prosdocimo Domenick A, Mitchell Robert, Collins-Hooper Henry, Giallourou Natasa, Swann Jonathan R, Potter Paul, Epting Thomas, Jain Mukesh K, Patel Ketan
Centre for Cardiovascular & Metabolic Research, Hull York Medical School, University of Hull, Hull, UK.
Case Cardiovascular Research Institute and Harrington Heart & Vascular Institute, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, USA.
Skelet Muscle. 2015 Dec 7;5:38. doi: 10.1186/s13395-015-0063-5. eCollection 2015.
Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet.
Pregnant as well as virgin myostatin null mice and age matched wild type animals were raised on a high fat diet for up to 10 weeks. The effect of the diet was tested on skeletal muscle, liver and fat. Quantitate PCR, Western blotting, immunohistochemistry, in-vivo and ex-vivo muscle characterisation, metabonomic and lipidomic measurements were from the four major cohorts.
We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization.
Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling.
肥胖成年人容易患代谢性疾病和心血管疾病。此外，超重的准妈妈会生出巨大儿，这些婴儿患代谢性疾病和心血管疾病的可能性也会增加。深入了解肥胖病理生理学的基础性进展对于开发抗肥胖疗法至关重要，这不仅关乎当代，也关乎后代。骨骼肌在脂肪代谢中起主要作用，许多研究致力于促进这种活动以控制肥胖的发展。研究评估了抑制肌肉生长抑制素作为预防肥胖发展的策略，并在某些情况下得出结论，它提供了一种针对高脂饮食的保护机制。
将怀孕及未孕的肌肉生长抑制素基因敲除小鼠和年龄匹配的野生型动物用高脂饮食饲养长达10周。测试该饮食对骨骼肌、肝脏和脂肪的影响。对四个主要队列进行定量PCR、蛋白质免疫印迹、免疫组织化学、体内和体外肌肉特征分析、代谢组学和脂质组学测量。
我们假设抑制肌肉生长抑制素不仅应保护母亲，还应保护其发育中的胎儿免受高脂饮食的有害影响。出乎意料的是，我们发现用高脂饮食饲养的肌肉生长抑制素基因敲除小鼠的胎儿肌肉发育减弱。因此，我们重新检查了高脂饮食对成年小鼠的影响，发现肌肉生长抑制素基因敲除小鼠通过涉及器官间脂肪利用受损的机制更容易患饮食诱导的肥胖。
肌肉生长抑制素的缺失改变了骨骼肌和肝脏中脂肪酸的摄取和氧化。我们表明，高脂饮食降低了肌肉生长抑制素基因敲除小鼠中异常高的脂肪代谢活性，导致脂肪过度沉积和脂毒性。总的来说，我们的基因功能丧失研究解释了许多缺乏肌肉生长抑制素信号的动物所表现出的瘦型表型。
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