Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI139496.
Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abnormal lipid deposition (e.g., nonalcoholic fatty liver disease in myopathies), our understanding of skeletal muscle regulation of systemic lipid homeostasis is not well understood. Here we show that skeletal muscle Krüppel-like factor 15 (KLF15) coordinates pathways central to systemic lipid homeostasis under basal conditions and in response to nutrient overload. Mice with skeletal muscle-specific KLF15 deletion demonstrated (a) reduced expression of key targets involved in lipid uptake, mitochondrial transport, and utilization, (b) elevated circulating lipids, (c) insulin resistance/glucose intolerance, and (d) increased lipid deposition in white adipose tissue and liver. Strikingly, a diet rich in short-chain fatty acids bypassed these defects in lipid flux and ameliorated aspects of metabolic dysregulation. Together, these findings establish skeletal muscle control of lipid flux as critical to systemic lipid homeostasis and metabolic health.
骨骼肌是决定全身代谢稳态的主要因素，在葡萄糖代谢和胰岛素敏感性方面发挥着关键作用。相比之下，尽管骨骼肌是脂肪酸的主要使用者，并且有证据表明肌肉疾病会导致异常脂质沉积（例如，肌病中的非酒精性脂肪肝），但我们对骨骼肌调节全身脂质稳态的理解还不够充分。在这里，我们表明，骨骼肌 Kruppel 样因子 15（KLF15）在基础条件下和营养超负荷时协调了与全身脂质稳态相关的途径。骨骼肌特异性 KLF15 缺失的小鼠表现出（a）参与脂质摄取、线粒体转运和利用的关键靶基因的表达降低，（b）循环脂质升高，（c）胰岛素抵抗/葡萄糖不耐受，以及（d）白色脂肪组织和肝脏中脂质沉积增加。引人注目的是，富含短链脂肪酸的饮食可以绕过这些脂质通量缺陷，并改善代谢失调的某些方面。总之，这些发现确立了骨骼肌对脂质通量的控制对全身脂质稳态和代谢健康至关重要。
