Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Department of Molecular Cellular Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
Nat Commun. 2014 Sep 26;5:4934. doi: 10.1038/ncomms5934.
Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7(+/-) mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7(+/-)-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7(+/-)-ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7(+/-)-ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.
尽管人们对自噬与全身代谢之间的关系越来越感兴趣，但自噬的全局变化如何影响代谢仍不清楚。在这里，我们发现，与 ob/ob 小鼠杂交时，必需自噬基因（Atg7(+/-) 小鼠）全局单倍不足的小鼠不会出现代谢异常，但会发展为糖尿病。Atg7(+/-)-ob/ob 小鼠表现出加重的胰岛素抵抗，脂质含量增加和炎症变化，表明自噬单倍不足会损害对代谢应激的适应性反应。我们进一步证明，由于自噬不足，脂质负荷后细胞内脂质含量和胰岛素抵抗增加，并为 Atg7(+/-)-ob/ob 小鼠中炎症小体激活增加提供了证据。伊马替尼或海藻糖可改善 Atg7(+/-)-ob/ob 小鼠的代谢参数，并增强自噬流。这些结果表明，全身自噬不足可能是肥胖发展为糖尿病的一个因素，自噬调节剂具有针对肥胖和炎症相关糖尿病的治疗潜力。
