Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, University of Strasbourg, Strasbourg, France.
FASEB J. 2012 Aug;26(8):3321-35. doi: 10.1096/fj.12-208751. Epub 2012 May 4.
Mutations of clock genes can lead to diabetes and obesity. REV-ERBα, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV-ERBα in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow-fed, unfed, or high-fat-fed Rev-erbα(-/-) mice and their wild-type littermates. Chow-fed Rev-erbα(-/-) mice displayed increased adiposity (2.5-fold) and mild hyperglycemia (∼10%) without insulin resistance. Indirect calorimetry indicates that chow-fed Rev-erbα(-/-) mice utilize more fatty acids during daytime. A 24-h nonfeeding period in Rev-erbα(-/-) animals favors further fatty acid mobilization at the expense of glycogen utilization and gluconeogenesis, without triggering hypoglycemia and hypothermia. High-fat feeding in Rev-erbα(-/-) mice amplified metabolic disturbances, including expression of lipogenic factors. Lipoprotein lipase (Lpl) gene, critical in lipid utilization/storage, is triggered in liver at night and constitutively up-regulated (∼2-fold) in muscle and adipose tissue of Rev-erbα(-/-) mice. We show that CLOCK, up-regulated (2-fold) at night in Rev-erbα(-/-) mice, can transactivate Lpl. Thus, overexpression of Lpl facilitates muscle fatty acid utilization and contributes to fat overload. This study demonstrates the importance of clock-driven Lpl expression in energy balance and highlights circadian disruption as a potential cause for the metabolic syndrome.
时钟基因的突变可导致糖尿病和肥胖。参与生物钟的核受体 REV-ERBα 已被证明可以控制脂质代谢。为了深入了解 REV-ERBα 在体内能量平衡中的作用，我们研究了正常饮食、禁食或高脂肪饮食喂养的 Rev-erbα(-/-) 小鼠及其野生型同窝仔鼠的碳水化合物和脂质的日常代谢。正常饮食喂养的 Rev-erbα(-/-) 小鼠表现出肥胖（增加 2.5 倍）和轻度高血糖（约 10%）而没有胰岛素抵抗。间接测热法表明，正常饮食喂养的 Rev-erbα(-/-) 小鼠在白天更多地利用脂肪酸。Rev-erbα(-/-) 动物 24 小时禁食期进一步促进了脂肪酸动员，而牺牲了糖原利用和糖异生，没有引发低血糖和低体温。高脂肪饮食喂养在 Rev-erbα(-/-) 小鼠中放大了代谢紊乱，包括脂生成因子的表达。脂蛋白脂肪酶（LPL）基因在脂质利用/储存中起关键作用，在 Rev-erbα(-/-) 小鼠的肝脏中在夜间被触发，并且在肌肉和脂肪组织中持续上调（约 2 倍）。我们表明，在 Rev-erbα(-/-) 小鼠中，夜间上调（2 倍）的 CLOCK 可以反式激活 Lpl。因此，Lpl 的过表达促进了肌肉脂肪酸的利用，并导致脂肪过载。这项研究表明了时钟驱动的 LPL 表达在能量平衡中的重要性，并强调了昼夜节律紊乱可能是代谢综合征的潜在原因。
