Dietary fat overload reprograms brown fat mitochondria.
Dietary fat overload reprograms brown fat mitochondria.
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DOI：
10.3389/fphys.2015.00272
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发表时间：
2015
影响因子：
4
通讯作者：
Aquilano K
中科院分区：
文献类型：
--
作者：
Lettieri Barbato D;Tatulli G;Vegliante R;Cannata SM;Bernardini S;Ciriolo MR;Aquilano K
慢性营养过载会加速几种与衰老有关的疾病的发病，降低预期寿命。虽然营养过剩影响许多组织代谢过程的机制已为人所知，但其在蝙蝠生理中的作用仍不清楚。在此，我们研究了不同生命阶段高脂饮食(HFD)对雌性小鼠BAT线粒体反应的影响。尽管成年小鼠的线粒体数量没有变化，但呼吸和OXPHOS亚基都受到了强烈的影响。不同的是，怀孕和哺乳期间暴露于HFD的后代幼崽显示出线粒体质量减少但氧化效率高，但这导致蝙蝠的生物能量学状态增加，而不是增强解偶联呼吸。有趣的是，HFD引发的代谢反应伴随着线粒体动力学的变化，其特征是母鼠和子代幼鼠的片段标记Drp1含量降低。HFD诱导的FoxO1转录因子失活似乎是棕色脂肪细胞中DRp1水平的上游调节器。此外，用正常饲料断奶的HFD仔鼠只能部分恢复HFD引起的线粒体功能障碍。最后，这些小鼠在冷暴露时未能激活产热程序。总而言之，我们的发现表明，母体膳食脂肪超载不可逆转地使蝙蝠对寒冷的温度等生理刺激没有反应，这种早期生命阶段的功能障碍可能会对健康和寿命产生负面调节。
Chronic nutrient overload accelerates the onset of several aging-related diseases reducing life expectancy. Although the mechanisms by which overnutrition affects metabolic processes in many tissues are known, its role on BAT physiology is still unclear. Herein, we investigated the mitochondrial responses in BAT of female mice exposed to high fat diet (HFD) at different steps of life. Although adult mice showed an unchanged mitochondrial amount, both respiration and OxPHOS subunits were strongly affected. Differently, offspring pups exposed to HFD during pregnancy and lactation displayed reduced mitochondrial mass but high oxidative efficiency that, however, resulted in increased bioenergetics state of BAT rather than augmented uncoupling respiration. Interestingly, the metabolic responses triggered by HFD were accompanied by changes in mitochondrial dynamics characterized by decreased content of the fragmentation marker Drp1 both in mothers and offspring pups. HFD-induced inactivation of the FoxO1 transcription factor seemed to be the up-stream modulator of Drp1 levels in brown fat cells. Furthermore, HFD offspring pups weaned with normal diet only partially reverted the mitochondrial dysfunctions caused by HFD. Finally these mice failed in activating the thermogenic program upon cold exposure. Collectively our findings suggest that maternal dietary fat overload irreversibly commits BAT unresponsiveness to physiological stimuli such as cool temperature and this dysfunction in the early stage of life might negatively modulate health and lifespan.