Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice.
Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice.
复制标题
DOI：
10.1073/pnas.1717420115
复制
发表时间：
2018-02-06
影响因子：
11.1
通讯作者：
Hobbs HH
中科院分区：
文献类型：
--
作者：
Banfi S;Gusarova V;Gromada J;Cohen JC;Hobbs HH
白色脂肪组织(WAT)在禁食期间充当能量储存库，并在重新进食时从循环中的甘油三酯中补充脂肪酸。我们以前发现，餐后脂肪酸在氧化和储存组织之间的分配是由血管生成素样蛋白3(A3)和8(A8)介导的。在这里，我们发现，在小鼠中，Angptl3和Angptl8的破坏都会导致能量代谢的显著变化：脂肪质量减少，体温升高，代谢率增加，皮下水分变黄。A3−/−A8−/−小鼠的高代谢特征在喂养的动物中最为明显，并通过禁食和β3肾上腺素能受体阻断而减弱。这些数据表明，A3和A8促进了组织对能量的有效利用，并限制了与食物摄入相关的能量消耗的增加。膳食甘油三酯(TG)是最有效的能量底物。它的加工和储存成本比蛋白质或碳水化合物低得多。在喂养的动物中，循环中的TGS优先通过血管生成素样蛋白3(A3)和8(A8)储存到白色脂肪组织(WAT)。在这里，我们发现缺乏A3和A8的小鼠(A3−/−A8−/−小鼠)在进食(但不禁食)状态下脂肪质量减少，温度显著升高(+1°C)，食物摄入量或体力活动没有改变。这些动物的皮下水(WAT-SQ)具有浅褐色的形态和代谢变化。A3−/−A8−/−小鼠WAT-SQ的耗氧率(OCR)和参与脂肪酸合成和脂肪酸氧化的基因表达增加，但其附睾部或棕色脂肪组织(BAT)的耗氧率(OCR)和基因表达未见增加。通过将A3−/−A8−/−小鼠维持在体温中性或用β3肾上腺素能受体(AR)拮抗剂治疗，可以阻断对喂养的体温反应。为了确定交感神经刺激是否足以提高A3−/−A8−/−小鼠的体温，将WT和A3−/−A8−/−动物维持在中温状态，然后用β3-AR激动剂治疗；治疗导致A3−/−A8−/−小鼠体温升高，但不诱导WT小鼠体温升高。抗体介导的循环A3和A8失活导致WT小鼠体温升高。综上所述，这些数据表明，A3和A8对于食物TG的有效储存是必不可少的，这些基因的干扰增加了摄食诱导的产热和能量利用。
White adipose tissue (WAT) serves as an energy reservoir during fasting and is replenished with fatty acids from circulating triglycerides upon refeeding. We showed previously that postprandial partitioning of fatty acids between oxidative and storage tissues is mediated by angiopoietin-like proteins 3 (A3) and 8 (A8). Here, we show that disruption of both Angptl3 and Angptl8 in mice causes striking alterations in energy metabolism: reduced fat mass, hyperthermia, increased metabolic rate, and beiging of subcutaneous WAT. The hypermetabolic features of the A3−/−A8−/− mice were most pronounced in fed animals, and attenuated with fasting and β3-adrenergic receptor blockade. These data indicate that A3 and A8 promote efficient energy utilization by tissues and limit the increase in energy expenditure associated with food intake. Dietary triglyceride (TG) is the most efficient energy substrate. It is processed and stored at substantially lower metabolic cost than is protein or carbohydrate. In fed animals, circulating TGs are preferentially routed for storage to white adipose tissue (WAT) by angiopoietin-like proteins 3 (A3) and 8 (A8). Here, we show that mice lacking A3 and A8 (A3−/−A8−/− mice) have decreased fat mass and a striking increase in temperature (+1 °C) in the fed (but not fasted) state, without alterations in food intake or physical activity. Subcutaneous WAT (WAT-SQ) from these animals had morphologic and metabolic changes characteristic of beiging. O2 consumption rates (OCRs) and expression of genes involved in both fatty acid synthesis and fatty acid oxidation were increased in WAT-SQ of A3−/−A8−/− mice, but not in their epididymal or brown adipose tissue (BAT). The hyperthermic response to feeding was blocked by maintaining A3−/−A8−/− mice at thermoneutrality or by treating with a β3-adrenergic receptor (AR) antagonist. To determine if sympathetic stimulation was sufficient to increase body temperature in A3−/−A8−/− mice, WT and A3−/−A8−/− animals were maintained at thermoneutrality and then treated with a β3-AR agonist; treatment induced hyperthermia in A3−/−A8−/−, but not WT, mice. Antibody-mediated inactivation of both circulating A3 and A8 induced hyperthermia in WT mice. Together, these data indicate that A3 and A8 are essential for efficient storage of dietary TG and that disruption of these genes increases feeding-induced thermogenesis and energy utilization.
登录
查看更多内容
DOI：
10.1016/j.tem.2015.11.002
发表时间：
2016-01
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
--
作者：
Kruglikov IL;Scherer PE
通讯作者：
Scherer PE
影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
6.5
作者：
Gusarova, Viktoria;Alexa, Corey A.;Gromada, Jesper
通讯作者：
Gromada, Jesper
影响因子：
9.8
作者：
KUWAJIMA, M;FOSTER, DW;MCGARRY, JD
通讯作者：
MCGARRY, JD
DOI：
10.1073/pnas.1217552109
发表时间：
2012-11-27
影响因子：
11.1
作者：
Quagliarini, Fabiana;Wang, Yan;Hobbs, Helen H.
通讯作者：
Hobbs, Helen H.