Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
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DOI：
10.1016/j.molmet.2016.09.009
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发表时间：
2016-12
影响因子：
8.1
通讯作者：
Czech MP
中科院分区：
文献类型：
--
作者：
DiStefano MT;Roth Flach RJ;Senol-Cosar O;Danai LV;Virbasius JV;Nicoloro SM;Straubhaar J;Dagdeviren S;Wabitsch M;Gupta OT;Kim JK;Czech MP
脂肪组织依赖于脂滴（LD）蛋白作为控制全身代谢的脂质储存内分泌器官。缺氧诱导基因2（Hypoxia-inducible Gene 2，Hig 2）是近年来发现的一种肝细胞内的LD相关蛋白，可促进肝脏脂质的储存，但其在脂肪细胞中的作用尚不清楚。在这里，我们测试了Hig 2定位于脂肪细胞中的LD促进脂肪组织脂质沉积和全身葡萄糖稳态的假设。制备白色和棕色脂肪细胞缺陷（Hig 2 fl/fl × Adiponectin cre+）和选择性棕色/米色脂肪细胞缺陷（Hig 2 fl/fl × Ucp 1 cre+）小鼠以研究Hig 2在脂肪库中的作用。此外，我们使用多种饲养温度来研究活性棕色/米色脂肪细胞在这一过程中的作用。Hig 2定位于人脂肪细胞株SGBS细胞中的LD。所有脂肪库中脂肪细胞特异性Hig 2缺乏的小鼠表现出内脏脂肪组织重量减少和葡萄糖耐量增加。由于Hig 2fl/fl × Ucp 1 cre+小鼠表现出相同的表型，因此这种代谢效应可能归因于棕色/米色脂肪细胞特异性Hig 2缺陷。此外，当脂肪细胞缺陷型Hig 2小鼠被转移到非颤抖性产热失活的热中性条件下时，这些改善被废除，葡萄糖耐受不良随之发生。脂肪细胞特异性Hig 2缺陷动物显示脂肪细胞脂解或能量消耗没有可检测的变化，这表明Hig 2可能不会通过抑制脂肪细胞中的脂解来介导这些代谢作用。我们得出结论，Hig 2定位于脂肪细胞中的LD，促进脂肪组织脂质沉积，并且其在活性棕色/米色脂肪组织中的选择性缺陷介导23 °C下葡萄糖耐量的改善。在能量消耗、脂肪量或肝脏甘油三酯中没有可检测到的变化的情况下，在热中性下对这种表型的抑制表明Hig 2缺乏引发了从棕色/米色脂肪细胞发出的有害内分泌或神经内分泌途径。Hig 2定位于脂肪细胞中的脂滴并促进脂肪组织脂质沉积。其在活性棕色/米色脂肪组织中的选择性缺乏介导23 °C下葡萄糖耐量的改善。代谢的改善与脂解的变化无关。
Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells. Hig2 localizes to lipid droplets in adipocytes and promotes adipose tissue lipid deposition. Its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Metabolic improvements are independent of changes in lipolysis.
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影响因子：
3.8
作者：
Kenny PA;Enver T;Ashworth A
通讯作者：
Ashworth A
DOI：
10.1073/pnas.90.24.12035
发表时间：
1993-12-15
影响因子：
11.1
作者：
GREENBERG, AS;EGAN, JJ;KIMMEL, AR
通讯作者：
KIMMEL, AR
影响因子：
4.8
作者：
DiStefano, Marina T.;Danai, Laura V.;Czech, Michael P.
通讯作者：
Czech, Michael P.
影响因子：
4.8
作者：
Brasaemle, DL;Rubin, B;Londos, C
通讯作者：
Londos, C
DOI：
10.1016/j.bbadis.2013.05.007
发表时间：
2014-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Konige M;Wang H;Sztalryd C
通讯作者：
Sztalryd C