GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
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DOI：
10.7554/elife.86452
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发表时间：
2023-10-11
期刊：
影响因子：
7.7
通讯作者：
Pereira RO
中科院分区：
文献类型：
--
作者：
Jena J;García-Peña LM;Weatherford ET;Marti A;Bjorkman SH;Kato K;Koneru J;Chen JH;Seeley RJ;Abel ED;Pereira RO
我们之前报道过，棕色脂肪组织（BAT）中缺乏蛋白optic atrophy 1 （OPA1 BKO）的小鼠显示出激活转录因子4 （ATF4）的诱导，ATF4促进成纤维细胞生长因子21 （FGF21）作为一种细胞因子的分泌。FGF21增加了基线条件下的代谢率，但对于在OPA1 BKO小鼠中报道的饮食诱导肥胖（DIO）的抵抗是必不可少的（Pereira et al., 2021）。为了确定这种表型的替代介质，我们进行了转录组分析，结果显示BAT中生长分化因子15 （GDF15）水平升高，蛋白激酶R （PKR）样内质网激酶（PERK）水平升高。为了研究PERK是否介导ATF4诱导，并评估GDF15对DIO抗性的贡献，我们在OPA1 BKO小鼠中选择性地删除了PERK或GDF15。BAT中OPA1和PERK水平降低的小鼠保留了ISR激活。重要的是，同时删除OPA1和GDF15部分逆转了对DIO的抗性，并取消了葡萄糖耐量的改善。此外，需要GDF15来改善OPA1 BKO小鼠的冷诱导产热。综上所述，我们的数据表明，PERK对于诱导ISR是必不可少的，但GDF15有助于抵抗DIO，并且通过增加能量消耗来维持OPA1 BKO小鼠的葡萄糖稳态和体温调节。
We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.
影响因子：
8.2
作者：
Kirschner KM;Foryst-Ludwig A;Gohlke S;Li C;Flores RE;Kintscher U;Schupp M;Schulz TJ;Scholz H
通讯作者：
Scholz H
影响因子：
4.6
作者：
Kim JM;Kosak JP;Kim JK;Kissling G;Germolec DR;Zeldin DC;Bradbury JA;Baek SJ;Eling TE
通讯作者：
Eling TE