The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations

该项目试图了解综合应激反应(ISR)在棕色脂肪组织中的作用 (BAT)用于全身代谢动态平衡。这里提出的研究有可能揭示一种 放大蝙蝠产热激活和诱导蝙蝠分泌体的新途径，可能是 不依赖于β3-肾上腺素能激活，可能被用来对抗肥胖症及其共病。 BAT在通过适应性产热来维持核心体温方面起着关键作用，并且可以影响 调节能量动态平衡的关键途径引起的肥胖。因此，旨在激活 BAT，以及促进白色脂肪组织的褐化(WAT)，可能在对抗肥胖方面具有吸引力 以及相关疾病，如糖尿病和心血管疾病(CVD)。最近的研究表明 BAT对急性寒冷暴露的ISR被激活，这与诱导 未折叠蛋白反应(UPR)和巴托酮的分泌对全身系统具有保护作用 代谢，如成纤维细胞生长因子21(FGF21)和生长分化因子15(GDF15)。 我们已经生成了初步数据，证实了这些发现。此外，我们观察到类似的诱因 BAT特异性线粒体蛋白视神经萎缩1(OPA1)缺失小鼠的UPR和ISR。 有趣的是，这些小鼠的新陈代谢能力得到了改善，对寒冷的适应能力也更强。虽然 研究表明，蝙蝠来源的FGF21在全身对寒冷的代谢适应中起着微不足道的作用 暴露，BAT来源的GDF15对适应性产热和系统代谢的贡献 对动态平衡的理解还不完全。因此，我们假设寒冷暴露和线粒体 胁迫诱导了ISR及其主调控因子激活转录因子4(ATF4)在BAT中的表达， 通过激活UPR激酶蛋白激酶R(PKR)样的内质网激酶(PERK)来 诱导BAT分泌GDF15，从而改善全身代谢动态平衡。广泛的考试 对蝙蝠体内ISR的研究将有助于揭示蝙蝠的生理和对压力的适应，并可能发现新的 肥胖症、糖尿病和心血管疾病的治疗目标。该提案的目标1将调查 冷胁迫和线粒体胁迫下蝙蝠对ISR和ATF4激活的PERK需求。目标 2将确定ATF4对于GDF15的诱导和适当的适应是否必要和足够 生热作用。目标3将确定是否需要GDF15来调节系统代谢 蝙蝠在冷暴露和线粒体应激后的适应及其是否介导其影响 通过中枢激活其受体胶质源性神经营养因子受体阿尔法样(GFERL)。 新型遗传小鼠模型的建立将揭示ISR激活的分子机制 以及ATF4和GDF15在BAT中的生理作用，这可能为新的治疗策略提供参考。 与肥胖症及其共病作斗争。

This project seeks to understand the role of the integrated stress response (ISR) in brown adipose tissue (BAT) for systemic metabolic homeostasis. The studies proposed herein have the potential of uncovering a novel pathway to amplify thermogenic activation of BAT and to induce the BAT secretome, that might be independent of β3-adrenergic activation, and might be leveraged to combat obesity and its comorbidities. BAT plays a critical role in maintaining core body temperature through adaptive thermogenesis, and can affect adiposity by regulating key pathways in energy homeostasis. Accordingly, strategies designed to activate BAT, as well as to promote browning of white adipose tissue (WAT), could be attractive for combating obesity and associated diseases, such as diabetes and cardiovascular disease (CVD). Recent studies demonstrated that the ISR is activated in BAT in response to acute cold exposure, which correlated with induction of the unfolded protein response (UPR) and secretion of batokines known to exert protective effects on systemic metabolism, such as fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15). We have generated preliminary data confirming these findings. In addition, we observed similar inductions of the UPR and the ISR in mice with BAT-specific deletion of the mitochondrial protein Optic atrophy 1 (OPA1). Interestingly, these mice had improved metabolic fitness and were better able to adapt to cold. Although studies suggest that BAT-derived FGF21 plays a negligible role on the systemic metabolic adaptations to cold exposure, the contribution of BAT-derived GDF15 on adaptive thermogenesis and on systemic metabolic homeostasis is incompletely understood. Therefore, we hypothesized that cold exposure and mitochondrial stress lead to the induction of the ISR and its master regulator activating transcription factor 4 (ATF4) in BAT, via the activation of the UPR kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) to induce BAT secretion of GDF15, thereby improving systemic metabolic homeostasis. Extensive examination of the ISR in BAT will shed light on BAT physiology and adaptation to stress and may uncover novel therapeutic targets for the treatment of obesity, diabetes and CVD. Aim 1 of this proposal will investigate the requirement of PERK for ISR and ATF4 activation in BAT in response to cold and mitochondrial stress. Aim 2 will determine whether ATF4 is required and sufficient for GDF15 induction and for proper adaptive thermogenesis. Aim 3 will determine whether GDF15 is required to mediate the systemic metabolic adaptations following cold exposure and mitochondrial stress in BAT, and whether it mediates its effects through central activation of its receptor glial-derived neurotrophic factor receptor alpha-like (GFRAL). Generation of novel genetic mouse models will reveal the molecular mechanisms underlying ISR activation and the physiological roles of ATF4 and GDF15 in BAT, which may inform novel therapeutic strategies to combat obesity and its comorbidities.