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

本项目旨在了解整合应激反应（ISR）在棕色脂肪组织中的作用 (BAT)维持系统代谢平衡本文提出的研究有可能揭示一个 一种新的途径来放大BAT的产热激活并诱导BAT分泌组，这可能是 独立于β3-肾上腺素能激活，并可能用于对抗肥胖及其合并症。 BAT在通过适应性产热维持核心体温方面起着关键作用，并且可以影响 通过调节能量稳态的关键途径来控制肥胖。因此，旨在激活 BAT以及促进白色脂肪组织（WAT）的布朗宁，对于对抗肥胖可能是有吸引力的 以及相关疾病，如糖尿病和心血管疾病（CVD）。最近的研究表明 急性冷暴露后BAT中ISR被激活，这与诱导 未折叠蛋白反应（UPR）和已知对全身性免疫系统发挥保护作用的batokines的分泌 在一些实施方案中，所述细胞因子包括促细胞生长因子21（FGF 21）和促细胞生长因子15（GDF 15）。 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导， 线粒体蛋白视神经萎缩1（OPA 1）BAT特异性缺失小鼠的UPR和ISR。 有趣的是，这些小鼠的代谢适应性得到了改善，并且能够更好地适应寒冷。虽然 研究表明，BAT衍生的FGF 21在对寒冷的全身代谢适应中起着微不足道的作用 暴露，BAT衍生的GDF 15对适应性产热和全身代谢的贡献 体内平衡尚未完全理解。因此，我们假设冷暴露和线粒体 胁迫导致BAT中ISR及其主调节因子激活转录因子4（ATF 4）的诱导， 通过激活UPR激酶蛋白激酶R（PKR）样内质网激酶（PERK）， 诱导BAT分泌GDF 15，从而改善全身代谢稳态。广泛审查 在BAT中的ISR将阐明BAT的生理学和对压力的适应，并可能揭示新的 用于治疗肥胖症、糖尿病和CVD的治疗靶点。本提案的目标1将研究 在BAT中响应于冷和线粒体应激的ISR和ATF 4活化的PERK需求。目的 2将确定是否需要ATF 4，是否足以进行GDF 15诱导和适当的自适应 产热作用目的3将确定是否需要GDF 15介导全身代谢 BAT中冷暴露和线粒体应激后的适应，以及它是否介导其影响 通过其受体神经胶质源性神经营养因子受体α样（GFRAL）的中枢激活。 新型遗传小鼠模型的建立将揭示ISR激活的分子机制 以及ATF 4和GDF 15在BAT中的生理作用，这可能为新的治疗策略提供信息， 与肥胖症及其并发症作斗争。

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.