Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn’t fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis. BA-specific Lrpprc knockout mice are cold resistant in a 4°C cold-tolerance test in the presence of food, which is accompanied by the activation of transcription factor 4 (ATF4) and proteome turnover in BAs. ATF4 activation genetically by BA-specific ATF4 overexpression or physiologically by a low-protein diet feeding can improve cold tolerance in wild-type and Ucp1 knockout mice. Furthermore, ATF4 activation in BAs improves systemic metabolism in obesogenic environment regardless of Ucp1’s action. Therefore, our study reveals a diet-dependent but Ucp1-independent thermogenic mechanism in BAs that is relevant to systemic thermoregulation and energy homeostasis.

吸热体中冷诱导的产热需要由线粒体呼吸和 Ucp1 介导的多房棕色脂肪细胞 (BAs) 中的解偶联促进的适应性产热。然而，BAs 中产热的饮食调节尚不完全清楚。在这里，我们描述了 BAs 中富含亮氨酸的五肽重复序列蛋白 (Lrpprc) 的缺乏会降低 mtDNA 编码的 ETC 基因表达，导致 ETC 蛋白质组失衡，并消除线粒体驱动的产热。BA 特异性 Lrpprc 敲除小鼠在 4°C 耐寒试验中在食物存在下具有耐寒性，这伴随着转录因子 4 (ATF4) 的激活和 BA 中的蛋白质组更新。通过 BA 特异性 ATF4 过表达或通过低蛋白饮食喂养在生理上激活 ATF4 可以提高野生型和 Ucp1 敲除小鼠的耐寒性。此外，无论 Ucp1 的作用如何，BAs 中的 ATF4 激活都能改善肥胖环境中的全身代谢。因此，我们的研究揭示了 BAs 中一种依赖于饮食但不依赖于 Ucp1 的产热机制，该机制与全身体温调节和能量稳态相关。