Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Integrative Biology and Physiology and Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
Nature. 2023 Aug;620(7972):192-199. doi: 10.1038/s41586-023-06361-5. Epub 2023 Jul 26.
Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1). The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.
在寒冷暴露期间，交感神经激活通过表达线粒体蛋白解偶联蛋白 1（UCP1）增加脂肪细胞的产热。脂肪细胞表达 UCP1 的倾向受到脂肪微环境的关键影响，并且在性别之间和各种脂肪储存库之间存在差异。在这里，我们报告脂肪基质中的乳腺导管上皮细胞调节雌性小鼠皮下白色脂肪组织（scWAT）中冷诱导的脂肪细胞 UCP1 表达。单细胞 RNA 测序表明，腺腔上皮细胞亚型表达编码在冷条件下控制脂肪细胞 UCP1 表达的分泌因子的转录本。我们将这些腔上皮细胞分泌因子称为“乳腺素”。通过对全组织免疫荧光的 3D 可视化，我们揭示了交感神经-导管接触点。我们表明，通过乳腺素脂联素 2，受交感神经激活的乳腺导管限制脂肪细胞 UCP1 的表达。体内和体外乳腺导管上皮细胞的消融增强了 scWAT 中冷诱导的脂肪细胞产热基因程序。由于乳腺导管网络在雌性小鼠的大部分 scWAT 中延伸，与雄性小鼠相比，雌性小鼠的 scWAT UCP1 表达、脂肪氧化、能量消耗和皮下脂肪量损失明显减少，这表明乳腺素在脂肪产热中的性别特异性作用。这些结果揭示了交感神经激活的腺上皮在脂肪细胞 UCP1 表达中的作用，并表明乳腺导管腔上皮在控制腺脂肪方面具有重要作用。
