School of Medicine, University of Leeds, Leeds, UK.
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Nat Commun. 2021 Mar 26;12(1):1905. doi: 10.1038/s41467-021-22272-3.
Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.
棕色和米色脂肪组织正在成为独特的内分泌器官。这些组织与骨骼肌、脂肪组织代谢和全身能量消耗功能相关，提示存在器官间信号网络。通过代谢组学，我们鉴定出 3-甲基-2-氧代戊酸、5-氧脯氨酸和β-羟基异丁酸是在棕色脂肪细胞中合成并通过单羧酸转运蛋白分泌的小分子代谢物。3-甲基-2-氧代戊酸、5-氧脯氨酸和β-羟基异丁酸在体外和体内诱导白色脂肪细胞中棕色脂肪细胞特异性表型和骨骼肌细胞中线粒体氧化能量代谢。3-甲基-2-氧代戊酸和 5-氧脯氨酸通过 cAMP-PKA-p38 MAPK 信号转导，β-羟基异丁酸通过 mTOR 信号转导。在人类中，血浆和脂肪组织中的 3-甲基-2-氧代戊酸、5-氧脯氨酸和β-羟基异丁酸浓度与脂肪棕色化的标志物相关，与体重指数呈负相关。这些代谢物可减少肥胖小鼠模型的脂肪堆积、增加能量消耗，并改善葡萄糖和胰岛素稳态。我们的研究结果确定了米色脂肪-棕色脂肪-肌肉的生理代谢物相互作用。
