Asparagine reinforces mTORC1 signaling to boost thermogenesis and glycolysis in adipose tissues. (27th October 2021) - Xu, Yingjiang
Abstract: Brown and beige fat are specialized for energy expenditure by dissipating energy from glucose and fatty acid oxidation as heat. While glucose and fatty acid metabolism have been extensively studied in thermogenic adipose tissues, the involvement of amino acids in regulating adaptive thermogenesis remains little studied. Here, we report that asparagine supplementation in brown and beige adipocytes drastically upregulated the thermogenic transcriptional program and lipogenic gene expression, so that asparagine‐fed mice showed better cold tolerance. In mice with diet‐induced obesity, the asparagine‐fed group was more responsive to β3‐adrenergic receptor agonists, manifesting in blunted body weight gain and improved glucose tolerance. Metabolomics and 13 C‐glucose flux analysis revealed that asparagine supplement spurred glycolysis to fuel thermogenesis and lipogenesis in adipocytes. Mechanistically, asparagine stimulated the mTORC1 pathway, which promoted expression of thermogenic genes and key enzymes in glycolysis. These findings show that asparagine bioavailability affects glycolytic and thermogenic activities in adipose tissues, providing a possible nutritional strategy for improving systemic energy homeostasis. SYNOPSIS: While lipid and glucose are known substrates for brown fat thermogenesis, the role of amino acids in adaptive energy expenditure remains unclear. Here, bioavailability of asparagine is shown to profoundly impact on thermogenic activity and metabolism of adipocytes. Asparagine supplementation increases thermogenesis, glucose influx, and lipogenesis in adipocytes. Asparagine feeding enhances sensitivity of obese mice to β3‐adrenergic receptor agonists in vivo . An asparagine‐mTORC1 axis promotes thermogenesis and glycolysis via transcriptional and post‐transcriptional mechanisms. Abstract : Adipocyte energy dissipation is fueled by the non‐essential amino acid asparagine via an mTORC1‐4E‐BP1‐glycolysis axis.