Asparagine reinforces mTORC1 signaling to boost thermogenesis and glycolysis in adipose tissues

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 b3-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.

Identifying targetable metabolic dependencies across colorectal cancer progression

“…At the time of writing, we found one other study -by Xu et al . - reporting that ASNS/ASN manipulation affects glycolysis in the context of thermogenesis in brown adipose tissue in mice (52). We also show that ASNS suppression reduces glutamine-derived carbon flux into the TCA cycle.…”

A unique profile of gut microbiota associated with metabolic syndrome: a remote island most afflicted by obesity in Japan

“…On the other hand, we found that level of serum asparagine was signi cantly reduced in OB in comparison to NO. In fact, serum levels of asparagine has been shown to increase after weight loss in humans 38 as well as to associate with adaptive thermogenesis via mTORC1 signaling in mice 39 . Therefore, elevation in serum level of asparagine would facilitate heat production, thereby contributing to maintenance of body shape (Fig.…”

mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells

“…Second, it is unknown whether amino acid sensing is tissue-specific, whether mTORC1 senses all amino acids, or if there are mTORC1 independent pathways. For example, a recent study showed that asparagine might affect glycolysis in brown adipose tissue via mTORC1 activation [ 13 ]. In this study, we conducted a multigroup comparison followed by a post-hoc secondary analysis to determine the differential effects of different treatment group modalities that altered amino acid metabolism.…”

“…However, aspartate, asparagine, and glycine amino acid sensors have not been identified. Recently, Xu et al suggested that asparagine may stimulate mTORC1 in brown adipose tissue [ 13 ]. Therefore, we applied the non-targeted metabolomics approach as a readout of the internal exposome and measured the levels of amino acids to gain insight into systems biology and mTORC1/mTORC2 mediated metabolic pathways enrichment.…”