mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

Abstract

In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold.

Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

“…7). We did not investigate the effect of rapamycin treatment on DNL during acute and chronic cold exposure because mTORC1 presents pleotropic effects, including mitochondrial biogenesis, oxidative metabolism, TCA, and nucleotide synthesis (33).…”

Adipocyte-specific DKO of Lkb1 and mTOR protects mice against HFD-induced obesity, but results in insulin resistance

“…Differently, DKO mice had reduction of BAT and iWAT mass and low levels of UCP1 and mitochondria-related proteins. Likewise, loss of Raptor in all mature adipocytes affects BAT expansion and adaptation to cold (25). Without functional mTORC1, Ucp1 expression in WAT cannot be induced by cold or AR3 agonists (34,35).…”

“…Adipocyte-specific KO of mTORC1 causes lipodystrophy, insulin resistance, and severe hepatic steatosis, but enhances energy expenditure and counteracts high-fat diet (HFD)-induced obesity (22)(23)(24). In BAT, loss of mTORC1 affects the BAT cold-adaptation and reduces BAT mass and lipid content (23,25), while activation of mTORC1 in WAT elevates Ucp1, PPAR coactivator 1 (Pgc1), and Ppar expression (26), suggesting a positive role of mTORC1 in regulating brown and beige adipogenesis. Adipose-specific mTORC2 ablation has little effect on fat cell size or fat mass, but leads to insulin resistance, affects glucose and lipid metabolism, and protects against HFD-induced obesity (19,20,27,28).…”

The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

“…Thus, in addition to its regulation by insulin, a well-known antagonist of PKA signaling, mTORC1 might also respond to catecholamines in adipocytes. Concurrently, other studies have shown that adrenergic stimulation may also stimulate mTORC2 and AKT signaling in certain settings suggesting that catecholamine-stimulated mTOR activity may be complex [72, 82]. Defining how PKA activates mTOR and what downstream mTOR-dependent pathways promote browning is an important future goal.…”

“…Using Raptor Adipoq-Cre mice, one study looked carefully at how losing mTORC1 in all mature adipocytes affects BAT adaptation to cold [72]. In wild type mice, prolonged cold challenge significantly increases mTORC1 activity in BAT through sympathetic signaling and this correlates with increased BAT mass, mitochondrial biogenesis, and oxidative metabolism.…”