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.
Highlights
In mammals, brown adipose tissue (BAT) serves as a key heat-producing organ required to maintain body temperature and homeothermy[1]
The rapid induction of BAT thermogenic capacity is highly dependent on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key transcriptional regulator that promotes the expression of several thermogenic genes, including Ucp[127]
Histological and biochemical analyses revealed that chronic cold exposure increased BAT density, total DNA and mitochondrial DNA content, indicating that the elevation in BAT mass is the result of increased cell number and mitochondrial mass (Fig. 1C,D)
Summary
Cold exposure promotes mTORC1 activity in BAT. Cold exposure rapidly activates thermogenesis in BAT1,26. In mice chronically exposed to cold, we noticed that the extraction coefficient (capacity for one gram of tissue to extract substrate from the circulation) was increased in response to mTORC1 loss (Fig. 3A and B left panel) Such increase in glucose uptake is likely the result of the elevation in Akt activation in BAT of Ad-RaptorKO mice (Fig. 2A), a kinase recognized to play a crucial role in promoting glucose transport in brown adipocytes[30,51]. We observed a significant reduction in the expression of the genes encoding proteins required for AcCa formation and mitochondrial transport (Fig. 6D) These results indicate that glucose and fatty acid oxidative metabolism are severely reduced in BAT of Ad-RaptorKO mice.
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