Tuberous Sclerosis Complex 1–Mechanistic Target of Rapamycin Complex 1 Signaling Determines Brown-to-White Adipocyte Phenotypic Switch

Abstract

Interconversion of white and brown adipocytes occurs between anabolic and catabolic states. The molecular mechanism regulating this phenotypic switch remains largely unknown. This study explores the role of tuberous sclerosis complex 1 (TSC1)–mechanistic target of rapamycin (mTOR) signaling in the conversion of brown to white adipose tissue (WAT). A colony of Fabp4-Tsc1−/− mice, in which the Tsc1 gene was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre, was established. Western blotting and immunostaining demonstrated the absence of TSC1 and activation of ribosomal protein S6 kinase 1, the downstream target of mTOR complex 1 (mTORC1) signaling, in the brown adipose tissues (BATs) of Fabp4-Tsc1−/− mice. Accumulation of lipid droplets in BAT was significantly increased. Levels of brown adipocyte markers were markedly downregulated, while white adipocyte markers were upregulated. Rapamycin reversed the conversion from BAT to WAT in Fabp4-Tsc1−/− mice. Deletion of the Tsc1 gene in cultured brown preadipocytes significantly increased the conversion to white adipocytes. FoxC2 mRNA, the transcriptional factor for brown adipocyte determination, was significantly decreased, while mRNAs for retinoblastoma protein, p107 and RIP140, the transcriptional factors for white adipocyte determination, increased in the BAT of Fabp4-Tsc1−/− mice. Our study demonstrates that TSC1-mTORC1 signaling contributes to the brown-to-white adipocyte phenotypic switch.

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages

“…In our study, phosphorylation of p38 MAPK also followed PKA induction, suggesting that p38 MAPK might be a downstream effecter of PKA in the ADM2-activated signaling pathway, but the precise relationship between these two signals needs to be further clarified. TSC1-mTORC1 signaling has recently been identified as a linker between extracellular signals and transcriptional factors to initiate the brown-to-white adipocyte phenotypic switch (38). Whether this pathway is also down-regulated upon ADM2 treatment is worth further investigation.…”

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

“…Loss of raptor and mTORC1 activity in fat leads to browning of WAT (Polak et al 2008;Tran et al 2016), while converse activation of mTOR via deletion of TSC1 leads to whitening of BAT (Xiang et al 2015), thus suggesting that mTOR suppresses adipose browning. In contrast, however, two reports now show that loss of raptor in fat or pharmacological inhibition of mTOR dramatically blocks cold-induced browning of WAT and that mTOR is a direct target of adrenergic signaling and protein kinase A (PKA) (Liu et al 2016;Tran et al 2016).…”

“…Loss of raptor in fat and portions of the brain leads to browning of WAT (Polak et al 2008), while activation of mTOR in the same tissue distribution via deletion of tuberous sclerosis complex-1 (TSC1) leads to whitening of BAT (Xiang et al 2015), suggesting that mTOR suppresses adipose browning in vivo. On the other hand, recent work shows that loss of raptor in fat or pharmacological inhibition of mTOR blocks cold-induced browning of WAT (Liu et al 2016;Tran et al 2016), demonstrating that mTOR can also promote adipose browning in vivo.…”

Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis

“…Constitutive activation of mTORC1 signaling by knocking out the Tsc1 gene leads to decreased expression of UCP1 and PPAR␥ coactivator 1␣ (PGC-1␣) in BAT (81). On the other hand, fat-specific knockout of Raptor, a positive regulator of the mTORC1 signaling pathway, increases UCP1 expression and the beigeing of WAT (56).…”