Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning
Dianxin Liu, … , Michael P. Czech, Sheila Collins
Dianxin Liu, … , Michael P. Czech, Sheila Collins
Published March 28, 2016
Citation Information: J Clin Invest. 2016;126(5):1704-1716. https://doi.org/10.1172/JCI83532.
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Research Article Endocrinology

Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning

Abstract

A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known βAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite adipocytes (so-called browning) in white adipose tissue (WAT). Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine residues, an effect that was independent of insulin/AKT signaling. Abrogation of the PKA site within RAPTOR disrupted βAR/mTORC1 activation of S6K1 without affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR augmented S6K1 activity. Together, these studies reveal a signaling pathway from βARs and PKA through mTORC1 that is required for adipose browning by catecholamines and provides potential therapeutic strategies to enhance energy expenditure and combat metabolic disease.

Authors

Dianxin Liu, Marica Bordicchia, Chaoying Zhang, Huafeng Fang, Wan Wei, Jian-Liang Li, Adilson Guilherme, Kalyani Guntur, Michael P. Czech, Sheila Collins

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Figure 3

Elevating SNS activity via cold exposure activates mTORC1 signaling in BATs and WATs.

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Elevating SNS activity via cold exposure activates mTORC1 signaling in B...
Male mice (n = 5/group) received either vehicle or rapamycin (Rapa; 4 mg/kg BW) by i.p. injection for 2 days followed by exposure to 4°C or 23°C for 6 hrs. (A and B) iBAT (A) and iWAT (B) were collected, homogenized, and assayed by immunoblot for p-S6 and total S6. GAPDH served as an internal control. Bar graphs show image quantification of p-S6 normalized to total S6. One-way ANOVA followed by post-hoc group comparisons; **P < 0.01. (C) Core body temperature was monitored and recorded for vehicle- or Rapa-treated mice during cold exposure. One-way ANOVA followed by post-hoc Bonferroni analysis. **P < 0.01. (D) iBAT and iWAT were dissected from cold-acclimated mice receiving either vehicle or Rapa for immunoblotting detection of UCP1 and internal-control GAPDH. (E) Core body temperature was recorded for vehicle- or Rapa-treated mice during cold adaptation (n = 4). C, control. One-way ANOVA followed by post-hoc Bonferroni analysis. *P < 0.05.