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 May 2, 2016; First published March 28, 2016
Citation Information: J Clin Invest. 2016;126(5):1704-1716. https://doi.org/10.1172/JCI83532.
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Categories: 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 1

βAR activation of mTORC1 in adipocytes.

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βAR activation of mTORC1 in adipocytes. (A–C) 3T3-L1 adipocytes were pre...
(A–C) 3T3-L1 adipocytes were pretreated or not with rapamycin (Rapa, 100 nM) for 30 minutes prior to the addition of Iso (1 μM) or Ins (10 nM) for 1 hour (A); HIB-1B brown adipocytes were pretreated or not with rapamycin. Iso was added for 1 hour (B); Human primary s.c. adipocytes were treated or not with Rapa for 30 minutes, followed by Iso for 1 hour (C), and levels of phosphorylated, total S6K1, and internal control GAPDH were measured by Western blotting. Bar graphs show image quantification of p-S6K1 normalized to total S6K1 (n = 3). One-way ANOVA followed by post-hoc comparisons. C, control. *P < 0.05, **P < 0.01.