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

J Clin Invest. 2016 May 2;126(5):1704-16. doi: 10.1172/JCI83532. Epub 2016 Mar 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • HEK293 Cells
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Receptors, Adrenergic, beta / genetics
  • Regulatory-Associated Protein of mTOR
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Uncoupling Protein 1 / biosynthesis
  • Uncoupling Protein 1 / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Insulin
  • Multiprotein Complexes
  • RPTOR protein, human
  • Receptors, Adrenergic, beta
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Cyclic AMP-Dependent Protein Kinases