University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network

Publication Date

5-2-2016

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Endocrinology

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 beta-adrenergic receptor (betaARs) 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 betaAR-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 betaAR/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 betaARs 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.

Rights and Permissions

Citation: J Clin Invest. 2016 May 2;126(5):1704-16. doi: 10.1172/JCI83532. Epub 2016 Mar 28. Link to article on publisher's site

Comments

Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of clinical investigation

PubMed ID

27018708

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