mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes

Ghada A. Soliman, Hugo A. Acosta-Jaquez, Diane C. Fingar

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immuno-suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3-L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulinstimulated TAG storage ̃50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2-adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenol-induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenol-stimulated phosphorylation of hormone sensitive lipase (HSL) on Ser-563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenol-mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the β-adrenergic-cAMP/PKA pathway to augment phosphorylation of HSL to promote hormone-induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage.

Original languageEnglish (US)
Pages (from-to)1089-1100
Number of pages12
JournalLipids
Volume45
Issue number12
DOIs
StatePublished - Dec 1 2010

Fingerprint

Lipolysis
Sirolimus
Nonesterified Fatty Acids
Adipocytes
Triglycerides
Phosphorylation
Cyclic AMP-Dependent Protein Kinases
Sterol Esterase
Isoproterenol
Transplantation (surgical)
Adrenergic Agonists
AMP-Activated Protein Kinases
Inhibition (Psychology)
Hypertriglyceridemia
Capsid Proteins
Organ Transplantation
Metabolism
Adrenergic Agents
Nutrients
Cues

Keywords

  • Adipocytes
  • Lipid metabolism
  • Lipolysis
  • Rapamycin
  • mTOR
  • mTORC1

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Cell Biology

Cite this

mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. / Soliman, Ghada A.; Acosta-Jaquez, Hugo A.; Fingar, Diane C.

In: Lipids, Vol. 45, No. 12, 01.12.2010, p. 1089-1100.

Research output: Contribution to journalArticle

Soliman, Ghada A. ; Acosta-Jaquez, Hugo A. ; Fingar, Diane C. / mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. In: Lipids. 2010 ; Vol. 45, No. 12. pp. 1089-1100.
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