, Volume 45, Issue 12, pp 1089–1100 | Cite as

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
Original Article


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 insulin-stimulated 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.


mTOR mTORC1 Rapamycin Lipid metabolism Lipolysis Adipocytes 



Adipocyte triacylglycerol lipase


AMP activated protein kinase


Adenosine triphosphate


Cyclic adenosine monophosphate


Eukaryotic initiation factor-4E


eIF-4E-binding protein or protein-1/heat and acid stable-activated by insulin


Huntington elongation factor 3, the A subunit of protein phosphatase 2A, and TOR1


Hormone sensitive lipase


Fetal bovine serum


FKBP-12 rapamycin associated protein


FKBP12-rapamycin binding domain


Free fatty acids


FK506 binding protein 12


GTPase activating protein


G protein β subunit-like protein also known as mLST8


Glucose transporter 4


Insulin receptor substrate


Tumor suppressor protein


Lysophosphatidic acid acyl transferase


Mouse embryonic fibroblasts


Monoacylglycerol lipase


Mammalian target of rapamycin (TOR)

mTOR P-S2481

mTOR phosphorylated on serine 2481


Mammalian target of rapamycin complex 1


Mammalian target of rapamycin complex 2


Newborn calf serum


Nonesterified fatty acids




Regulatory associated protein of mammalian target of rapamycin


Ras homolog enriched in brain


Rapamycin-insensitive companion of mTOR


Regulatory subunit II of PKA


TOR signaling motif


Phosphatidic acid




Phospholipase D


Phosphatidylinositol 3-OH kinase

Pol I

Polymerase I


Protein kinase A


Protein kinase B


Peroxisome proliferator-activated receptor-γ


Phosphatase and tensin homologue deleted on chromosome 10


p70 ribosomal protein S6 kinase 1

S6K1 P-T389

S6K1 phosphorylated on threonine 389




Tuberous sclerosis complex


Very low density lipoprotein



The authors would like to express their gratitude to Drs. Nancy Weigel (Baylor College of Medicine) and Victoria Knutson (University of Texas) for sharing reagents, encouragement, support, and advice. Funding: This work was funded by grants from the National Institutes of Health (K01 DK60654) and the American Heart Association (0750060Z) to GS and NIH-R01 (DK-078135) to DCF.

Conflict of interest

Nothing to disclose; there are no commercial or other associations that may pose a conflict of interest.


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Copyright information

© AOCS 2010

Authors and Affiliations

  • Ghada A. Soliman
    • 1
    • 3
  • Hugo A. Acosta-Jaquez
    • 2
  • Diane C. Fingar
    • 1
    • 2
  1. 1.Division of Metabolism, Endocrinology, and Diabetes, Department of MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Cell and Developmental BiologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Department of Family and Consumer SciencesWestern Michigan UniversityKalamazooUSA

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