title: Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes.
abstract: Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we report that β-adrenergic-mediated inhibition of glucose uptake requires lipolysis. We also show that lipolysis suppresses glucose uptake by inhibiting the mammalian target of rapamycin (mTOR) complexes 1 and 2 through complex dissociation. In addition, we show that products of lipolysis inhibit mTOR through complex dissociation in vitro. These findings reveal a previously unrecognized intracellular signaling mechanism whereby lipolysis blocks the phosphoinositide 3-kinase-Akt-mTOR pathway, resulting in decreased glucose uptake. This previously unidentified mechanism of mTOR regulation likely contributes to the development of insulin resistance.
authors.affiliation: Department of Pharmacology and.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Mullins
authors.affiliation: Center of Cell Signaling, University of Virginia Health System, Charlottesville, VA 22908; and teh3c@virginia.edu lw6j@virginia.edu.
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Raje
authors.affiliation: Department of Pharmacology and.
authors.forename: Samantha G
authors.initials: SG
authors.lastname: Sherwood
authors.affiliation: Department of Pharmacology and.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Grande
authors.affiliation: Department of Pharmacology and.
authors.forename: Salome
authors.initials: S
authors.lastname: Boroda
authors.affiliation: Department of Pharmacology and.
authors.forename: James M
authors.initials: JM
authors.lastname: Eaton
authors.affiliation: Institute of Interdisciplinary Research, Université Libre de Bruxelles, B-1070 Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Blancquaert
authors.affiliation: Institute of Interdisciplinary Research, Université Libre de Bruxelles, B-1070 Brussels, Belgium.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Roger
authors.affiliation: Department of Pharmacology and.
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.affiliation: Department of Pharmacology and teh3c@virginia.edu lw6j@virginia.edu.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002395:Catecholamines / Q000737:chemistry*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005947:Glucose / Q000493:pharmacokinetics*; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009287:Naphthyridines / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D002395:Catecholamines; D007328:Insulin; D008055:Lipids; D009287:Naphthyridines; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: ATGL; adrenergic; insulin; lipase; torin 1