title: Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor.
abstract: Glycerol-3-phosphate acyltransferase (GPAT) activity is highly induced in obese individuals with insulin resistance, suggesting a correlation between GPAT function, triacylglycerol accumulation, and insulin resistance. We asked whether microsomal GPAT4, an isoform regulated by insulin, might contribute to the development of hepatic insulin resistance. Compared with control mice fed a high fat diet, Gpat4(-/-) mice were more glucose tolerant and were protected from insulin resistance. Overexpression of GPAT4 in mouse hepatocytes impaired insulin-suppressed gluconeogenesis and insulin-stimulated glycogen synthesis. Impaired glucose homeostasis was coupled to inhibited insulin-stimulated phosphorylation of Akt(Ser⁴⁷³) and Akt(Thr³⁰⁸). GPAT4 overexpression inhibited rictor's association with the mammalian target of rapamycin (mTOR), and mTOR complex 2 (mTORC2) activity. Compared with overexpressed GPAT3 in mouse hepatocytes, GPAT4 overexpression increased phosphatidic acid (PA), especially di16:0-PA. Conversely, in Gpat4(-/-) hepatocytes, both mTOR/rictor association and mTORC2 activity increased, and the content of PA in Gpat4(-/-) hepatocytes was lower than in controls, with the greatest decrease in 16:0-PA species. Compared with controls, liver and skeletal muscle from Gpat4(-/-)-deficient mice fed a high-fat diet were more insulin sensitive and had a lower hepatic content of di16:0-PA. Taken together, these data demonstrate that a GPAT4-derived lipid signal, likely di16:0-PA, impairs insulin signaling in mouse liver and contributes to hepatic insulin resistance.
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Chongben
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cooper
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Trisha J
authors.initials: TJ
authors.lastname: Grevengoed
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Lei O
authors.initials: LO
authors.lastname: Li
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Klett
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: James M
authors.initials: JM
authors.lastname: Eaton
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina; rcoleman@unc.edu.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011994:Recombinant Proteins / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D010712:Phosphatidic Acids; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011994:Recombinant Proteins; C525637:rictor protein, mouse; C529425:GPAT4 protein, mouse; D005992:Glycerol-3-Phosphate O-Acyltransferase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: diabetes; glycerolipids; insulin signaling; lipid metabolism; mammalian target of rapamycin complex 2; phosphatidic acid