Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor.
Am J Physiol Endocrinol Metab
; 307(3): E305-15, 2014 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-24939733
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(Thr³°8). 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 di160-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 160-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 di160-PA. Taken together, these data demonstrate that a GPAT4-derived lipid signal, likely di160-PA, impairs insulin signaling in mouse liver and contributes to hepatic insulin resistance.
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MEDLINE
Assunto principal:
Resistência à Insulina
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Proteínas de Transporte
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Hepatócitos
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Serina-Treonina Quinases TOR
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Glicerol-3-Fosfato O-Aciltransferase
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Hipoglicemiantes
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Insulina
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article