Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity.
OBJECTIVE
Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity.


METHODS
Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep(+/?)), lean-Gpat1(-/-), ob/ob (Lep(ob/ob)), and ob/ob-Gpat1(-/-) mice. RESULTS Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1(-/-) mice, insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin-stimulated Akt activation.


CONCLUSIONS
These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.
Wendel
Angela A
AA
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.
Li
Lei O
LO
Li
Yue
Y
Cline
Gary W
GW
Shulman
Gerald I
GI
Coleman
Rosalind A
RA
D000818:Animals; D003433:Crosses, Genetic; D005234:Fatty Liver / Q000453:epidemiology / Q000517:prevention & control*; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000172:deficiency; D008055:Lipids / Q000502:physiology; D051379:Mice; D008820:Mice, Obese / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D020738:Leptin; D008055:Lipids; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D005992:Glycerol-3-Phosphate O-Acyltransferase