Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue.
Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two DGAT enzymes known to catalyze the final step in mammalian triglyceride synthesis. Mice deficient in DGAT1 are resistant to obesity and have enhanced insulin sensitivity. To understand better the relationship between triglyceride synthesis and energy and glucose metabolism, we generated transgenic (aP2-Dgat1) mice in which expression of murine DGAT1 in the white adipose tissue (WAT) was twofold higher than normal. aP2-Dgat1 mice that were fed a regular diet had larger adipocytes and greater total fat pad weight than wild-type (WT) mice. In response to a high-fat diet, aP2-Dgat1 mice became more obese ( approximately 20% greater body weight after 15 weeks) than WT mice. However, the increase in adiposity in aP2-Dgat1 mice was not associated with impaired glucose disposal, as demonstrated by glucose and insulin tolerance tests. Correlating with this finding, triglyceride deposition in the liver and skeletal muscle, two major target tissues of insulin, was similar in aP2-Dgat1 and WT mice. Thus, DGAT1 overexpression in murine WAT provides a model in which obesity does not impair glucose disposal. Our findings support the lipotoxicity hypothesis that the deposition of triglycerides in insulin-sensitive tissues other than adipocytes causes insulin resistance.
Chen
Hubert C
HC
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100, USA.
Stone
Scot J
SJ
Zhou
Ping
P
Buhman
Kimberly K
KK
Farese
Robert V
RV
D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology*; D002001:Adipose Tissue, Brown / Q000201:enzymology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D051048:Diacylglycerol O-Acyltransferase; D004041:Dietary Fats; D018149:Glucose Intolerance / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin
D017931:DNA Primers; D004041:Dietary Fats; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D000217:Acyltransferases; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase