Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.
Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triacylglycerol (TG) biosynthesis, in the liver (Liv-DGAT2 mice). Liv-DGAT2 mice developed hepatic steatosis, with increased amounts of TG, diacylglycerol, ceramides, and unsaturated long-chain fatty acyl-CoAs in the liver. However, they had no abnormalities in plasma glucose and insulin levels, glucose and insulin tolerance, rates of glucose infusion and hepatic glucose production during hyperinsulinemic-euglycemic clamp studies, or activities of insulin-stimulated signaling proteins in the liver. DGAT1 overexpression in the liver also failed to induce glucose or insulin intolerance. Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance.
Monetti
Mara
M
Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Levin
Malin C
MC
Watt
Matthew J
MJ
Sajan
Mini P
MP
Marmor
Stephen
S
Hubbard
Brian K
BK
Stevens
Robert D
RD
Bain
James R
JR
Newgard
Christopher B
CB
Farese
Robert V
RV
Hevener
Andrea L
AL
Farese
Robert V
RV
D000818:Animals; D053302:Apolipoprotein C-I; D001786:Blood Glucose / Q000032:analysis; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014280:Triglycerides / Q000378:metabolism
D053302:Apolipoprotein C-I; D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; C494881:DGAT1 protein, human; C494885:DGAT2 protein, human; C516957:DGAT2 protein, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase