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Papers In Press, published online ahead of print October 1, 2003
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TNO - Prevention and Health, Leiden
Corresponding Author: m.muurling{at}pg.tno.nl
Obese obob-mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive FFA and triglyceride (TG) levels, and strongly reduced body weight due to absence of subcutaneous adipose tissue and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less extreme model, we generated obob-mice with mild overexpression of APOC1 (obob/APOC1+/-), and performed hyperinsulinemic clamp analysis. Compared with obob-littermates, obob/APOC1+/- mice showed reduced body weight (- 25%), increased plasma levels of TG (+ 632%), TC (+ 134%), FFA (+ 65%), glucose (+ 73%) and insulin (+ 49%). Hyperinsulinemic clamp analysis revealed severe whole body and hepatic insulin resistance in obob/APOC1+/- mice and, in addition, increased hepatic uptake of FFA and hepatic TG-content. Treatment of obob/APOC1+/- mice with rosiglitazone strongly improved whole body insulin sensitivity, as well as hepatic insulin sensitivity, despite a further increase of hepatic FA-uptake and a panlobular increase of hepatic TG-accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA-uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA-intermediates has a major effect on insulin sensitivity of the liver.
Revised on September 21, 2003
Accepted on September 25, 2003
Overexpression of APOC1 in obob mice leads to hepatic steatosis and severe hepatic insulin resistance
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