Leptin normalizes the impaired response of proinsulin mRNA to long chain fatty acids in heterozygous Zucker diabetic fatty rats.
To determine if underleptinization of islets of Zucker diabetic fatty (ZDF) rats is the proximal cause of their inability to compensate for obesity, we compared the proinsulin/beta-actin mRNA ratio in heterozygous (fa/+) ZDF rats with that of wild-type (+/+) and homozygous (fa/fa) ZDF rats. In +/+ islets cultured with 2 mM free fatty acids (FFA) the proinsulin mRNA ratio rose 2.4-fold at 12 h. In fa/+ islets, the ratio rose only 65% above normal. There was no change in fa/fa islets. The presence of leptin (20 ng/ml) in the culture medium increased the FFA-induced response of proinsulin mRNA of fa/+ islets to that of +/+ islets while reducing FFA incorporation into triglycerides. The leptin-induced improvement in the proinsulin mRNA response was independent of any changes in glucose usage. These findings support a causal relationship between diminished leptin action on islets and the impaired beta-cell response to FFA in ZDF rats.
Zhou
Y T
YT
Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Shimabukuro
M
M
Lee
Y
Y
Koyama
K
K
Trieu
F
F
Unger
R H
RH
D000199:Actins / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D020738:Leptin; D008297:Male; D016297:Mutagenesis, Site-Directed; D009765:Obesity / Q000235:genetics*; D011384:Proinsulin / Q000235:genetics*; D011506:Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin
D000199:Actins; D002352:Carrier Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011384:Proinsulin; D005947:Glucose