title: Leptin normalizes the impaired response of proinsulin mRNA to long chain fatty acids in heterozygous Zucker diabetic fatty rats.
abstract: 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.
authors.affiliation: Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
authors.forename: Y T
authors.initials: YT
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Shimabukuro
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Koyama
authors.forename: F
authors.initials: F
authors.lastname: Trieu
authors.forename: R H
authors.initials: RH
authors.lastname: Unger
mesh_terms: 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
chemical_list: 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