Down-regulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice.
Obese (ob) is a recently identified gene involved in the regulation of energy balance in the mouse. We report here that AD-5075, a potent thiazolidinedione which lowered plasma glucose and triglyceride in Zucker diabetic fatty (ZDF) rats and db/db mice, decreased the expression of the ob gene in these animal models of obesity and non-insulin-dependent diabetes mellitus. The level of adipose ob mRNA in ZDF rats was 3-fold greater than that detected in the Zucker lean littermates. Chronic treatment with AD-5075 elicited a 67 and 70% reduction of ob mRNA in ZDF and control lean rats, respectively. Furthermore, the amount of adipose ob mRNA in db/db mice was 7 times higher than that detected in lean littermates. Treatment of db/db mice with AD-5075 resulted in a 78% reduction of the level of ob mRNA with parallel changes in circulating level of the ob gene product, leptin. The reduction of the ob mRNA in the Zucker lean rats was accompanied by significantly greater food intake and weight gain. However, in ZDF rats and db/db mice, there was profound increase in body weight without hyperphagia. The results demonstrate that the expression of the ob gene is up-regulated in these two rodent models of diabetes compared to their lean counterparts and that such overexpression is attenuated by treatment with an agent that improves insulin sensitivity and glucose homeostasis in vivo.
Zhang
B
B
Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Graziano
M P
MP
Doebber
T W
TW
Leibowitz
M D
MD
White-Carrington
S
S
Szalkowski
D M
DM
Hey
P J
PJ
Wu
M
M
Cullinan
C A
CA
Bailey
P
P
Lollmann
B
B
Frederich
R
R
Flier
J S
JS
Strader
C D
CD
Smith
R G
RG
D000273:Adipose Tissue / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D015342:DNA Probes; D018076:DNA, Complementary; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020738:Leptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009765:Obesity; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D017931:DNA Primers; D015342:DNA Probes; D018076:DNA, Complementary; D007004:Hypoglycemic Agents; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C089947:AD 5075; D005947:Glucose