Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal Yellow agouti mutation - Usefulness of leptin for thetreatment of obesity-associated diabetes
H. Masuzaki et al., Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal Yellow agouti mutation - Usefulness of leptin for thetreatment of obesity-associated diabetes, DIABETES, 48(8), 1999, pp. 1615-1622
Leptin acts as an adipocyte-derived blood-borne satiety factor that can inc
rease glucose metabolism. To elucidate the therapeutic implications of lept
in for obesity-associated diabetes, we crossed transgenic skinny mice overe
xpressing leptin (Tg/+), which we have developed recently, and lethal yello
w KKA(y) mice (A(y)/+), a genetic model for obesity-diabetes syndrome, and
examined the metabolic phenotypes of F-1 animals. At 6 weeks of age, plasma
leptin concentrations in Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) were
significantly higher than those in A(y)/+ mice. Although no significant di
fferences in body weight were noted among Tg/+:A(y)/+ mice, A(y)/+ mice, an
d their wild-type lean littermates (+/+), glucose and insulin tolerance tes
ts revealed increased glucose tolerance and insulin sensitivity in Tg/+:A(y
)/+ compared with A(y)/+ mice. However, at 12 weeks of age, when plasma lep
tin concentrations in A(y)/+ mice were comparable to those in Tg/+:A(y)/+ m
ice, Tg/+:A(y)/+ mice developed obesity-diabetes syndrome similar to that o
f A(y)/+ mice. Body weights of la-week-old Tg/+:A(y)/+ and A(y)/+ mice were
reduced to those of +/+ mice by a 3-week food restriction; when plasma lep
tin concentrations remained high in Tg/+:A(y)/+ mice but were markedly redu
ced in A(y)/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg
/+:A(y)/+ mice were markedly improved as compared with A(y)/+ and +/+ mice.
The present study demonstrates that hyperleptinemia can delay the onset of
impaired glucose metabolism and accelerate the recovery from diabetes duri
ng caloric restriction in Tg/+:A(y)/+ mice, thereby suggesting the potentia
l usefulness of leptin in combination with a long-term caloric restriction
for the treatment of obesity-associated diabetes.