title: Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.
abstract: Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Y
authors.initials: Y
authors.lastname: Ogawa
authors.forename: M
authors.initials: M
authors.lastname: Aizawa-Abe
authors.forename: K
authors.initials: K
authors.lastname: Hosoda
authors.forename: J
authors.initials: J
authors.lastname: Suga
authors.forename: K
authors.initials: K
authors.lastname: Ebihara
authors.forename: N
authors.initials: N
authors.lastname: Satoh
authors.forename: H
authors.initials: H
authors.lastname: Iwai
authors.forename: G
authors.initials: G
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004435:Eating / Q000502:physiology; D005260:Female; D005508:Food Deprivation / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000502:physiology*; D020738:Leptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009765:Obesity; D011506:Proteins / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D007328:Insulin; D020738:Leptin; D011506:Proteins; D005947:Glucose