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

Hiroaki Masuzaki, Yoshihiro Ogawa, Megumi Aizawa-Abe, Kiminori Hosoda, Junko Suga, Ken Ebihara, Noriko Satoh, Hidenori Iwai, Gen Inoue, Haruo Nishimura, Yasunao Yoshimasa, Kazuwa Nakao

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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 KK(y) mice (A(y)/+), 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 A(y) allele (Tg/+:A(y)/+) were significantly higher than those in A(y)/+ mice. Although no significant differences in body weight were noted among Tg/+:A(y)/+ mice, A(y)/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:A(y)/+ compared with A(y)/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in A(y)/+ mice were comparable to those in Tg/+:A(y)/+ mice, Tg/+:A(y)/+ mice developed obesity-diabetes syndrome similar to that of A(y)[+ mice. Body weights of 12-week-old Tg/+:A(y)/+ and A(y)/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:A(y)/+ mice but were markedly reduced 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 during caloric restriction in Tg/+:A(y)/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long- term caloric restriction for the treatment of obesity-associated diabetes.

Original languageEnglish
Pages (from-to)1615-1622
Number of pages8
JournalDiabetes
Volume48
Issue number8
DOIs
Publication statusPublished - Aug 1 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Masuzaki, H., Ogawa, Y., Aizawa-Abe, M., Hosoda, K., Suga, J., Ebihara, K., Satoh, N., Iwai, H., Inoue, G., Nishimura, H., Yoshimasa, Y., & Nakao, K. (1999). 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. Diabetes, 48(8), 1615-1622. https://doi.org/10.2337/diabetes.48.8.1615