Transgenic complementation of leptin receptor deficiency. II. Increased leptin receptor transgene dose effects on obesity/diabetes and fertility/lactation in lepr-db/db mice

Streamson C. Chua, Shun Mei Liu, Qiong Li, Aijun Sun, Walter F. DeNino, Steven B. Heymsfield, X. Edward Guo

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

We have generated mice that are homozygous for a leptin receptor transgene that is expressed exclusively in neurons (NSE-LEPR-B). We had previously shown that this transgene in the hemizygous state is effective in ameliorating almost all aspects of leptin receptor deficiency. Now, we show that the transgene, in the homozygous state, almost fully corrects the excess adiposity of LEPR-deficient (db/db) mice. Body composition analyses indicate that the transgene is able to restrain the massive increase in adiposity observed in LEPR-deficient mice. Examination of hypothalamic agouti gene-related peptide and proopiomelanocortin mRNA shows normalization of these leptin-regulated transcripts. Interestingly, despite normalization of circulating leptin concentrations by the transgene in the fed state, transgenic db3J/db mice did not show fasting-induced reductions of circulating leptin. Increased adiposity of the transgenic db/db mice at 4 wk of age, immediately postweaning, suggests that the transgene is less effective in correcting the preferential fat deposition caused by LEPR deficiency. We noted that the morphology of brown adipose tissue is nearly normal, concordant with the cold tolerance conferred by the transgene. Aspects of the diabetes phenotype are also corrected: glucose and insulin concentrations are nearly normal, and islet hyperplasia is greatly diminished. The transgene also corrects the infertility of db/db females and confers the ability to lactate sufficiently to nurse normal-sized litters. Finally, the slightly increased adiposity and mild insulin resistance of transgenic db/db dams were not a contributory factor to the increased fat content of transgenic db/db male progeny.

Original languageEnglish (US)
Pages (from-to)E384-E392
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume286
Issue number3 49-3
DOIs
StatePublished - Mar 2004

Keywords

  • Hypothalamus
  • Monogenic model of obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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