Animal models of obesity: Genetic aspects

Patricia R. Johnson, M. R C Greenwood, Barbara A Horwitz, Judith S. Stern

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Among the candidate genes that have been reviewed herein, adipsin, calcitonin, cholecystokinin, G(i)α and G(s) subunits of G proteins, insulin I and II, and lipoprotein lipase have all been mapped to specific chromosomes in mouse or rat or both. In none of these cases is the chromosomal location syntenic with murine obesity genes db (on chromosome 4), or ob (on chromosome 6). Thus, all of these genes that code for metabolic modulators that are altered in obese animals but not in lean animals can be ruled out as possible loci of the primary genetic defect, at least for the murine models of obesity. In the case of neuropeptide Y, growth hormone, glucose transporter GLUT-4, the insulin receptor, and glyceraldehyde-3-phosphate dehydrogenase, chromosomal mapping has not yet been reported. However, in each of these cases, the evidence available strongly argues against any one of these physiologic modulators as the likely site of the primary defect for any one of the obesity mutations. Rather, in all of these cases, regardless of whether or not the gene has been mapped, the evidence suggests that posttranscriptional and/or posttranslational processes are involved in bringing about the specific alterations in level or activity of the protein product that is seen in the obese animal. Often hormonal regulation is invoked as a possible explanation for the changes observed in gene expression. The hormones most commonly identified as having a mediating effect on the particular metabolic pathways involved are insulin and/or the adrenal glucocorticoids. Since in each of the obese mutants, circulating amounts of these hormones are elevated, severely so in the case of insulin, it would not be surprising to find that they influence the levels and activities of many protein products involved in a variety of central nervous system and peripheral metabolic pathways. Glucocorticoids are known to exert direct effects on gene expression; however, with respect to adipsin gene expression, a direct effect has not been found (142). Furthermore, insulin itself has been considered as a candidate for the genetic lesion in these animals and has been ruled out by chromosomal localization. Thus, while it may certainly prove to be the case that both insulin and glucocorticoids affect these systems in some way, their effects appear to be indirect. The work by Platt and colleagues (154) in transgenic mice provides the first evidence of signal transduction between an obese mutant allele and the promoter sequence for a gene that shows significantly altered expression in the obese animal. Future studies should reveal how obese mutations exert their influence on the expression of many other structural genes in a variety of tissues that undergo significant alterations in obesity. Current data suggest that the mutant allele, in this case db, may code for a regulatory element that can interact with promoter sequences to alter gene expression in a variety of tissues. In 1982, we proposed that the fa gene may exert its influence on a fundamental cellular regulatory function pleiotropically (201). Given the information now available on numerous candidate genes that have altered levels of expression in tissues ranging from specific hypothalamic brain regions to liver, pancreas, and adipose tissue, and given the ability to construct appropriate vectors for production of transgenic animals, investigators interested in understanding genetic obesity will be able to test similar hypotheses.

Original languageEnglish (US)
Pages (from-to)325-353
Number of pages29
JournalAnnual Review of Nutrition
StatePublished - 1991


  • candidate genes
  • gene expression
  • genetic obesity
  • obob and dbdb mice
  • Zucker and Wistar diabetic fatty rats

ASJC Scopus subject areas

  • Medicine (miscellaneous)


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