Animal Models of Obesity: Genetic Aspects

Abstract

Among the candidate genes that have been reviewed herein, adipsin, calcitonin, cholecystokin, Gi alpha and Gs 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 post-translational 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. 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 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

“…To address this, we also used the fructose-fed rat model, which develops insulin resistance secondary to elevated sugar consumption, allowing the examination of insulin resistance without the potentially confounding effects of obesity (25). Third, we employed the ob/ob mouse (22), which presents with obesity and insulin resistance, but not the leptin resistance in OZR. A final model of insulin resistance was generated in vitro in endothelial cells and excludes the in vivo complications of metabolic, hormonal, and hemodynamic forces.…”

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

“…Recent studies showed that the insulin-sensitizing thiazolidinedione class of compounds are synthetic ligands for PPARg and there seems to be a close relation between the potency of various thiazolidinediones to stimulate PPARg and their anti-diabetic action [22]. Although a large number of experimental rat models of obesity and insulin resistance have been used to study the pathogenesis, therapy and prevention of diabetes [23], molecular cloning of PPARg1 and g2 cDNAs have been reported only in mice and humans [13,20]. In our study, we succeeded in isolating and determining the sequence of rat PPARg1 and g2 cDNAs.…”

Effects of the CRF1 receptor antagonist SSR125543 on energy balance and food deprivation-induced neuronal activation in obese Zucker rats

“…In order to examine how a sub-chronic treatment with SSR125543 could block the stress response, Zucker rats were subjected to a 6-h daytime food deprivation, which represents a mild stress in obese Zucker rats. In addition to their hyper-responsive stress axis, obese Zucker rats present several characteristics of the metabolic syndrome including hypertriglyceridemia, hyperinsulinemia, and insulin resistance (Johnson et al 1991).…”