Identifikation und Charakterisierung von Suszeptibilitätsloci für Adipositas und Hypercholesterinämie in der NZO-Maus

A backcross model of the obese, hyperglycemic New Zealand obese (NZO) mouse with the lean SJL strain was established in order to locate genes responsible for obesity and the associated syndrome of insulin resistance, hyperglycemia and dyslipidemia, and to compare the effects under a standard and a high fat diet. The pattern of symptoms presented by the NZO mouse closely resembles the human metabolic syndrome, suggesting a common pathophysiology. A genome wide scan revealed a susceptibility locus for obesity and hyperinsulinemia (Nob1) on mouse chromosome 5 in the vicinity of the markers D5Mit392 and D5Mit302. Nob1 contributed to higher body weight and insulin resistance (LOD-score for BMI > 11). The effect of Nob1 on body weight and insulin resistance was enhanced by a high fat diet. Although a sole effect of the leptin receptor variant of the NZO mouse (LeprA720T/T1044I) on the development of obesity could not be observed, LeprNZO significantly contributed to higher body weight in combination with Nob1. Furthermore, Nob1 accelerated and aggravated the development of diabetes in carriers of the diabetogenic Nidd/SJL allele. The synergistic effects of the susceptibility locus for hyperglycemia and islet cell failure Nidd/SJL, and the obesity locus Nob1 accounted for 90% of the diabetes observed in the backcross population. The combined effects were dependent on a high dietary fat content. The data indicate that the decompensation of glucose homeostasis in the NZO mouse reflects the synergistic effects of diabetes (Nidd/SJL) and obesity genes (Nob1). A susceptibility locus for hypercholesterolemia, but not obesity, insulin resistance or hyperglycemia, was located 44 cM distal from Nob1 on the mouse chromosome 5 near D5Mit244. Homozygous male and female carriers of the responsible NZO allele exhibited significantly elevated cholesterol levels. Although the cholesterol levels of mice raised on a standard diet were significantly lower compared to animals fed a high fat diet, the absolute effect of Chol1/NZO was not altered by the dietary fat content. It is suggested that the responsible gene is involved in the cholesterol metabolism.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2004

Author dc:creator

• Giesen, Kirsten

Contributors dc:contributor

• Joost, Hans-Georg

• info:eu-repo/classification/ddc/610
• Medizin
• Adipositas
• Hypercholesterinämie
• metabolisches Syndrom
• NZO-Maus
• QTL-Analyse

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-121412%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:59646