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Uteroplacental Insufficiency after Bilateral Uterine Artery Ligation in the Rat: Impact on Postnatal Glucose and Lipid Metabolism and Evidence for Metabolic Programming of the Offspring by Sham Operation

Kai-Dietrich Nüsken, Jörg Dötsch, Manfred Rauh, Wolfgang Rascher and Holm Schneider

Ligation of the uterine arteries (LIG) in rats serves as a model of intrauterine growth restriction and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia, and adiposity in the offspring. Its impact on lipid metabolism has been less well investigated. We compared parameters of glucose and lipid metabolism and glucocorticoid levels in the offspring of dams that underwent either LIG or sham operation (SOP) with those of untreated controls. Blood parameters including insulin, leptin, and visfatin as well as body weight, food intake, and creatinine clearance were recorded up to an age of 30 wk. Glucose tolerance tests were performed, and both leptin and visfatin expression in liver, muscle, and epididymal and mesenteric fat was quantified by RT-PCR. After catch-up growth, weight gain of all groups was similar, despite lower food intake of the LIG rats. LIG offspring showed impaired glucose tolerance from the age of 15 wk as well as elevated glycosylated hemoglobin and corticosterone levels. However, the body fat content of both LIG and SOP animals increased relative to controls, and both showed elevated triglyceride, total cholesterol, and leptin levels as well as a reduced proportion of high-density lipoprotein cholesterol. Thus, use of the LIG model requires both SOP and untreated controls. Although only LIG is associated with impaired glucose tolerance, pathogenic programming of the lipid metabolism can also be induced by SOP. Visfatin does not appear to be involved in the disturbed glucose metabolism after intrauterine growth restriction and may represent only a marker of fat accumulation.

IN INDUSTRIALIZED COUNTRIES, placental insufficiency is the most important reason for intrauterine growth restriction (IUGR) (1), which may predispose the fetus to the development of adiposity, diabetes mellitus type 2, and cardiovascular diseases in later life (2), depending on early postnatal nutrition (3). To investigate potential sequelae of IUGR, ligation of the uterine arteries in rats has been used frequently as an animal model of uteroplacental insufficiency. Offspring of dams that underwent bilateral uterine artery ligation (LIG), compared with offspring of sham-operated animals (SOP), show reduced body length and weight at birth together with hypoglycemia (4, 5), hypoinsulinemia (5), and elevated concentrations of circulating corticosterone (6). In the affected neonates, the levels of circulating triglycerides (7, 8) and leptin (9) are unaltered. In adulthood, LIG animals are characterized by hyperglycemia, insulin resistance progressing to type 2 diabetes, obesity (10), and hypertriglyceridemia (8). The serum leptin concentration is similar to that of SOP animals (11). Data on circulating cholesterol have not been reported for LIG or for SOP rats.

Current research on this model of uteroplacental insufficiency focuses on the phenomenon of metabolic programming by the altered intrauterine environment and its impact on the postnatal development (12, 13). LIG in the study group to be compared with SOP control animals has been preferred to the model of unilateral uterine artery ligation with internal controls (fetuses of the unligated uterine horn), because hyperperfusion of the unligated horn is supposed to result in increased fetal growth with possible metabolic consequences (4). However, it has not been investigated yet whether sham operation by itself may cause metabolic programming, because the intrauterine milieu is affected at least temporarily by surgery and recovery.

The adipocytokine visfatin, which is expressed in bone marrow, liver, muscle (14), and adipose tissue of mice and humans, has been reported to promote anabolic effects in vitro (15). There are controversial results concerning the association of visfatin with obesity and diabetes (15, 16). However, data on visfatin in the LIG model are not yet available.

This study focused on the hypothesis that not only bilateral uterine artery ligation but also sham operation may result in IUGR and its potential metabolic sequelae. Therefore, we examined offspring of LIG, SOP, and untreated control dams. Additionally, we investigated serum visfatin as well as visfatin expression in liver, muscle, and adipose tissue and its potential contribution to impaired glucose tolerance subsequent to IUGR. Remarkably, we have found that sham operation may result in both significant IUGR and metabolic programming.