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

Abstract

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.

Plasma lipid levels and body weight altered by intrauterine growth restriction and postnatal fructose diet in adult rats

“…In addition, the effects of postnatal growth patterns vary between artery ligation studies, and there are also differences between the studies in the nutrition during lactation. Evidence for catch-up growth after lactation has (17,18) or has not been obtained (16). However, the majority of these studies have reported impaired glucose tolerance in male progeny by the time they reach adulthood (16)(17)(18).…”

Intrauterine growth restriction and adult disease: the role of adipocytokines

“…In this respect, numerous studies indicated that prenatal exposure to maternal undernutrition leads to the development of diet-induced obesity, hyperleptinemia, hyperinsulinism, and hypertension in the rat offspring (85)(86)(87)(88)(89)(90). Suggested underlying mechanisms include pre-existing fetal leptin resistance (87), excessive fetal exposure to glucocorticoids associated with IUGR (88) and permanent dysregulation of the adipoinsular feedback system, leading to hyperinsulinism and compensatory leptin production by pancreatic deltacells (89) or adipose tissue (90).…”

“…We hypothesize that higher visfatin concentrations in IUGR could probably serve as an early marker with prognostic value for the later development of the metabolic syndrome in this population (143). By contrast, a recent study concluded that visfatin may not be involved in the disturbed glucose metabolism of the IUGR rat offspring and may only represent a marker of fat accumulation (86). Table 1 summarizes the results of major articles investigating circulating concentrations of adipocytokines in IUGR versus AGA subjects.…”

Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction

“…Two rat models are widely used: the uterine artery ligation model is commonly used to examine the effect of fetal programming on metabolic disorders such as diabetes mellitus. 7,8 The ligation of both uterine arteries leads to a reduced blood flow to the placentas of the different individual rat fetuses. This model is therefore reminiscent of placental insufficiency in humans.…”