Increased Hepatic Peroxisome Proliferator-activated Receptor-␥ Coactivator-1 Gene Expression in a Rat Model of Intrauterine Growth Retardation and Subsequent Insulin Resistance

Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of type 2 diabetes in humans and rats. Unsuppressed endogenous hepatic glucose production is a common component of the insulin resistance associated with type 2 diabetes. Peroxisome proliferator-activated receptor-␥ coactivator-1 (PGC-1) mediates hepatic glucose production by controlling mRNA levels of glucose-6-phospha-tase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBPase). We therefore hypothesized that gene expression of PGC-1 would be increased in juvenile IUGR rat livers, and this increase would directly correlate with hepatic mRNA levels of PEPCK, G-6-Pase, and FB-Pase, but not glucokinase. We found that IUGR hepatic PGC-1 protein levels were increased to 230 ؎ 32% and 310 ؎ 47% of control values at d 0 and d 21 of life, respectively. Similarly, IUGR hepatic PGC-1 mRNA levels were significantly elevated at both ages. Concurrent with the increased PGC-1 gene expression , IUGR hepatic mRNA levels of G-6-Pase, PEPCK, and FB-Pase were also significantly increased, whereas glucokinase mRNA levels were significantly decreased. These data suggest that increased PGC-1 expression and subsequent hepatic glucose production contribute to the insulin resistance observed in the IUGR juvenile rat. B ARKER'S FETAL ORIGINS of Adult Disease Hypothesis proposes that fetal adaptation to a deprived intrauter-ine milieu leads to permanent changes in cellular biology and systemic physiology. Intrauterine growth retardation (IUGR) predisposes affected newborns toward long-term morbidity from type 2 diabetes, as well as other components of syndrome X (1). Though both insulin deficiency and resistance contribute to the IUGR diabetic phenotype, low-ponderal-index [weight/length (see Ref. 3)] IUGR individuals are often characterized by a preponderance of insulin resistance (2). Uteroplacental insufficiency, a morbidity associated with many common complications of pregnancy (such as pregnancy induced hypertension) induces low pon-deral index IUGR. In the rat, uteroplacental insufficiency results in juvenile IUGR animals whose glucose homeostasis is abnormal only when physiologically challenged on a pharmacological level (3). By adulthood, adult IUGR rats develop overt diabetes that is characterized by fasting hyperglycemia and hyperinsulinemia (3, 4). An important component of the peripheral insulin resistance associated with type 2 diabetes is impaired suppression of endogenous hepatic glucose production, which is predominately the result of gluconeogenesis (5). The enzymes glucose-6-phosphatase (G-6-Pase), phos-phoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBPase) determine the rate of glu-coneogenesis. It has been recently demonstrated that hepatic gene expression of these enzymes is controlled by peroxisome proliferator-activated receptor-␥ coactivator-1 (PGC-1) (6). IUGR persistently affects hepatic gene expression and …