Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

Abstract

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127-130 and 140-145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T 3 ), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127-130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140-145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2-3 mg (kg body wt) _1 day _1 ) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T 3 infusion (8-12 mg (kg body wt) _1 day _1 ), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.

Intrauterine Growth Restriction and Differential Patterns of Hepatic Growth and Expression of IGF1, PCK2, and HSDL1 mRNA in the Sheep Fetus in Late Gestation1

“…Thus, one explanation of the findings in the present study is that in the subset of hypoxic, hypoglycemic, growth-restricted fetuses in which liver growth is sacrificed, low hepatic glucose uptake results in the increased expression of HSDL1, the enzyme that converts cortisone to cortisol in the hepatocyte. Cortisol has been shown to play a key role in the upregulation of hepatic PCK2 activity and expression in the late-gestation fetus [26,27], so the increase in hepatic HSDL1 mRNA expression and intrahepatic cortisol production may stimulate increased PCK2 mRNA expression.…”

Prenatal origins of adult disease

“…PEPCK is the key gluconeogenic enzyme and this nutrionally induced change indicates the fetal need to increase gluconeogenesis in the face of decreased glucose availability. Forhead and colleagues [108] have shown in the chronically catheterized fetal sheep that an increase in PEPCK is one of the many changes the fetus normally makes in late development to prepare to perform gluconeogenesis postnatally. If the neonate has an imbalance in liver glucose metabolism tending towards increased glucose production, that adaptation will be of value if food shortage is experienced postnatally.…”

Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity

“…We have suggested that low hepatic glucose uptake results in the stimulation of increased expression of 11βHSD1, the enzyme that converts cortisone to cortisol in the hepatocyte. Cortisol plays a key role in the upregulation of hepatic PEPCK activity and expression in the late gestation fetus [60,61] and so the increase in hepatic 11βHSD1 mRNA expression and intra-hepatic cortisol production may lead to an increase in PEPCK mRNA expression.…”