Regulation of glucogenesis by thyroid hormones in fetal sheep during late gestation A L Fowden, J Mapstone and A J Forhead Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK (Requests for offprints should be addressed to A L Fowden, Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK; Email: alf1000@cam.ac.uk) Abstract The effects of thyroid hormone deficiency in utero on the fetal glucogenic capacity were investigated by measuring glucose production and hepatic levels of glycogen and gluconeogenic enzymes in normal sheep fetuses in the fed and fasted states during late gestation and in those made thyroid hormone deficient by fetal thyroidectomy (TX). In the fed state, fetal TX had no effect on glucose uptake, utilisation or production by the fetus. It also had no apparent effect on the glycogen content or activities of the key gluconeogenic enzymes in the fetal liver. In addition, fetal plasma concentrations of insulin, cortisol, adrenaline or noradrenaline were unaffected by fetal TX in the fed state. In contrast, the rates of fetal O 2 consumption and CO 2 production per kilogram fetal bodyweight were significantly lower in TX than in intact fetuses in the fed state (P < 0·05). TX prevented fetal glucose production in response to maternal fasting for 48 h. It also abolished the normal decreases in the fetal glucose carbon oxidation fraction, the rate of CO 2 production from glucose carbon and in the fraction of the umbilical O 2 uptake used for glucose carbon oxidation that occur during fasting in intact fetuses. At the end of the fast, plasma noradrenaline concentrations and hepatic levels of glycogen, glucose 6-phosphatase, fructose diphosphatase and alanine amino- transferase were significantly lower in TX than in intact fetuses. These observations show that thyroid hormones are essential for glucogenesis in the sheep fetus during late gestation and suggest that these hormones act both on the hepatic glucogenic pathways and on the mechanisms activating glucogenesis in utero. Journal of Endocrinology (2001) 170, 461–469 Introduction In normal well-fed pregnant ewes, the fetal requirement for glucose is met almost entirely by transplacental trans- port of glucose from the mother with little, if any, glucogenesis by the fetus itself (Hay 1995). However, during adverse intrauterine conditions such as under- nutrition, hypoxia or placental insufficiency, glucogenesis has been shown to occur in the sheep fetus, particularly in animals close to term (Jones et al. 1983, Hay et al. 1984, Owens et al. 1989, Dalinghaus et al. 1991, Fowden et al. 1998b). Glucogenesis is also a major source of circulating glucose at birth during the period between placental separation and the establishment of nutritive suckling (Fowden et al. 1998a). The ability of the fetus to produce glucose endogenously depends on the hepatic glycogen and gluconeogenic enzyme levels and on the functional capacity of the mechanisms that normally activate the glucogenic pathways, such as catecholamine release (see Silver 1990). In turn, deposition of hepatic glycogen, upregulation of gluconeogenic enzymes and induction of hepatic adrenoreceptors all depend on the prepartum increase in fetal plasma cortisol (Barnes et al. 1978, Fowden et al. 1993, Barnes 1997). In adult animals, glucogenesis is also influenced by thyroid hormones (see Dauncey 1990). Hyperthyroidism enhances gluconeogenesis and glucose utilisation, while conversely, hypothyroidism reduces the capacity for glu- cogenesis, in part, by lowering hepatic glycogen synthesis (Malbon & Campbell 1984, Bollen & Stalman 1988). Much less is known about the effects of thyroid hormones on glucogenesis in utero, although thyroid hormones are known to mediate some of the maturational effects of cortisol close to term (Fowden et al. 1998b). In the lungs, thyroid hormones synergise with cortisol in regulating lung liquid reabsorption and the structural changes which enable pulmonary gas exchange to occur at birth (Barker et al. 1988, Liggins 1994). Similarly, in fetal liver, thyroid hormones contribute to the switch in somatotrophic gene expression which activates the endocrine synthesis of insulin-like growth factor-I essential for postnatal growth (Forhead et al. 1998, 2000). Administration of thyroxine (T 4 ) to neonatal rats has been shown to enhance the hepatic activity of glucose 6-phosphatase (G6P), the 461 Journal of Endocrinology (2001) 170, 461–469 0022–0795/01/0170–461  2001 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology.org Downloaded from Bioscientifica.com at 07/31/2021 06:27:23AM via free access