Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep

Abstract

The liver is a major metabolic and endocrine organ of critical importance in the regulation of growth and metabolism. Its function is determined by a complex interaction of nutritionally regulated counter-regulatory hormones. The extent to which hepatic endocrine sensitivity can be programed in utero and whether the resultant adaptations persist into adulthood is unknown and was therefore the subject of this study. Young adult male sheep born to mothers that were fed either a control diet (i.e.100% of total live weight-maintenance requirements) throughout gestation or 50% of that intake (i.e. nutrient restricted (NR)) from 0 to 95 days gestation and thereafter 100% of requirements (taking into account increasing fetal mass) were entered into the study. All mothers gave birth normally at term, the singleton offspring were weaned at 16 weeks, and then reared at pasture until 3 years of age when their livers were sampled. NR offspring were of similar birth and body weights at 3 years of age when they had disproportionately smaller livers than controls. The abundance of mRNA for GH, prolactin, and IGF-II receptors, plus hepatocyte growth factor and suppressor of cytokine signaling-3 were all lower in livers of NR offspring. In contrast, the abundance of the mitochondrial protein voltage-dependent anion channel and the pro-apoptotic factor Bax were up regulated relative to controls. In conclusion, maternal nutrient restriction in early gestation results in adult offspring with smaller livers. This may be mediated by alterations in both hepatic mitogenic and apoptotic factors.

Early developmental influences on hepatic organogenesis

“…Nevertheless, the precise mechanisms responsible for programming liver size remain unknown, although they may be mediated, for example, by nutritional alterations in both hepatic mitogenic and apoptotic factors. 16 Further studies are needed to confirm whether the livers of nutrient restricted offspring are altered as a consequence of impaired organogenesis (altered cell number) or hepatic hypertrophy (altered cell size). Whether one or both of these final pathways are influenced depends upon the timing and severity of the gestational insult.…”

“…88 Nutritional manipulation of liver growth is accompanied by a range of endocrine adaptations including increased plasma GH and decreased plasma IGF-I and IGF-II, glucose and insulin concentrations, 97,98 together with decreased expression of hepatic GH and IGF-II receptors. 16,38,86 In contrast, maternal nutrient restriction between early to mid gestation, coincident with the period of maximal placental growth, 99 has no effect on liver mass in singleton fetuses, 38,91,100 although an increase in liver weight has been observed when both singleton and twin pregnancies were studied. 101 Absolute, but not relative, liver mass is also reduced in lambs born to adolescent mothers that were undernourished during mid-gestation.…”

“…[81][82][83][84] Numerous sheep studies have reported a link between various maternal constraints upon pregnancy including placentation, body condition, parity, adolescence, ambient temperature, fetal number and nutrition on liver growth, maturation and function in the resultant offspring. 16,38,62,76,81,[85][86][87][88][89] Such constraints upon fetal development may result in an increase or decrease in offspring liver mass depending upon the timing, duration and severity of the gestational insult. That said, hepatic cellular and molecular adaptations also occur in the presence of normal liver growth.…”

“…However, the magnitude of hepatic adaptation is dependent upon the timing and duration of the nutritional insult and on fetal number. For example, fetal and adult liver growth is markedly impaired by severe 97 and/or prolonged (encompassing a number of critical windows) 16 periods of nutrient deprivation, respectively. Furthermore, liver mass is reduced in twin compared with singleton offspring and in singleton lambs exposed to maternal nutrient restriction during late gestation.…”

“…15 Further markers of metabolic development include glucogenic proteins: Phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The fetus does not produce glucose until the prepartum cortisol surge in late gestation, 16,17 relying prior to that on placental uptake of maternal glucose into the fetal circulation. Coincident with the late gestational prepartum cortisol surge, there is a corresponding increase in hepatic PEPCK and G-6-Pase activity17 and a three-to-four-fold increase in glycogen content, which provides the major source of glucose for the newborn infant.…”