leptin and Fetal-Hypoxia

By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.

Topics: Adaptation, Physiological; Adipose Tissue; Altitude; Animals; Biomarkers; Female; Fetal Hypoxia; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Nitric Oxide; Pituitary-Adrenal System; Pregnancy; Sheep

The late gestation increase in adrenal responsiveness to adrenocorticotropin (ACTH) is dependent upon the upregulation of the ACTH receptor (ACTH-R), steroidogenic acute regulatory protein (StAR), and steroidogenic enzymes in the fetal adrenal. Long-term hypoxia decreases the expression of these and adrenal responsiveness to ACTH in vivo. Leptin, an adipocyte-derived hormone which attenuates the peripartum increase in fetal plasma cortisol is elevated in hypoxic fetuses. Therefore, we hypothesized that increases in plasma leptin will inhibit the expression of the ACTH-R, StAR, and steroidogenic enzymes and attenuate adrenal responsiveness in hypoxic fetuses. Spontaneously hypoxemic fetal sheep (132 days of gestation, PO(2) ≈ 15 mm Hg) were infused with recombinant human leptin (n = 8) or saline (n = 7) for 96 hours. An ACTH challenge was performed at 72 hours of infusion to assess adrenal responsiveness. Plasma cortisol and ACTH were measured daily and adrenals were collected after 96 hours infusion for messenger RNA (mRNA) and protein expression measurement. Plasma cortisol concentrations were lower in leptin- compared with saline-infused fetuses (14.8 ± 3.2 vs 42.3 ± 9.6 ng/mL, P < .05), as was the cortisol:ACTH ratio (0.9 ± 0.074 vs 46 ± 1.49, P < .05). Increases in cortisol concentrations were blunted in the leptin-treated group after ACTH(1-24) challenge (F = 12.2, P < .0001). Adrenal ACTH-R, StAR, and P450c21 expression levels were reduced in leptin-treated fetuses (P < .05), whereas the expression of Ob-Ra and Ob-Rb leptin receptor isoforms remained unchanged. Our results indicate that leptin blunts adrenal responsiveness in the late gestation hypoxemic fetus, and this effect appears mediated by decreased adrenal ACTH-R, StAR, and P450c21 expression.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Female; Fetal Hypoxia; Gestational Age; Humans; Hydrocortisone; Leptin; Phosphoproteins; Pregnancy; Receptors, Corticotropin; Receptors, Leptin; Sheep; Steroid 21-Hydroxylase

The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus.. We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 +/- 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic.. The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5-135.1 vs median 16.2; range, 3.7-52.2 micrograms/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = -0.440, p = 0.032), and pH (r = -0.414, p = 0.040).. Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia.

Topics: Amniotic Fluid; Birth Weight; Body Constitution; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy in Diabetics; Reference Values; Regression Analysis