Leptin receptor antagonist treatment ameliorates the effects of long-term maternal hypoxia on adrenal expression of key steroidogenic genes in the ovine fetus

Abstract

We previously reported elevated adipose leptin expression, plasma leptin concentrations, and adrenocortical leptin receptor expression in the long-term hypoxic (LTH) ovine fetus. This study addressed whether leptin antagonist (LA) administration to LTH fetal sheep altered expression of key genes governing cortisol synthesis. Ewes were maintained at high altitude (3,820 meters) from 40 to 130 days gestation (dG), returned to Loma Linda University, and implanted with a maternal tracheal catheter. Reduced Po2 was maintained by nitrogen infusion. On 132 dG, LTH (n = 11) and age-matched, normoxic control (n = 11) fetuses underwent vascular catheter implantation. At 138 dG, fetuses were continuously infused with either saline or the LA (1.5 mg·kg(-1)·day(-1)) for 4 days and samples collected for blood gases, ACTH, and cortisol. Fetal adrenal cortex was collected for determination of steriodogenic acute regulatory protein (StAR), ACTH, and leptin receptor, cholesterol side-chain cleavage (CYP11A1), cytochrome P-450 11β-hydroxylase (CYP11B1), 17α-hydroxylase (CYP17), 21-hydroxylase (CYP21), signal transducer and activator of transcription 3 (STAT3), pSTAT3, and 17β-hydroxysteroid dehydrogenase (HSD3B) expression. In the saline-infused LTH fetuses, StAR, ACTH receptor, CYP11A1, and CYP17 expression was significantly lower compared with control (P < 0.05), whereas levels of CYP11B1, CYP21, and HSD3B mRNA were similar between groups. LA infusion restored expression of StAR, pSTAT3, CYP11A1, and CYP17, but not ACTH receptor, to normal ontogenic levels in the LTH group while having no effect on control fetuses. Neither fetal plasma ACTH nor cortisol concentrations were altered by LA infusion. We speculate that while leptin plays a role in governing expression of key enzymes and StAR in response to LTH, other factors play a role in modulating cortisol synthesis in these fetuses.

The Emerging Role of Leptin Antagonist as Potential Therapeutic Option for Inflammatory Bowel Disease

“…In a recent review, it was also clearly shown that leptin antagonism therapy works for the prevention and treatment of immunity-related disorder in mice [82]. It has been shown that LR antagonists abrogate the effects of long-term maternal hypoxia by governing the key enzyme StAR, and other factors play a role in modulating cortisol synthesis in these fetuses [83]. As mentioned above, leptin mediates several physiological functions, such as regulation of energy metabolism and reproductive function, and induces autoimmune diseases by enhancing immune response, tumorogenesis, elevated blood pressure and cardiovascular pathologies.…”

Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus

“…The leptin mutant competes with endogenous leptin for binding sites on all forms of the leptin receptor but lacks biological activity (34). In fetal sheep, a less potent form of the recombinant ovine leptin receptor antagonist (mutant L39A/D40A/FA1A/I42A, OLA) at a dose of 1.5 mg•kg Ϫ1 •day Ϫ1 iv has previously been shown to reduce STAT-3 phosphorylation by~50% in the adrenal cortex (11). The treatments were administered via the fetal venous catheter at a rate of 3 ml/day using a Graseby portable infusion pump.…”

Long-Term Gestational Hypoxia Modulates Expression of Key Genes Governing Mitochondrial Function in the Perirenal Adipose of the Late Gestation Sheep Fetus

“…Upon arrival at Loma Linda University Medical Center Animal Research Facility (elevation: 346 m), arterial and nonocclusive tracheal catheters were surgically placed as we previously described. [23][24][25] Maternal PO 2 was maintained at *60 mm Hg for the LTH ewes by adjusting the flow of humidified nitrogen (N 2 ) gas through the maternal tracheal catheter. Normoxic control ewes (n ¼ 6) were maintained near sea level (*300 m) throughout gestation.…”

“…We have previously published this methodology in our laboratories for NOS isoforms and other proteins. 20,23,25 Locule Size and Distribution…”

“…We have previously published this methodology in our laboratories for NOS isoforms and other proteins. 20,23,25 Locule Size and Distribution Tissue fixation and sectioning methods were similar to those we previously described. 20 Briefly, perirenal adipose tissue was collected and fixed in 4% paraformaldehyde.…”