The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).

Hypoxia leads to a decrease in food intake and attenuated weight gain in rats. The purpose of this study was to measure plasma leptin and insulin in young rats exposed to hypoxia for 7 d as compared to a normoxic control group of the same age. One group was exposed from birth to 7 d of age; the other was exposed from 28 to 35 d of age (weaned at 21 d of age). As expected, body weight was significantly lower in rats of either age exposed to hypoxia for 7 d. Plasma leptin was significantly lower in hypoxic (2.0+/-0.2 ng/mL; n = 41) compared with normoxic (2.6+/-0.3 ng/mL; n = 30) 7-d-old rats. Plasma leptin was also significantly lower in hypoxic (1.1+/-0.1 ng/mL; n = 20) as compared to normoxic (1.5+/-0.1 ng/mL; n = 20) 35-d-old rats. Seven-day-old rats exposed to hypoxia demonstrated significant increases in plasma glucose and insulin whereas 35-d-old rats exhibited a decrease in both variables. We conclude that exposure to hypoxia for 7 d leads to a decrease in body weight and plasma leptin in infant and juvenile rats. The decrease in leptin may be an attempt to reverse hypoxia-induced anorexia.

Neonatal hypoxia increases aldosterone production and plasma lipids. Because fatty acids can inhibit aldosterone synthesis, we hypothesized that increases in plasma lipids restrain aldosteronogenesis in the hypoxic neonate. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Plasma was analyzed for lipid content, and steroidogenesis was studied in dispersed whole adrenal glands untreated and treated to wash away lipids. Hypoxia increased plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rat only. Washing away lipids increased aldosterone production in cells from 7-day-old rats exposed to hypoxia, but not in cells from normoxic 7-day-old rats or from normoxic or hypoxic 35-day-old rats. Addition of oleic or linolenic acid to washed cells inhibited both aldosterone and corticosterone production, although cells from hypoxic 7-day-old rats were less sensitive. We conclude that hypoxia induces hyperlipidemia in the suckling neonate and that elevated nonesterified fatty acids inhibit aldosteronogenesis.

Hypoxia leads to a decrease in aldosterone that cannot be entirely explained by extrinsic controllers of adrenal function. We have shown that acute hypoxia attenuates aldosterone synthesis via a direct inhibition of the function of the aldosterone enzyme pathway. The mechanism of the sustained decrease in aldosterone during chronic hypoxia is unknown. The present study evaluated the hypothesis that chronic hypoxia leads to a decrease in the expression of the steroidogenic enzyme P-450c11AS unique to the aldosterone pathway. Rats were exposed to 3 days of normoxia, moderate hypoxia (12% O2), or severe hypoxia (10% O2). Adrenal glands were removed and prepared for biochemical analysis of steroidogenesis in vitro (dispersed capsular cells) and for measurement of steady-state enzyme mRNA levels by reverse-transcription competitive polymerase-chain reaction (RT-cPCR) and by in situ hybridization histochemistry (ISHH). Moderate hypoxia had no effect on steroidogenesis. Adrenal cells from rats exposed to severe hypoxia demonstrated a decreased conversion of corticosterone to aldosterone (late pathway catalyzed by P-450c11AS) without a change in the other mitochondrial cytochrome P-450 enzyme activities. Adrenal cells from rats exposed to hypoxia also demonstrated a three- to fourfold decrease in P-450c11AS mRNA without a change in the other mitochondrial cytochrome P-450 enzymes mRNAs, as determined by either RT-cPCR or ISHH. We conclude that relatively short-term chronic hypoxia in rats leads to a decrease in aldosteronogenesis by decreasing the expression of the gene for the late-pathway enzyme unique to the aldosterone pathway (P-450c11AS).