Abstract
The effect of gestational hypoxia on the neonatal leptin surge, development of hypothalamic arcuate nuclei (ARH) projections and appetite that could contribute to the programming of offspring obesity is lacking. We examined the effect of 12% O2 from gestational days 15–19 in the Sprague-Dawley rat on post-weaning appetite, fat deposition by MRI, adipose tissue cytokine expression, the neonatal leptin surge, ARH response to exogenous leptin, and αMSH projections to the paraventricular nucleus (PVN) in response to a high fat (HFD) or control diet (CD) in male offspring. Normoxia (NMX) and Hypoxia (HPX) offspring exhibited increased food intake when fed a HFD from 5–8 weeks post-birth; HPX offspring on the CD had increased food intake from weeks 5–7 vs. NMX offspring on a CD. HPX offspring on a HFD remained hyperphagic through 23 weeks. Body weight were the same between offspring from HPX vs. NMX dams from 4–12 weeks of age fed a CD or HFD. By 14–23 weeks of age, HPX offspring fed the CD or HFD as well as male NMX offspring fed the HFD were heavier vs. NMX offspring fed the CD. HPX offspring fed a CD exhibited increased abdominal adiposity (MRI) that was amplified by a HFD. HPX offspring fed a HFD exhibited the highest abdominal fat cytokine expression. HPX male offspring had higher plasma leptin from postnatal day (PN) 6 through 14 vs. NMX pups. HPX offspring exhibited increased basal c-Fos labeled cells in the ARH vs. NMX pups on PN16. Leptin increased c-Fos staining in the ARH in NMX but not HPX offspring at PN16. HPX offspring had fewer αMSH fibers in the PVN vs. NMX offspring on PN16. In conclusion, gestational hypoxia impacts the developing ARH resulting in hyperphagia contributing to adult obesity on a control diet and exacerbated by a HFD.
Highlights
According to the Centers for Disease Control, obesity has reached epidemic levels with 34.9% of adults and approximately 17% of young adults in the United States considered obese
Moderate sustained gestational hypoxia (11.5% O2 for the final six days of gestation) that resulted in intra-uterine growth restriction (IUGR) pups in Sprague-Dawley (SD) rats was shown to increase abdominal adiposity and metabolic disorders in male offspring when fed a high fat diet (HFD) post-weaning [20, 21]
In a pregnant sheep model of sustained moderate gestational hypoxia, we found that late gestation fetal plasma leptin was elevated as well as leptin expression in fetal abdominal adipose [33] indicative that gestational hypoxia may impact leptin expression
Summary
According to the Centers for Disease Control, obesity has reached epidemic levels with 34.9% of adults and approximately 17% of young adults in the United States considered obese (http:// www.cdc.gov/obesity/data/adult.html). A number of maternal perturbations during gestation in experimental animals produce offspring exhibiting obesity and metabolic disorders or significantly increased the risk of these disorders by adulthood if the offspring are placed on high fat, high energy (“Western”) diets, supporting the epidemiological findings of Barker and colleagues. These maternal perturbations include maternal nutritional restriction, maternal obesity, and various maternal physiological or psychological stressors [2,3,4,5,6,7,8]. Moderate sustained gestational hypoxia (11.5% O2 for the final six days of gestation) that resulted in IUGR pups in Sprague-Dawley (SD) rats was shown to increase abdominal adiposity and metabolic disorders (e.g. insulin resistance) in male offspring when fed a high fat diet (HFD) post-weaning [20, 21]
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