Gestational hypoxia disrupts the neonatal leptin surge and programs hyperphagia and obesity in male offspring in the Sprague-Dawley rat.

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.

Differential regulation of human cathelicidin LL-37 by free fatty acids and their analogs.

LL-37 is the single cathelicidin host defense peptide in humans with direct antimicrobial and immunomodulatory activities. Specific regulation of LL-37 synthesis has emerged as a novel non-antibiotic approach to disease control and prevention. Short-chain fatty acids, and butyrate in particular, were found recently to be strong inducers of LL-37 gene expression without causing inflammation. Here, we further evaluated the LL-37-inducing efficiency of a broad range of saturated free fatty acids and their derivatives in human HT-29 colonic epithelial cells and U-937 monocytic cells by real-time RT-PCR. Surprisingly, we revealed that valerate, hexanoate, and heptanoate with 5-7 carbons are more potent than 4-carbon butyrate in promoting LL-37 gene expression in both cell types. Free fatty acids with longer than 7 or shorter than 4 carbons showed only a marginal effect on LL-37 expression. Studies with a series of fatty acid derivatives with modifications in the aliphatic chain or carboxylic acid group yielded several analogs such as benzyl butyrate, trans-cinnamyl butyrate, glyceryl tributyrate, and phenethyl butyrate with a comparable LL-37-inducing activity to sodium butyrate. On the other hand, although reactive, the anhydride derivatives of short- and medium-chain fatty acids are as potent as their corresponding free acid forms in LL-37 induction. Thus, these newly identified free fatty acids and their analogs with a strong capacity to augment LL-37 synthesis may hold promise as immune boosting dietary supplements for antimicrobial therapy.

Cellular host responses to gliomas.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites. METHODOLOGY/PRINCIPAL FINDINGS: Human glioma cell lines and glioma spheroid orthotopic implants were used in rodents. In both models, the xenografts recruited large numbers of host nestin-expressing cells, which formed a 'network' with glioma. The host nestin-expressing cells appeared to originate in the subventricular zone ipsilateral to the tumor, and were clearly distinguishable from pericytes that expressed smooth muscle actin. These distinct cell populations established close physical contact in a 'pair-wise' manner and migrated together to the deeper layers of tumor satellites and gave rise to tumor vasculature. The GBM biopsy xenografts displayed two different phenotypes: (a) low-generation tumors (first in vivo passage in rats) were highly invasive and non-angiogenic, and host nestin-positive cells that infiltrated into these tumors displayed astrocytic or elongated bipolar morphology; (b) high-generation xenografts (fifth passage) had pronounced cellularity, were angiogenic with 'glomerulus-like' microvascular proliferations that contained host nestin-positive cells. Stromal cell-derived factor-1 and its receptor CXCR4 were highly expressed in and around glioma xenografts, suggesting their role in glioma progression and invasion. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a robust migration of nestin-expressing host cells to glioma, which together with pericytes give rise to tumor vasculature. Mapping the cellular composition of glioma microenvironment and deciphering the complex 'crosstalk' between tumor and host may ultimately aid the development of novel anti-glioma therapies.