CXCL12 promotes development of hypothalamic peptide neurons responsive to fat

Rockefeller University, New York NY

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Abstract

DESCRIPTION (provided by applicant): Global obesity is an epidemic problem that has been steadily increasing over the past several decades, leading to a higher percentage of women overeating and being obese during pregnancy. Many studies have shown that high fat diet (HFD) and obesity during pregnancy produces offspring that are similarly prone to overeating and gaining weight, further exacerbating the obesity problem. Recent evidence suggests that this may be attributed to increased neurogenesis and expression of the orexigenic peptides, enkephalin (ENK), galanin (GAL) and melanin-concentrating hormone (MCH) in the hypothalamus of offspring, with these peptides in this brain region being stimulators of HFD intake. Although the mechanism for this change has not been established, current evidence suggests that inflammatory mediators may be involved. Chemokines are a group of small proteins that have been found to play a role in neuronal modulation, development, migration, and growth. There are studies showing chemokines to be increased with ingestion of a HFD and in dietary obesity, but there is little known about he relationship of chemokines to the orexigenic peptides in the brain. To establish the relationship between chemokines and HFD intake, this grant will investigate, both in adult rats and in offspring prenatally exposed to HFD, the relationship of a specific chemokine, CXCL12, to hypothalamic peptides, HFD consumption and behaviors associated with excess intake. Aim 1 will determine in adult animals whether the receptors, CXCR4 and CXCR7, are co-expressed with ENK, GAL and MCH neurons and if CXCL12 functions through these receptors to stimulate peptide expression and HFD intake, by using immunohistochemistry, mRNA quantification, western blotting, siRNA knockdown and behavioral paradigms. Preliminary results show that HFD stimulates the expression of CXCL12, CXCR4, and CXCR7 in the hypothalamus and that treatment of cultured neurons with CXCL12 increases the expression of ENK, GAL and MCH. Aim 2 will provide a direct test of the possible role of CXCL12 in mediating the neurogenesis and migration of peptide neurons into the hypothalamus and in increasing the propensity for increased HFD intake in the offspring, by using immunofluorescence histochemistry and behavioral tests. Preliminary results show an increase in circulating CXCL12 in dams ingesting the HFD, increased levels of CXCL12 and CXCR4 in the hypothalamus of embryos, and increased migration of cultured neurons in response to CXCL12. The data thus far implicate CXCL12 in mediating the effects of prenatal fat exposure and also reveal an important relationship to the orexigenic peptides. These studies will yield new evidence to support the function of CXCL12 in mediating the behavioral programming induced by dietary fat.