Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring

Abstract

Exposure to a high fat diet (HFD) during gestation stimulates neurogenesis and expression of hypothalamic orexigenic neuropeptides that affect consummatory and emotional behaviors. With recent studies showing a HFD to increase inflammation, this report investigated the neuroinflammatory chemokine, CXCL12, and compared the effects of prenatal CXCL12 injection to those of prenatal HFD exposure, first, by testing whether the HFD affects circulating CXCL12 in the dam and the CXCL12 system in the offspring brain, and then by examining whether prenatal exposure to CXCL12 itself mimics the effects of a HFD on hypothalamic neuropeptides and emotional behaviors. Our results showed that prenatal exposure to a HFD significantly increased circulating levels of CXCL12 in the dam, and that daily injections of CXCL12 induced a similar increase in CXCL12 levels as the HFD. In addition, prenatal HFD exposure significantly increased the expression of CXCL12 and its receptors, CXCR4 and CXCR7, in the hypothalamic paraventricular nucleus (PVN) of the offspring. Finally, the results revealed strong similarities in the effects of prenatal HFD and CXCL12 administration, which both stimulated neurogenesis and enkephalin (ENK) expression in the PVN, while having inconsistent or no effect in other regions of the hypothalamus, and also increased anxiety as measured by several behavioral tests. These results focus attention specifically on the CXCL12 chemokine system in the PVN of the offspring as being possibly involved in the stimulatory effects of prenatal HFD exposure on ENK-expressing neurons in the PVN and their associated changes in emotional behavior.

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

“…In adult rats, we have shown intracerebroventricular injection of Cxcl12 to increase the genesis and proliferation of hypothalamic neurons that express neuropeptides (Poon et al, 2016). Further, with prenatal exposure, we have also demonstrated in the rat a stimulatory effect of Cxcl12 on hypothalamic neurogenesis (Poon et al, 2017) and also of EtOH administration on the Ccl2 colocalization with its receptor Ccr2, an effect blocked by a Ccr2 antagonist (Chang et al, 2018, 2020a), and on the density of BLBP‐labeled radial glia progenitor cells and their coexpression of Cxcr4 in the neuroepithelium, the primary source of hypothalamic neurons (Chang et al, 2020a). With EtOH shown to alter chemokine expression shortly after EtOH exposure (Neupane et al, 2016; Yang et al, 2000) and with chemokines known to stimulate neuroprogenitor cell proliferation (Wu et al, 2009) and both cxcr4b and cxcl12a shown to be expressed within zebrafish radial glia progenitor cells (Palevitch et al, 2010), this evidence provides a possible mechanistic link between EtOH stimulation of chemokine activity in radial glia progenitor cells and the number of differentiated neurons observed shortly after EtOH exposure.…”

“Hypothalamic Microinflammation” Paradigm in Aging and Metabolic Diseases

“…Some chemokines could also be involved in the embryonic development of certain hypothalamic neurons, which are important for energy balance. Recently, it was shown that prenatal HFD feeding can alter gene expression of chemokines such as CXCL12 and CCL2 in the hypothalamus and thus affect the development of hypothalamic orexigenic neurons in the offspring (Poon et al, 2016a(Poon et al, , 2017. Also, CCL5 deficiency was shown to affect hypothalamic insulin signaling in a genetic mouse model (Chou et al, 2016).…”

Single-cell analysis reveals cellular heterogeneity and molecular determinants of hypothalamic leptin-receptor cells

“…Many cells in this cluster also expressed Cxcl12 ( Fig. 3a ), a chemokine mainly expressed in the PVH, LH and lower in Arc, with its mRNA levels increasing upon high-fat diet in these nuclei 44 .…”