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.
Highlights
It is currently understood that continued ingestion of a diet rich in fat causes inflammatory responses that lead to chronic disease (Fritsche, 2015; Walker and Harrison, 2015; Welty et al, 2016)
In the paraventricular nucleus (PVN), a significant main effect of treatment was found at P15 on the expression of CXCR4 [F(4, 28) = 2.14, p < 0.05] and CXCR7 [F(4, 28) = 2.96, p < 0.05], with post hoc tests showing prenatal high fat diet (HFD) exposure to significantly increase the expression of both CXCR4 (15%; p < 0.01) and CXCR7 (18%; p < 0.01)
In contrast to these significant effects of prenatal HFD exposure, peripheral injection of CXCL12 into the pregnant rats had no effect on the endogenous CXCL12 system. It produced no change in the expression of CXCL12, CXCR4, or CXCR7 in the PVN, perifornical lateral hypothalamus (PFLH) or arcuate nucleus (ARC), at either dose tested (2 or 8 μg) or either age tested (P15 or P30; p > 0.05) (Figures 2A–C). These results show that prenatal exposure to a HFD, in addition to elevating circulating CXCL12 as shown in the first experiment, has a significant stimulatory effect on CXCL12 and its receptors in the PVN, but not the PFLH or ARC, while prenatal exposure to CXCL12 elevated to the same levels induced by a HFD has no effect on the development of its own endogenous system
Summary
It is currently understood that continued ingestion of a diet rich in fat causes inflammatory responses that lead to chronic disease (Fritsche, 2015; Walker and Harrison, 2015; Welty et al, 2016). Prenatal exposure to a HFD increases endogenous inflammatory mediators in the periphery and brain of the offspring and affects emotional behavior and food intake (Zhu et al, 2008; Stofkova et al, 2009; White et al, 2009; Bilbo and Tsang, 2010; Grayson et al, 2010) While this evidence supports a causal link between HFD exposure and inflammatory processes, it is not clear how and where the immune system when stimulated by a HFD functions to exert its effects on neuronal function during the gestational period and to produce long-lasting changes in the offspring’s behavior
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