Abstract
The intake of a high fat diet (HFD), in addition to stimulating orexigenic neuropeptides in the hypothalamus while promoting overeating and reducing locomotor behavior, is known to increase inflammatory mediators that modulate neuronal systems in the brain. To understand the involvement of chemokines in the effects of a HFD, we examined in rats whether HFD intake affects a specific chemokine, CXCL12, and its receptors, CXCR4 and CXCR7, in the hypothalamus together with the neuropeptides and whether CXCL12 itself acts similarly to a HFD in stimulating the neuropeptides and altering ingestion and locomotor behavior. Compared to low-fat chow, a HFD for 5 days significantly increased the expression of CXCL12 and its receptors, in both the paraventricular nucleus (PVN) where the neuropeptides enkephalin (ENK) and galanin were also stimulated and the perifornical lateral hypothalamus (PFLH) where orexin (OX) and melanin-concentrating hormone (MCH) were increased. In contrast, the HFD had no impact on expression of CXCL12 or its receptors in the arcuate nucleus (ARC) where the carbohydrate-related peptide, neuropeptide Y (NPY), was suppressed. Analysis of protein levels revealed a similar stimulatory effect of a HFD on CXCL12 levels in the PVN and PFLH, as well as in blood, and an increase in the number of CXCR4-positive cells in the PVN. In the ARC, in contrast, levels of CXCL12 and number of CXCR4-positive cells were too low to measure. When centrally administered, CXCL12 was found to have similar effects to a HFD. Injection of CXCL12 into the third cerebral ventricle immediately anterior to the hypothalamus significantly stimulated the ingestion of a HFD, reduced novelty-induced locomotor activity, and increased expression of ENK in the PVN where the CXCR4 receptors were dense. It had no impact, however, on NPY in the ARC or on OX and MCH in the PFLH where the CXCR4 receptors were not detected. These results, showing CXCL12 in the hypothalamus to be stimulated by a HFD and to mimic the effects of the HFD where its receptors are located, suggest that this chemokine system may have a role in mediating both the neuronal and behavioral effects induced by a fat-rich diet.
Highlights
The intake of a diet rich in fat has been associated with a higher prevalence of obesity (Bray et al, 1981; Flatt, 1988), which is accompanied by behavioral changes including an increase in ingestive behavior (Warwick et al, 2003; Chang et al, 2004) and a reduction in spontaneous, overall locomotor activity (Barzel et al, 2015; Wong et al, 2015)
With dietary fat known to induce inflammation and stimulate fat-related neuropeptides, this experiment tested whether high fat diet (HFD) intake affects endogenous expression of CXCL12 and its receptors, CXCR4 and CXCR7, in the same hypothalamic regions where it affects the orexigenic neuropeptides
These effects in the paraventricular nucleus (PVN) reflected a significant, HFD-induced increase in the expression of CXCL12 [t(10) = 4.27, p < 0.01], CXCR4 [t(10) = 5.11, p < 0.001], and CXCR7 [t(10) = 4.21, p < 0.01], which was accompanied by an increase in mRNA levels of the orexigenic neuropeptides, ENK [t(10) = 2.93, p < 0.05] and GAL [t(10) = 3.36, p < 0.01] (Figure 4A)
Summary
The intake of a diet rich in fat has been associated with a higher prevalence of obesity (Bray et al, 1981; Flatt, 1988), which is accompanied by behavioral changes including an increase in ingestive behavior (Warwick et al, 2003; Chang et al, 2004) and a reduction in spontaneous, overall locomotor activity (Barzel et al, 2015; Wong et al, 2015). Central injection of these neuropeptides or their analogs stimulates preferential intake of a high-fat diet (HFD) (Robert et al, 1989; Kyrkouli et al, 1990a,b; Gomori et al, 2003; Naleid et al, 2007), and HFD intake in turn increases the expression and levels of these orexigenic neuropeptides in the PVN and PFLH (Akabayashi et al, 1994; Elliott et al, 2004; Chang et al, 2007; Gaysinskaya et al, 2007), suggesting that they function within a positive feedback circuit to promote excess consumption Administration of these neuropeptides induces changes in locomotor behavior, with subcutaneous or intracerebral injection of an ENK analog found to depress locomotor activity (Bhargava, 1978; Szekely et al, 1980), similar to an effect produced by the consumption of a HFD (Novak et al, 2010; Wong et al, 2015). This evidence, closely relating these orexigenic peptides to dietary macronutrients, lead us to question the molecular and cellular mechanisms that may mediate the effects of a HFD on these neuropeptide systems and subsequently on the ingestive and locomotor behaviors they control
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
