Ghrelin-induced adiposity is independent of orexigenic effects

Abstract

Ghrelin is a hormone produced predominantly by the stomach that targets a number of specific areas in the central nervous system to promote a positive energy balance by increasing food intake and energy storage. In that respect, similarities exist with the effects of consuming a high-fat diet (HFD), which also increases caloric intake and the amount of stored calories. We determined whether the effects of ghrelin on feeding and adiposity are influenced by the exposure to an HFD. Chronic intracerebroventricular ghrelin (2.5 nmol/d) increased feeding in lean rats fed a low-fat control diet (CD) [192 ± 5 g (ghrelin+CD) vs. 152 ± 5 g (control i.c.v. saline+CD), P<0.001], but the combination of ghrelin plus HFD did not result in significantly greater hyperphagia [150 ± 7 g (ghrelin+HFD) vs. 136 ± 4 g (saline+HFD)]. Despite failing to increase food intake in rats fed the HFD, ghrelin nonetheless increased adiposity [fat mass increase of 14 ± 2 g (ghrelin+HFD) vs. 1 ± 1 g (saline+HFD), P<0.001] up-regulating the gene expression of lipogenic enzymes in white adipose tissue. Our findings demonstrate that factors associated with high-fat feeding functionally interact with pathways regulating the effect of ghrelin on food intake. We conclude that ghrelin's central effects on nutrient intake and nutrient partitioning can be separated and suggest an opportunity to identify respective independent neuronal pathways.

Figure 1.

Short-term exposure to HFD abrogates the orexigenic effect of ghrelin. Male Long-Evans rats were injected i.c.v. (1 μl, third ventricle) with saline or ghrelin (10 μg) 2 h after the onset of the light phase, and food intake was recorded after 2 h. A) Rats had been fed low-fat, chow diet (CD) at all times prior to the injection. Immediately after the i.c.v. injection, rats received CD or an HFD. B) A subset of rats was fed an HFD during the dark phase prior to i.c.v. injection and was fed the same HFD after the treatment. The rest of the rats were fed CD for the entire duration of the experiment. Acute access to an HFD does not prevent the orexigenic response induced by ghrelin (A). In contrast, the short-term (overnight) exposure to HFD prevents the hyperphagia induced by ghrelin when compared to the corresponding saline-infused control group (B). Data are expressed as mean ± se percentage of change vs. corresponding control group (n=8). Ghre, ghrelin; sal, saline. **P<0.01, ***P<0.001 vs. corresponding saline; 2-way ANOVA with Bonferroni post hoc test.

Figure 2.

High-fat feeding prevents the hyperphagia induced by chronic central infusion of ghrelin but does not prevent the ghrelin-induced adiposity. Male Wistar rats fed CD were infused i.c.v. (lateral ventricle) for 1 wk with saline or ghrelin (2.5 nmol/d). Immediately after initiation of infusion, diet of half of the rats was switched to HFD. A) Ghrelin induced a significant increase in food intake in the rats fed CD, but this orexigenic effect was prevented by feeding the rats HFD, independently of the dose of ghrelin administered. B) Consequently, the cumulative caloric intake over 1 wk increased with the i.c.v. injection of ghrelin in CD- but not in HFD-fed rats, when compared with the corresponding saline-infused control group. C) Despite the similar caloric intake from HFD, i.c.v. ghrelin still induced a significant increase in fat mass in HFD-fed rats compared to saline-infused control rats. D) HF feeding suppressed the increase in lean mass induced by central infusion of ghrelin. Data are expressed as means ± se (n=8–10). Ghre, ghrelin; sal, saline. *P < 0.05, **P < 0.01, ***P < 0.001 vs. corresponding saline; 2-way ANOVA with Bonferroni post hoc test. ^##P < 0.01, ^###P < 0.001 vs. corresponding CD; t test.

Figure 3.

High-fat feeding does not prevent the hyperphagia induced by chronic central infusion of the melanocortin receptor blocker SHU9119. Male Wistar rats fed CD were infused i.c.v. (lateral ventricle) for 1 wk with saline or SHU9119 (2.5 nmol/d). Immediately after initiation of infusion, diet of half of the rats was switched to HFD. A–C) Intracerebroventricular infusion of SHU for 1 wk induced a significant increase in food intake, irrespectively of the diet (A), which led to a significant increase in caloric intake (B), and fat mass content (C) in comparison with the saline-infused control rats. D) HF feeding suppressed the increase in lean mass induced by central infusion of SHU. Data are expressed as means ± se (n=8–10). Ghre, ghrelin; sal, saline. **P < 0.01, ***P < 0.001 vs. corresponding saline; 2-way ANOVA with Bonferroni post hoc test. ^##P < 0.01, ^###P < 0.001 vs. corresponding CD; t test.

Figure 4.

Chronic central infusion of ghrelin up-regulates the gene expression of lipogenic enzymes in WAT in CD- and HFD-fed rats. A–C) Chronic infusion of ghrelin significantly increased the gene expression of the lipogenic enzymes Scd-1 (A), Acca (B), and Fasn (C) in epididymal WAT. D). In contrast, gene expression of Fasn in liver was only significantly increased in ghrelin-infused CD-fed rats. Data are expressed as means ± se (n=7). a.u., arbitrary units; ghre, ghrelin; sal, saline. *P < 0.05, ***P < 0.001 vs. corresponding saline; 2-way ANOVA with Bonferroni post hoc test.