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Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

ABSTRACT: Ghrelin is a potent orexigenic hormone that likely impacts eating via several mechanisms. Here, we hypothesized that ghrelin can regulate extra homeostatic, hedonic aspects of eating behavior.In the current study, we assessed the effects of different pharmacological, physiological, and genetic models of increased ghrelin and/or ghrelin-signaling blockade on two classic behavioral tests of reward behavior: conditioned place preference (CPP) and operant conditioning.Using both CPP and operant conditioning, we found that ghrelin enhanced the rewarding value of high-fat diet (HFD) when administered to ad lib-fed mice. Conversely, wild-type mice treated with ghrelin receptor antagonist and ghrelin receptor-null mice both failed to show CPP to HFD normally observed under calorie restriction. Interestingly, neither pharmacologic nor genetic blockade of ghrelin signaling inhibited the body weight homeostasis-related, compensatory hyperphagia associated with chronic calorie restriction. Also, ghrelin's effects on HFD reward were blocked in orexin-deficient mice and wild-type mice treated with an orexin 1 receptor antagonist.Our results demonstrate an obligatory role for ghrelin in certain rewarding aspects of eating that is separate from eating associated with body weight homeostasis and that requires the presence of intact orexin signaling.

SUBMITTER: Perello M

PROVIDER: S-EPMC2854245 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

Perello Mario M Sakata Ichiro I Birnbaum Shari S Chuang Jen-Chieh JC Osborne-Lawrence Sherri S Rovinsky Sherry A SA Woloszyn Jakub J Yanagisawa Masashi M Lutter Michael M Zigman Jeffrey M JM

Biological psychiatry 20091224 9

<h4>Background</h4>Ghrelin is a potent orexigenic hormone that likely impacts eating via several mechanisms. Here, we hypothesized that ghrelin can regulate extra homeostatic, hedonic aspects of eating behavior.<h4>Methods</h4>In the current study, we assessed the effects of different pharmacological, physiological, and genetic models of increased ghrelin and/or ghrelin-signaling blockade on two classic behavioral tests of reward behavior: conditioned place preference (CPP) and operant condition ...[more]

PMID: 20034618

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Project description:Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer's disease (AD). Diets high in saturated fat potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin and/or orexin fiber loss are linked to neurodegeneration, cognitive impairment, and neuroinflammation. Prior studies show that orexin is neuroprotective, suppresses neuroinflammation, and that treatment with orexin improves cognitive processes in orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration. Our overall hypothesis is that loss of orexin contributes to high fat diet (HFD)-induced hippocampal neuroinflammation and cognitive decline. To examine this, we tested male O/A3 mice (7-8 mo. of age) in a two-way active avoidance (TWAA) hippocampus-dependent memory task. We tested whether (1) orexin loss impaired cognitive function; (2) HFD worsened cognitive impairment; and (3) HFD increased microglial activation and neuroinflammation. O/A3 mice showed significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p?<?0.05, reduced avoidances p?<?0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4?weeks. Learning impairment was evident at both 2 and 4?weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p?<?0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker Iba-1 (measured via qRT-PCR, p?<?0.001). Further characterization of the microglial immune response genes in hippocampal tissue revealed a significant increase in CX3 chemokine receptor 1 (CX3CR1), tumor necrosis factor-alpha (TNF-?) and the mitochondria-associated enzyme immune responsive gene-1 (Irg1). Collectively, our results indicate that orexin loss impairs memory, and that HFD accelerates hippocampus-dependent learning deficits and the onset of neuroinflammation.

Project description:The gut microbiome is involved in metabolic disorders. Osteopontin (OPN), as a key cytokine, contributes to various inflammation-related diseases. The underlying role of OPN in the microbiome remains poorly understood. Here, we investigated whether OPN could modulate metabolic disorders by affecting gut microbiota. In our present study, we found that the expression of OPN was elevated in individuals with obesity compared to that observed in healthy controls. There was a positive correlation between plasma OPN levels and body mass index (BMI) in humans. Moreover, OPN significantly exacerbated lipid accumulation and metabolic disorders in high-fat diet (HFD)-fed mice. Importantly, OPN significantly aggravated HFD-induced gut dysbiosis with a key signature profile. Fecal microbiota transplantation also supported the role of OPN in HFD-induced metabolic disorders in a microbiota-dependent manner. Moreover, the microbiome shift of OPN-deficient mice would be compensated to resemble those of wild-type mice by feeding with either OPN-containing milk or recombinant OPN protein in vivo. Furthermore, metagenomic analysis showed that OPN induced a higher abundance of Dorea and a lower abundance of Lactobacillus, which were positively and negatively correlated with body weight, respectively. Indeed, the abundance of Dorea was significantly decreased after Lactobacillus administration, suggesting that OPN may regulate the intestinal abundance of Dorea by reducing the colonization of Lactobacillus. We further confirmed that OPN decreased the adhesion of Lactobacillus to intestinal epithelial cells through the Notch signaling pathway. This study suggested that OPN could exacerbate HFD-induced metabolic dysfunctions through the OPN-induced alteration of the gut microbiome. Therefore, OPN could be a potential therapeutic target for metabolic syndrome. IMPORTANCE Gut microbiota are involved in metabolic disorders. However, microbiome-based therapeutic interventions are not always effective, which might be due to interference of the host factors. Here, we identified a strong positive correlation between OPN levels and BMI in humans. Next, we confirmed that OPN could aggravate high-fat diet-induced metabolic disorders in mice. Importantly, we found that fecal microbiota transplantation from OPN-deficient mice significantly alleviated metabolic disorders in WT mice. OPN directly induces the remodeling of the gut microbiota both in vitro and in vivo. These findings indicate that OPN could contribute to metabolic disorders by inducing an alteration of gut microbiota. OPN regulated the relative abundance of Lactobacillus by decreasing the adhesion of Lactobacillus to intestinal epithelial cells through the Notch signaling pathway. These data identify OPN as a potential pharmaceutical target for weight control and for the treatment of metabolic disorders.

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Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

Publications

Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

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