Immunomodulatory actions of central ghrelin in diet-induced energy imbalance

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Abstract

We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1β, IFN-γ) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1β, IL-6, IFN-γ, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-β remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 μg/day) for five consecutive days significantly reduced TNF, IL-1β and IFN-γ levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of IFN-γ, IL-17, IL-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways.

Highlight

► Central ghrelin influences obesity- and starvation-induced inflammatory response through modulation of HPA axis and leptin.

Introduction

Increasing evidence indicates the coupling of metabolic status to the immune system. As seen in obesity or in calorie restriction, neuroendocrine-immune interactions are intensified both in states of positive or negative energy balance. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, acute myocardial infarction and stroke, and increased concentration of inflammatory markers is associated with obesity-related cardiovascular risk factors, such as dyslipidemia, glucose intolerance and type 2 diabetes (Dandona et al., 2004, Hansson et al., 2006, Rana et al., 2007, Shoelson et al., 2007). Unlike beneficial anti-inflammatory and possibly life span-prolonging effects of limited caloric restriction (Fontana, 2009), severe malnutrition is also associated with inflammatory response that can induce anorexia, potentiate infection-induced liver damage and contribute to uterine dysfunction and reduced fertility (Wathes et al., 2007, Adams et al., 2009, Gautron and Layé, 2010). Therefore, at their extremes, both positive and negative energy balance are associated with chronic inflammation which can lead to further metabolic disturbances and other complications. An understanding of the mechanisms responsible for energy imbalance-mediated inflammation and its regulation is important in designing novel therapeutic paradigms for restoring energy homeostasis.

Communication between the neuroendocrine and immune systems is mediated via a complex array of cytokines, hormones and neuropeptides (Delgado and Ganea, 2008, Dixit, 2008). Certain metabolic hormones, such as adipokines leptin, adiponectin, visfatin and resistin, have potent immunomodulatory properties, directly linking regulation of systemic and cellular energy balance with inflammation (Pfeiffer, 2008; Maury and Brichard, 2010). Ghrelin is a 28-amino acid peptide originally isolated from rat stomach as a natural ligand of the growth hormone secretagogue receptor (GHS-R) type 1a (Kojima et al., 1999). Ghrelin increases food intake in both rodents and humans (Tschöp et al., 2000, Nakazato et al., 2001, Wren et al., 2001) by mechanisms involving the stimulation of the intracellular energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus (Andersson et al., 2004, Kola et al., 2005). Interestingly, ghrelin inhibits leptin- and immune stimuli-induced proinflammatory cytokine production by human monocytes and T cells by binding to cell surface GHS-R (Dixit et al., 2004), and blocks nuclear factor-κB-dependent proinflammatory cytokine production in human endothelial cells in vitro (Li et al., 2004). Accordingly, ghrelin exerts anti-inflammatory and tissue-protective effects in various disease models such as sepsis (Dixit et al., 2004, Wu et al., 2007a), lung injury (Sehirli et al., 2008), arthritis (Granado et al., 2005), pancreatitis (Dembinski et al., 2003), gastritis (Osawa et al., 2005, Brzozowski et al., 2004), collitis/inflammatory bowel disease (Gonzalez-Rey et al., 2006, Konturek et al., 2009), hepatic inflammation (Granado et al., 2008), autoimmune encephalomyelitis (Theil et al., 2009), myocardial infarction (Huang et al., 2009) and intestinal ischemia–reperfusion (Wu et al., 2008). There are indications that in addition to its direct effects on immune cells (Dixit et al., 2004) ghrelin may suppress inflammation via the central nervous system (CNS) by stimulating parasympathetic and inhibiting sympathetic nervous system activity (Wu et al., 2007a, Wu et al., 2007b). However, to the best of our knowledge, the ability of centrally applied ghrelin to inhibit systemic inflammation has not been directly tested. Additionally, it has been suggested that ghrelin may participate in alterations of metabolic status during inflammatory stress (Otero et al., 2004). The converse interaction, the effect of ghrelin on inflammation induced by energy imbalance, has not been assessed thus far.

The aim of the present study was to investigate the ability of ghrelin to influence energy-imbalance-induced inflammatory response in rats by acting on the CNS. We assessed the effect of central ghrelin administration to obese and starved rats on blood and heart tissue levels of some cytokines and hormones that act as important mediators/regulators of inflammation.

Section snippets

Experimental design

The experimental design is schematically depicted in Fig. 1. To assess the effect of central ghrelin administration on energy imbalance-induced inflammation, experimental animals were subjected for four weeks to three different diets: standard, high-fat and food-restricted, corresponding to normal (“lean” animals), positive (“obese” animals) and negative (“starved” animals) energy balance, respectively. Each group was subsequently divided into two subgroups receiving intracerebroventricular

The effects of central ghrelin on body weight and food intake

To evaluate the effectiveness of the dietary regimes and responsiveness to ICV ghrelin we first assessed body weight and food intake (Fig. 2). The significant main effects were observed for both diet (F = 1219.453, p < 0.001) and ghrelin treatment (F = 23.083, p < 0.001) in the absence of significant interaction (F = 0.296, p = 0.746). In comparison with the standard food regime, the food-restricted and fat-enriched diets caused a significant reduction and increase, respectively, in body mass of

Discussion

We believe this to be the first report demonstrating the immunomodulatory actions of centrally applied ghrelin in energy imbalance-induced inflammation. A complex pattern of immunomodulatory effects was observed, depending on the type of energy imbalance (positive or negative) and tissue examined (blood or heart). The observed effects were associated with the alterations of leptin levels and HPA axis activity, as well as with modulation of intracellular signaling molecules governing ghrelin’s

Conflict of Interest Statement

All authors declare that there are no conflicts of interest.

Acknowledgments

The study was supported by the Ministry of Science and Technological Development of the Republic of Serbia (Grant Nos. 41025 and 175067). The authors wish to thank Dr. Esma Isenovic (Vinca Institute of Nuclear Sciences, Belgrade, Serbia) for providing the RNA samples.

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