Immunomodulatory actions of central ghrelin in diet-induced energy imbalance
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► 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.
References (69)
- et al.
IL-17 in obesity and adipogenesis
Cytokine Growth Factor Rev.
(2010) - et al.
AMP-activated protein kinase plays a role in the control of food intake
J. Biol. Chem.
(2004) - et al.
Ghrelin and its therapeutic potential for cachectic patients
Peptides
(2009) - et al.
High-fat diet induces increased tissue expression of TNF-α
Life Sci.
(2005) - et al.
Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage
Regul. Pept.
(2004) - et al.
Inflammation: the link between insulin resistance, obesity and diabetes
Trends Immunol.
(2004) - et al.
Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents
Brain Behav. Immun.
(2008) Three questions about leptin and immunity
Brain Behav. Immun.
(2009)Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction
Exp. Gerontol.
(2009)- et al.
Therapeutic action of ghrelin in a mouse model of colitis
Gastroenterology
(2006)