The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract (original) (raw)
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Anorexia/cachexia of chronic diseases: a role for the TGF-β family cytokine MIC-1/GDF15
2012
Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes overlapping, processes have been identified to mediate anorexia/cachexia: those that act primarily on muscle reducing its mass and function, and processes that decrease nutrition leading to loss of both fat and muscle. In the case of at least some cancers, the latter process is sometimes driven by marked overexpression of macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). MIC-1/GDF15 is a transforming growth factor beta (TGF-β) family cytokine that is found in the serum of all normal individuals at an average concentration of about 0.6 ng/ml. Its increased expression in both cancers and other diseases can result in 10-100-fold or more elevation of its serum levels. In experimental animals, serum MIC-1/GDF15 levels at the lower end of this range induce anorexia by direct actions of the circulating cytokine on feeding centres in the brain. Mice with tumours overexpressing MIC-1/GDF15 display decreased food intake, loss of lean and fat mass and cachexia. That this process also mediates anorexia/cachexia in humans is suggested by the fact that there is a direct correlation between the degree of serum MIC-1/GDF15 elevation and the amount of cancer-related weight loss, the first such relationship demonstrated. Further, in experimental animals, weight loss can be reversed by neutralisation of tumour-produced MIC-1/GDF15 with a specific monoclonal antibody, suggesting the possibility of effective therapy of patients with the devastating complication of anorexia/ cachexia.
Journal of cachexia, sarcopenia and muscle, 2016
The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC-1 in mice. Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we an...
TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator
PLoS ONE, 2013
The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/ cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1 2/2 ) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1 2/2 mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1 2/2 mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.
Current Opinion in Supportive & Palliative Care, 2018
Purpose of review To review recent finding on MIC-1/GDF15 and re-evaluate it as a potential target for the therapy of anorexia/cachexia syndromes. Recent findings MIC-1/GDF15 consistently induces anorexia/cachexia in animal models. Its actions on brainstem feeding centers leads to anorexia, inducing prolonged undernutrition and consequent loss of both lean and fat mass. Epidemiological studies by multiple groups have linked substantially elevated serum levels of this cytokine to anorexia/cachexia syndromes in diverse diseases such as cancer, chronic renal and cardiac failure, and chronic obstructive lung disease. These elevated serum levels are similar to those required to induce this syndrome in animals. Recent identifications of its previously elusive receptor as GFRAL, has enhanced understanding of its biology and suggests that modulating the MIC-1/GDF15-GFRAL pathway may be a therapeutic target for anorexia/cachexia syndrome.
Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1
2007
Abstract Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss.
Brain-Derived Neurotrophic Factor Plays a Role as an Anorexigenic Factor in the Dorsal Vagal Complex
Endocrinology, 2005
Brain-derived neurotrophic factor (BDNF) has recently been implicated as an anorexigenic factor in the central control of food intake. Previous studies focused on the hypothalamus as a probable site of action for this neurotrophin. It was demonstrated that BDNF is an important downstream effector of melanocortin signaling in the ventromedial hypothalamus. In this study, we addressed whether BDNF can modulate food intake in the hindbrain autonomic integrator of food intake regulation, i.e. the dorsal vagal complex (DVC). To this end, we used two complementary methodological approaches in adult rats. First, we measured the effects of intraparenchymal infusions of exogenous BDNF within the DVC on food intake and body weight. Second, we measured the endogenous BDNF protein content in the DVC and hypothalamus after food deprivation, refeeding, or peripheral treatments by the anorex-igenic hormones leptin and cholecystokinin (CCK). BDNF infusion within the DVC induced anorexia and weight loss. In the DVC, BDNF protein content decreased after 48 h food deprivation and increased after refeeding. Acute and repetitive peripheral leptin injections induced an increase of the BDNF protein content within the DVC. Moreover, peripheral CCK treatment induced a transient increase of BDNF protein content first in the DVC (30 min after CCK) and later on in the hypothalamus (2 h after CCK). Taken together, these results strongly support the view that BDNF plays a role as an anorexigenic factor in the DVC. Our data also suggest that BDNF may constitute a common downstream effector of leptin and CCK, possibly involved in their synergistic action. (Endocrinology 146: 5612-5620, 2005) R ECENT EVIDENCE INDICATES that brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, contributes to food intake and body weight control, acting as an anorexigenic factor in adult rodents. Indeed, infusion of BDNF in the lateral ventricles induces a reduction in food intake associated with weight loss in rats (1). Conversely, mice heterozygous for targeted disruption of BDNF, as well as conditional BDNF mutants, show hyperphagia and obesity (2, 3). Moreover, the same phenotype was observed in mice with a reduced expression of BDNF high-affinity tyrosine kinase receptor type B (TrkB) at a quarter of the normal amount (4). Mechanistic interpretations of these data all focused on the hypothalamus, which is indeed the best documented among autonomic centers involved in energy homeostasis integration. Xu et al. (4) demonstrated that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH), in which its expression is regulated by nutritional state and melanocortin-4 receptor (MC4R) signaling. In addition, the same authors showed that intracerebroventricular infusion of BDNF suppresses the hyperphagia and excessive weight gain observed on high-fat diets in mice with deficient MC4R signaling, suggesting that BDNF functions as a downstream effector through which MC4R signaling regulates energy balance.
Integrative role of neuropeptides and cytokines in cancer anorexia–cachexia syndrome
Clinica Chimica Acta, 2012
Background: The cachexia anorexia syndrome is a complex metabolic syndrome associated with cancer and some other palliative conditions characterized by involuntary weight loss involving fat and muscle, weight loss, anorexia, early satiety, fatigue, weakness due to shifts in metabolism caused by tumour by-products and cytokines. Various neuropeptides like Leptin, neuropeptide Y, melanocortin, agouti-related peptides have been known to regulate appetite and body weight. Method: A comprehensive literature search was carried out on the websites of Pubmed Central (http://www. pubmedcentral.nih.gov/), National Library of Medicine (http://www.ncbl.nlm.nih.gov) and various other net resources. Result: Data from observational studies shows that various cytokines (TNF-α, IL-6 and IL-1) are associated with metabolic changes resulting in cachexia in cancer patients. These cytokines may mimic the action of various neuropeptides resulting in anorexia, various metabolic effects resulting from enhanced catabolic state and weight loss. Conclusion: There is a need to understand and explore the role of various neuropeptides and cytokines in the pathophysiology of cancer-anorexia syndrome so that therapeutic measures may be designed for effective palliative care.
Neurobiology of inflammation-associated anorexia
Frontiers in Neuroscience, 2009
Patients with chronic infl ammation commonly complain about early satiety and loss of appetite, which in the case of cancerous and HIV-positive individuals can accompany dramatic weight loss known as cachexia (Laviano et al., 2003; Tisdale, 2009). The microenvironment surrounding tumoral cells, as well as tumoral cells themselves, are thought to produce pro-infl ammatory cytokines
AJP: Endocrinology and Metabolism, 2012
Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several...
High-fat diet-induced downregulation of anorexic leukemia inhibitory factor in the brain stem
Obesity (Silver Spring, Md.), 2016
High-fat diet (HFD) is known to induce low-grade hypothalamic inflammation. Whether inflammation occurs in other brain areas remains unknown. This study tested the effect of short-term HFD on cytokine gene expression and identified leukemia inhibitory factor (LIF) as a responsive cytokine in the brain stem. Thus, functional and cellular effects of LIF in the brain stem were investigated. Male rats were fed chow or HFD for 3 days, and then gene expression was analyzed in different brain regions for IL-1β, IL-6, TNF-α, and LIF. The effect of intracerebroventricular injection of LIF on chow intake and body weight was also tested. Patch clamp recording was performed in the nucleus tractus solitarius (NTS). HFD increased pontine TNF-α mRNA while downregulating LIF in all major parts of the brain stem, but not in the hypothalamus or hippocampus. LIF injection into the cerebral aqueduct suppressed food intake without conditioned taste aversion, suggesting that LIF can induce anorexia via l...