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Identification of rat brainstem neuronal structures activated during cancer-induced anorexia
Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
2007 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 504, no 3, 275-286 p.Article in journal (Refereed) Published
Abstract [en]

In cancer-related anorexia, body weight loss is paradoxically associated with reduced appetite, which is contrary to the situation during starvation, implying that the normal coupling of food intake to energy expenditure is disarranged. Here we examined brainstem mechanisms that may underlie suppression of food intake in a rat model of cancer anorexia. Cultured Morris 7777 hepatoma cells were injected subcutaneously in Buffalo rats, resulting in slowly growing tumor and reduced food intake and body weight loss after about 10 days. The brainstem was examined for induced expression of the transcription factors Fos and FosB as signs of neuronal activation. The results showed that anorexia and retarded body weight growth were associated with Fos protein expression in the area postrema, the general visceral region of the nucleus of the solitary tract, and the external lateral parabrachial nucleus, structures that also display Fos after peripheral administration of satiating or anorexigenic stimuli. The magnitude of the Fos expression was specifically related to the size of induced tumor, and not associated with weight loss per se, because it was not present in pair-fed or food-deprived rats. It also appeared to be independent of proinflammatory cytokines, as determined by the absence of increased cytokine levels in plasma and induced cytokine and cyclooxygenase expression in the brain. The findings thus provide evidence that cancer-associated anorexia and weight loss in this model is associated with activation of brainstem circuits involved in the suppression of food intake, and suggest that this occurs by inflammatory-independent mechanisms. © 2007 Wiley-Liss, Inc.

Place, publisher, year, edition, pages
2007. Vol. 504, no 3, 275-286 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-40433DOI: 10.1002/cne.21407Local ID: 53241OAI: oai:DiVA.org:liu-40433DiVA: diva2:261282
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2012-05-28Bibliographically approved
In thesis
1. Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia
Open this publication in new window or tab >>Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anyone who has experienced influenza or a bacterial infection knows what it means to be ill. Apart from feeling feverish, experiencing aching joints and muscles, you lose the desire to eat. Anorexia, defined as loss of appetite or persistent satiety leading to reduced energy intake, is a hallmark of acute inflammatory disease. The anorexia is part of the acute phase response, triggered as the result of activation of the innate immune system with concomitant release of inflammatory mediators, which interact with the central nervous system. A chronic condition, and a severe medical problem, that resembles inflammation-induced anorexia is cachexia. Cachexia, which is commonly associated with malignant cancer, is typified as a cytokine-associated metabolic derangement leading to weight loss, mediated by activation of the immune system. Paradoxically, weight loss in cancer patients is often associated with reduced food intake, indicating that the normal coupling of energy intake to body weight is disarranged. Accumulating evidence indicates that inflammation- and cancer-induced anorexia are associated with Toll-like receptor and cycloxygenase (Cox) activation. However, the nature of these pathways is far from understood, and a series of experiments addressing this issue was therefore undertaken.

In paper I, we injected Morris hepatoma 7777 cells or vehicle into rats, and we analyzed the distribution pattern of the transcription factor Fos, an index of neuronal activity, in the brainstem. We found that the anorexia and weight loss in tumor-bearing rats were associated with extensive expression of Fos in the area postrema and the general visceral region of the nucleus of the solitary tract in the medulla oblongata, as well as in the external lateral pontine parabrachial nucleus, and that the magnitude of the Fos expression correlated positively with tumor weight and negatively with body weight development, respectively. The Fos expression occurred without any obvious signs of peripheral or central inflammation, and was not secondary to alterations in body weight or reduced food intake. Thus, in paper I, we found a tumor-elicited activation of three interconnected autonomic structures, which integrate and transmit afferent visceral and sensory information, and which are known to play vital roles for energy homeostasis.

In paper II we evaluated the effects of tumor growth on feeding behaviour in mice as well as the role of Cox-1 and Cox-2, and prostaglandin E2 (PGE2) for the decreased appetite. We implanted mice with a MCG 101 tumor, which resulted in decreased meal frequency but not decreased meal size or meal duration. We found that indomethacin, a non-selective Cox-inhibitor, attenuated the anorexia as well as the tumor growth. When given acutely at manifest anorexia, Cox-inhibitors rescued the loss of appetite and prevented body weight loss without affecting tumor weight. Despite Cox-2 gene induction in the brain and Cox-2 protein induction in cells associated to the blood-brain barrier in tumor-bearing mice, a Cox-2 inhibitor had no impact on tumor-induced anorexia. By contrast, manipulating Cox-1 activity with a selective Cox-1 inhibitor delayed the onset of the anorexic response. Tumor growth was associated with large elevations in plasma PGE2, a response that was prevented by indomethacin. In contrast, however, PGE2 levels in liquor were largely unaffected, in line with tumor-bearing mice being afebrile. Neutralisation of peripheral PGE2 with anti-PGE2 antibodies did not temper the anorexia, and deletion of host mPGES-1 did not affect the anorexia or tumor growth. Furthermore, we found that tumor-bearing mice lacking EP4 receptors in the nervous system, created by Cre-LoxP-targeted mutagenesis, developed anorexia. The most important conclusions from paper II are that decreased meal frequency caused the anorexia, and that Cox-enzymes, most likely Cox-1, are critical for cancer-elicited anorexia and weight loss and that these changes occur independently of host mPGES-1, PGE2 and neuronal EP4 receptor signaling.

In paper III, we investigated whether the inflammatory response critical for tumor-induced anorexia (paper II) was a result of innate immune signaling mechanisms. In paper IV, we also included measurements of food intake in mice injected with bacterial endotoxin, lipopolysaccharide (LPS; a Toll-like receptor 4 ligand), and aimed at identifying at which site(s) the activation of the innate immune system occurs during acute (LPS) as well as chronic (tumor) inflammation. To do so we examined the anorexic response in mice ubiquitously lacking (born without the gene in every cell) MyD88, the intracellular adaptor for Toll-like receptor and IL-1/18 receptor signalling, or lacking MyD88 in specific cell types. We found that a ubiquitous null deletion conferred complete resistance to LPS- and tumor-induced anorexia, as well as protected against weight loss. MyD88 knock-out mice, which had been subjected to whole-body irradiation to delete hematopoietic cells, and then transplanted with wild-type bone-marrow, developed anorexia when challenged with LPS. In line with this, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia. Similarly, inactivation of MyD88 in hematopoietic cells attenuated the tumor-induced anorexia development and protected from body weight loss. In contrast, genetic disruption of MyD88 signaling in neural cells or cerebrovascular endothelial cells affected neither LPS- or tumor-induced anorexia, nor weight loss. Thus, the key findings in paper III and IV are that genetic inactivation of MyD88 protects mice from developing cancer- and LPS-induced anorexia, indicating that innate immune signaling mechanisms are critical for this response. The findings also identify hematopoietic cells, but not neural cells or cerebrovascular endothelial cells, as a critical nexus for inflammatory driven anorexia and weight loss associated with acute (LPS) and chronic (malignant) disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 111 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1311
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77754 (URN)978-91-7519-879-8 (ISBN)
Public defence
2012-06-08, Berzeliussalen, ingång 64, plan 9, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2012-05-28Bibliographically approved

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