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Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-77754ISBN: 978-91-7519-879-8 (print)OAI: oai:DiVA.org:liu-77754DiVA: diva2:528924
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
List of papers
1. Identification of rat brainstem neuronal structures activated during cancer-induced anorexia
Open this publication in new window or tab >>Identification of rat brainstem neuronal structures activated during cancer-induced anorexia
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40433 (URN)10.1002/cne.21407 (DOI)53241 (Local ID)53241 (Archive number)53241 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2012-05-28Bibliographically approved
2. A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptors
Open this publication in new window or tab >>A putative role for Cox-1 in the initiation of cancer anorexia independent of mPGES-1, PGE2 and neuronal EP4 receptors
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the so called anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PG and the cyclooxygenase (Cox) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the reduced food intake in the tumor-bearing animals was due to decreased meal frequency. Treatment with a nonselective Cox inhibitor attenuated the anorexia, and also tumor growth. However, when given at manifest anorexia, the nonselective Cox inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite the pronounced effect of nonselective Cox-inhibitors, a selective Cox-2 inhibitor had no effect on the anorexia, whereas Cox-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma - a response blocked by nonselective Cox-inhibition - but not in the cerebrospinal fluid, and there was no rise in body temperature. Neutralization of PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1), the inducible terminal isomerase for PGE2 synthesis, affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that Cox-enzymes, most likely Cox-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77751 (URN)
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2016-05-04Bibliographically approved
3. Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model
Open this publication in new window or tab >>Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model
2010 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 24, no 4, 554-557 p.Article in journal (Refereed) Published
Abstract [en]

The anorexia-cachexia syndrome, characterized by a rise in energy expenditure and loss of body weight that paradoxically are associated with loss of appetite and decreased food intake, contributes significantly to the morbidity and mortality in cancer. While the pathophysiology of cancer anorexia-cachexia is poorly understood, evidence indicates that pro-inflammatory cytokines are key mediators of this response. Although inflammation hence is recognized as an important component of cancer anorexia-cachexia, the molecular pathways involved are largely unknown. We addressed this issue in mice carrying a deletion of the gene encoding MyD88, the key intracellular adaptor molecule in Toll-like and interleukin-1 family receptor signaling. Wild-type and MyD88-deficient mice were transplanted subcutaneously with a syngenic methylcholanthrene-induced tumor (MCG 101) and daily food intake and body weight were recorded. Wild-type mice showed progressively reduced food intake from about 5 days after tumor transplantation and displayed a slight body weight loss after 10 days when the experiment was terminated. In contrast, MyD88-deficient mice did not develop anorexia, and displayed a positive body weight development during the observation period. While the MyD88-deficient mice on average developed somewhat smaller tumors than wild-type mice, this did not explain the absence of anorexia, because anorexia was seen in wild-type mice with similar tumor mass as non-anorexic knock-out mice. These data suggest that MyD88-dependent mechanisms are involved in the metabolic derangement during cancer anorexia-cachexia and that innate immune signaling is important for the development of this syndrome.

Place, publisher, year, edition, pages
Amsterdam: Elsevier Science B.V., 2010
Keyword
Anorexia, Cachexia, Cancer, MyD88, Mice, Innate immunity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-56458 (URN)10.1016/j.bbi.2010.01.006 (DOI)000277206600006 ()
Available from: 2010-05-17 Created: 2010-05-17 Last updated: 2012-05-28Bibliographically approved
4. MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite
Open this publication in new window or tab >>MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Loss of appetite concomitant with reduced food intake is a hallmark of both acute and chronic inflammatory diseases. Yet, despite extensive investigations, the underlying mechanisms remain undefined. Here we addressed this issue using mice lacking MyD88, critical for Tolllike and IL-1 receptor family signaling, generally or in specific cell types. Ubiquitous null deletions conferred complete resistance to bacterial lipopolysaccharide (LPS) induced anorexia, but this resistance was lost when knock-out mice subjected to whole-body irradiation to delete hematopoietic cells were transplanted with wild-type bone-marrow. In line with this observation, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia, whereas mice with abrogated MyD88 signaling in neural cells, being leaner and smaller, developed anorexia of similar magnitude as wild-type littermates. The effect of hematopoietic MyD88-deletion on feeding seemed however partially dissociated from the effect on body weight, since LPS triggered weight loss, although attenuated, in these mutants. Furthermore, MyD88 deficiency in the cerebrovascular endothelium affected neither LPS-induced anorexia nor weight loss. In a model for the cancer anorexia-cachexia syndrome, inactivation of MyD88 in hematopoietic cells strongly impaired the anorexia development and protected against body weight loss. These findings identify hematopoietic cells as a critical nexus for acute inflammatory driven anorexia as well as for chronic anorexia associated with malignant disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77753 (URN)
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2012-05-28Bibliographically approved

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