Inhibitors of prostaglandin synthesis do not improve food intake or body weight of tumor-bearing rats

McCarthy, Donna O.

doi:10.1002/(sici)1098-240x(199910)22:5<380::aid-nur4>3.0.co;2-1

Cited by 20 publications

(13 citation statements)

References 31 publications

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“…However, several lines of evidence suggest that the mechanisms of acute inflammation-induced anorexia may be distinct (at least in part) from those present in a chronic inflammatory state. For example, the acute anorexic effects of peripheral administration of IL-1b appear to be dependent on prostaglandin synthesis (Hellerstein et al 1989, Elander et al 2007) whereas inhibiting prostaglandin synthesis in chronic disease states has proven to have relatively little effect on food intake (McCarthy 1999, Lundholm et al 2004). Many lines of evidence indicate that the central melanocortin system plays a key role in the tonic regulation of body weight in healthy individuals and that excessive activation of this system is one important mechanism in the production of cachexia in chronic disease states (Marks et al 2001, Cheung et al 2005.…”

Section: Discussionmentioning

confidence: 99%

“…The severity of cachexia in many illnesses is the primary determining factor in both quality of life and eventual mortality (Tisdale 1997, Larkin 1998; however, despite intense research efforts, disease-associated wasting remains poorly understood and there is currently no effective pharmacologic treatment. Much of the work on cachexia to date has focused on the hypothesis that interleukins (IL) and other cytokines released during inflammation and malignancy act on the central nervous system (CNS) to alter the release and function of a number of key neurotransmitters, thereby altering both appetite and metabolic rate (PlataSalaman 1989, 1999, Tisdale 1997, Inui 1999b. In addition to cytokines, a number of secreted hormones from the pancreas and gut have been shown to affect both short-term appetite and long-term body weight through central signals to the brainstem and hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

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Prostacyclin signaling regulates circulating ghrelin during acute inflammation

Madison

Scarlett

Levasseur

et al. 2007

Journal of Endocrinology

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Ghrelin is an octanoylated 28 amino acid peptide predominantly secreted by the stomach, and has potent stimulatory effects on appetite. Several laboratories, including our own, have demonstrated that ghrelin levels fall in states of acute inflammation brought about by injection of bacterial lipopolysaccharide (LPS). We now demonstrate that the decrease in circulating ghrelin is not due to a decrease in ghrelin gene expression, but is instead likely to be due to an acute decrease in ghrelin secretion. Furthermore, we have found that the change in circulating ghrelin during acute inflammation required a prostaglandin second messenger, but did not require the synthesis of nitric oxide. Interestingly, i.v. injection of prostaglandin E 2 failed to decrease circulating ghrelin levels, whereas prostacyclin decreased circulating ghrelin to a similar extent as did LPS. We also provide anatomical evidence for the mechanism of the regulation of ghrelin by inflammation. We demonstrate that the type 1 interleukin-1b (IL-1b) receptor is expressed within the gastric mucosa, but is not expressed by ghrelin cells. The prostacyclin receptor was also expressed in the gastric mucosa, and the majority of ghrelin-producing cells were found to co-express this receptor. Mice with genetic deletion of the type 1 IL-1 receptor do not suppress circulating ghrelin levels with LPS administration. Collectively, these data support a model in which the mechanism of inflammation induced decreases in ghrelin are due to the action of IL-1b on cells within the gastric mucosa that in turn produce prostacyclin as a second messenger. These data provide further support for the potential role of ghrelin as a therapeutic agent in acute and chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prostacyclin signaling regulates circulating ghrelin during acute inflammation

Madison

Scarlett

Levasseur

et al. 2007

Journal of Endocrinology

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“…To minimize the metabolic and other consequences associated with large tumours (5–10% of body weight) obtained from transplanted tumours (Strelkov et al ., 1989; McCarthy, 1999; Cahlin et al ., 2000), cultured tumour cells were administered subcutaneously to rats in the present study. This approach resulted in a relatively slowly growing tumour inducing ≈ 7% body weight loss and a 20% reduction in food intake when the tumour represented 1–2% of body weight.…”

Section: Discussionmentioning

confidence: 99%

Forebrain patterns of c‐Fos and FosB induction during cancer‐associated anorexia–cachexia in rat

Konsman

Blomqvist

2005

Eur J of Neuroscience

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Forebrain structures are necessary for the initiation of food intake and its coupling to energy expenditure. The cancer-related anorexia-cachexia syndrome is typified by a prolonged increase in metabolic rate resulting in body weight loss which, paradoxically, is accompanied by reduced food intake. The aim of the present work was to study the forebrain expression of Fos proteins as activation markers and thus to identify potential neurobiological mechanisms favouring catabolic processes or modulating food intake in rats suffering from cancer-related anorexia-cachexia. Neurons in forebrain structures showing most pronounced induction of Fos proteins were further identified neurochemically. To provoke anorexia-cachexia, cultured Morris hepatoma 7777 cells were injected subcutaneously in Buffalo rats. This resulted in a slowly growing tumour inducing approximately 7% body weight loss and a 20% reduction in food intake when the tumour represented 1-2% of body mass. Anorexia-cachexia in these animals was found to be accompanied by Fos induction in several hypothalamic nuclei including the paraventricular and ventromedial hypothalamus, in the parastrial nucleus, the amygdala, the bed nucleus of the stria terminalis, ventral striatal structures and the piriform and somatosensory cortices. Neurochemical identification revealed that the vast majority of FosB-positive neurons in the nucleus accumbens, ventral caudate-putamen and other ventral striatal structures contained prodynorphin or proenkephalin mRNA. These findings indicate that forebrain structures that are part of neuronal networks modulating catabolic pathways and food ingestion are activated during tumour-associated anorexia-cachexia and may contribute to the lack of compensatory eating in response to weight loss characterizing this syndrome.

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“…The resulting malnutrition and loss of lean body mass reduces the quality of life for the affected individual and compromises recovery by decreasing tolerance to therapy and increasing postsurgical complications (Inui, 1999a;Larkin, 1998). Attempts at drug therapy for cachexia with a variety of agents have met with limited success (DeConno et al, 1998;Windisch et al, 1998;Rivandeneria et al, 1999;McCarthy, 1999). The most-widely utilized agent, megestrol acetate, has shown some promise in reversing weight loss.…”

Section: Melanocortins and Cancer Cachexiamentioning

confidence: 99%

Central Melanocortins and the Regulation of Weight During Acute and Chronic Disease

Marks

Cone

2001

Recent Progress in Hormone Research

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Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these processes. Investigations of the neural targets for leptin action -as well as characterization of the agouti obesity syndrome -have, in turn, led to the discovery of fundamental neural pathways involved in the central regulation of energy homeostasis. In particular, the central melanocortin system has been shown to regulate appetite and metabolic rate in rodents; mutations in this system have been demonstrated to result in obesity in humans. Overall, the melanocortin system appears to function as a bidirectional rheostat in the regulation of energy intake and expenditure in rodents and potentially in humans. The first section of this chapter will focus on the development of our understanding of melanocortin physiology in the context of obesity. In particular, recent data regarding the interplay between melanocortin and neuropeptide Y (NPY) signaling at a cellular level will be discussed. The following section will discuss the hypothesis that melanocortin signaling plays a role in pathological weight loss and hypermetabolism observed in murine cachexia models. The potential role of this system in integrating a variety of anorexic and cachexic signals, as well as the potential for its pharmacological manipulation in the treatment of human cachexia, will be discussed. I. The Central Melanocortin System and Energy Homeostasis A. INTRODUCTIONThe last decade has witnessed significant advances in our understanding of energy homeostasis and regulation of body weight. The recent cloning and characterization of the genes responsible for obesity syndromes in the mouse -fatty, tubby, obesity, diabetes, and agouti -had led to our current understanding of the role of the adipocyte hormone leptin and its receptor in the feedback regulation of appetite and metabolic rate (Chua et al., 1996;Tartaglia et al., 1995;Zhang et al., 1997). Furthermore, we have started to unravel the neuronal pathways that mediate many of the effects of leptin and exert central control over processes fundamental to the intake, use, and storage of body fuels. In particular, the cloning of the agouti gene (Bultman et al., 1992;Miller et al., 1993) and the discovery of its mechanism of action (Fan et al., 1997;Huszar et al., 1997;Lu et al., 1994) led to the identification of a set of neuronal pathways that we will refer to as the melanocortin system. In general, the melanocortin system can be detined as the hypothalamic and brainstem neurons expressing pro-opiomelanocortin (POMC), the hypothalamic neurons coexpressing neuropeptide Y (NPY) and the melanocortin antagonist agouti-related protein (AGRP), and the neurons downstream of these systems. For the purposes of this chapter, these downstream neurons will be defined by the presence of the two primary central melanocortin receptors, melanocortin 3 receptor (MC3-R) (Roselli-Rehfuss et ...

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Inhibitors of prostaglandin synthesis do not improve food intake or body weight of tumor-bearing rats

Cited by 20 publications

References 31 publications

Prostacyclin signaling regulates circulating ghrelin during acute inflammation

Prostacyclin signaling regulates circulating ghrelin during acute inflammation

Forebrain patterns of c‐Fos and FosB induction during cancer‐associated anorexia–cachexia in rat

Central Melanocortins and the Regulation of Weight During Acute and Chronic Disease

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