Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice.

Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions.

Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

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 anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing 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 anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) 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, PGE(2) and neuronal EP(4) signaling.

Anorexic behavior and elevation of hypothalamic malonyl-CoA in socially defeated rats.

Suppression of body weight and eating disorders, such as anorexia, are one of the major symptoms of psychiatric disorders such as depression. However, the mechanisms of weight loss and reduced appetite in depressive patients and in animal models of depression are largely unknown. In this study, we characterized the mechanism of anorexia resulting from depression using socially defeated rats as an animal model of depression. Socially defeated rats showed suppressed body weight gain, enlarged adrenal glands, decreased home cage activity, decreased food intake, and increased immobility in the forced swim test. These results are representative of some of the core symptoms of depression. Simultaneously, we observed decreased levels of phosphorylated AMP-activated protein kinase (AMPK) and acetyl-coenzyme A (CoA) carboxylase (ACC) and increased levels of malonyl-CoA in the hypothalamus of socially defeated rats. Hypothalamic malonyl-CoA controlled feeding behavior and elevation of malonyl-CoA in the hypothalamus induced inhibition of food intake. Our findings suggest that the suppression of body weight gain caused by social defeat stress is caused by anorexic feeding behavior via an increased concentration of malonyl-CoA in the hypothalamus.

Peptide tyrosine tyrosine levels are increased in patients with urea cycle disorders.

Nutritional management is essential for patients with inborn errors of metabolism, such as urea cycle disorders (UCDs). Lack of appetite is common in these patients and can lead to underconsumption of calories, catabolism, and subsequently loss of metabolic control. The etiology of anorexia in these patients is largely unexplored. The neuroendocrine hormone peptide tyrosine tyrosine (PYY), secreted postprandially from endocrine cells of the ileum and colon, induces feelings of satiety and decreases food intake. While plasma PYY levels have been characterized in a number of populations, they have not been examined in UCD patients. In a retrospective study, plasma PYY concentrations were measured in UCD (n=42) patients and controls (n=28) via an ELISA to determine if levels of this anorexigenic hormone are altered in this patient population. Median PYY levels were significantly higher in UCD patients compared to controls (p=3.5×10(-5)). Body mass index was significantly associated with increased PYY levels in controls (p=0.02), while UCD diagnosis subtype was associated with PYY levels (p=1×10(-3)) in cases. Median PYY levels were significantly lower in ornithine carbamoyltransferase deficient patients compared with all other UCD subtypes (p=9×10(-3)), but significantly higher compared to controls (p=1.6×10(-3)). Overall, this study demonstrates that UCD cases have increased PYY levels compared to controls, suggesting that regulation of PYY may be altered in these patients. These observations may lead to a better understanding of the development of anorexia in UCD patients.

Suspected side effects of doxycycline use in dogs - a retrospective study of 386 cases.

This study investigated doxycycline-related side effects in a large population of dogs. Data from 386 dogs that had received doxycycline for the treatment of various infectious diseases were analysed retrospectively. Potential side effects that developed during treatment were documented, and correlations with signalment, dose, duration of treatment, frequency of application, doxycycline preparation and use of additional drugs were investigated. Vomiting was reported in 18.3 per cent of dogs, 7.0 per cent developed diarrhoea and 2.5 per cent developed anorexia. While being treated with doxycycline, 39.4 per cent of dogs showed an increase in alanine aminotransferase (ALT) activity and 36.4 per cent showed an increase in alkaline phosphatase (ALP) activity. There was a dose-related risk of an increase in ALP activity (P=0.011, odds ratio [OR]=1.27, 95 per cent confidence interval [CI] 1.06 to 1.53), and older dogs treated with doxycycline were more likely to develop an increase in ALT activity (P=0.038, OR=1.23, 95 per cent CI 1.01 to 1.50) and vomiting (P=0.017, OR=1.11, 95 per cent CI 1.02 to 1.21).

Knocking down the transcript of protein kinase C-lambda modulates hypothalamic glutathione peroxidase, melanocortin receptor and neuropeptide Y gene expression in amphetamine-treated rats.

It has been reported that neuropeptide Y (NPY) contributes to the behavioral response of amphetamine (AMPH), a psychostimulant. The present study examined whether protein kinase C (PKC)-λ signaling was involved in this action. Moreover, possible roles of glutathione peroxidase (GP) and melanocortin receptor 4 (MC4R) were also examined. Rats were given AMPH daily for 4 days. Hypothalamic NPY, PKCλ, GP and MC4R were determined and compared. Pretreatment with α-methyl-para-tyrosine could block AMPH-induced anorexia, revealing that endogenous catecholamine was involved in regulating AMPH anorexia. PKCλ, GP and MC4R were increased with maximal response on Day 2 during AMPH treatment, which were concomitant with the decreases in NPY. cAMP response element binding protein (CREB) DNA binding activity was increased during AMPH treatment, revealing the involvement of CREB-dependent gene transcription. An interruption of cerebral PKCλ transcript could partly block AMPH-induced anorexia and partly reverse NPY, MC4R and GP mRNA levels to normal. These results suggest that PKCλ participates in regulating AMPH-induced anorexia via a modulation of hypothalamic NPY gene expression and that increases of GP and MC4R may contribute to this modulation. Our results provided molecular evidence for the regulation of AMPH-induced behavioral response.

The effect of protein kinase C-delta knockdown on anti-free radical enzyme and neuropeptide Y gene expression in phenylpropanolamine-treated rats.

Hypothalamic neuropeptide Y (NPY) has been reported to involve in regulating behavioral response of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored if protein kinase C (PKC)-delta signaling participated in this regulation. Moreover, possible roles of anti-free radical enzyme catalase (CAT) and nitrogen oxide synthase (NOS) were also examined. Rats were treated daily with PPA for 4 days. Changes in food intake and hypothalamic NPY, PKCdelta, CAT, and NOS contents were assessed and compared. Results showed that PKCdelta and CAT increased during PPA treatment, which were concomitant with decreases in NPY content and food intake, while the change of NOS was expressed differently. Moreover, PKCdelta knockdown could modify PPA anorexia as well as NPY and CAT expression, while NOS expression remained unchanged. Furthermore, pre-treatment with NOS inhibitor could modify both PPA anorexia and NPY content. It is suggested that PKCdelta participates in the anorectic response of PPA via the modulation of NPY and CAT, while NOS contribute to this modulation via a different mechanism during PPA treatment. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the therapeutic research of PPA and other anti-obesity drugs.

Atypical protein kinase C activity in the hypothalamus is required for lipopolysaccharide-mediated sickness responses.

By activating the Toll-like receptor 4-nuclear factor-kappaB signal transduction pathway, the bacterial endotoxin lipopolysaccharide (LPS) induces anorexia, weight loss, fever, and other components of the sickness response. By comparison, the hormones leptin and insulin cause anorexia without sickness via a central mechanism involving the phosphatidylinositol-3 kinase signaling pathway. In the current study, we investigated whether a common Toll-like receptor 4 and phosphatidylinositol-3 kinase signaling intermediate, atypical protein kinase Czeta/lambda (aPKC), contributes to changes of energy balance induced by these stimuli. Immunohistochemistry analysis revealed that aPKC is expressed in the arcuate and paraventricular nuclei of the hypothalamus, key sites of leptin, insulin, and LPS action. Although administration of LPS, insulin, and leptin each acutely increased hypothalamic aPKC activity at doses that also reduce food intake, LPS treatment caused over 10-fold greater activation of hypothalamic a PKC signaling than that induced by leptin or insulin. Intracerebroventricular pretreatment with an aPKC inhibitor blocked anorexia induced by LPS but not insulin or leptin. Similarly, LPS-induced hypothalamic inflammation (as judged by induction of proinflammatory cytokine gene expression) and neuronal activation in the paraventricular nucleus (as judged by c-fos induction) were reduced by central aPKC inhibition. Although intracerebroventricular aPKC inhibitor administration also abolished LPS-induced fever, it had no effect on sickness-related hypoactivity or weight loss. We conclude that although hypothalamic aPKC signaling is not required for food intake inhibition by insulin or leptin, it plays a key role in inflammatory anorexia and fever induced by LPS.

mPGES-1 knock-out mice are resistant to cancer-induced anorexia despite the absence of central mPGES-1 up-regulation in wild-type anorexic mice.

Anorexia-cachexia syndrome is a very common symptom observed in individuals affected by chronic inflammatory diseases. The present study was designed to address the possible involvement of the inducible microsomal prostaglandin E synthase-1 (mPGES-1) in the hypopaghia observed during these pathological states. To this end, we used a model of cancer-induced anorexia and we report here that despite the absence of up-regulation of the mPGES-1 enzyme within the brain during anorexia-cachexia syndrome, mPGES-1 knock-out mice exhibit resistance to tumor-induced anorexia and maintain their body mass.

A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia.

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1beta, and TNF-alpha and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.

Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA.

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.

Involvement of central microsomal prostaglandin E synthase-1 in IL-1beta-induced anorexia.

In response to infection or inflammation, individuals develop a set of symptoms referred to as sickness behavior, which includes a decrease in food intake. The characterization of the molecular mechanisms underlying this hypophagia remains critical, because chronic anorexia may represent a significant health risk. Prostaglandins (PGs) constitute an important inflammatory mediator family whose levels increase in the brain during inflammatory states, and their involvement in inflammatory-induced anorexia has been proposed. The microsomal PGE synthase (mPGES)-1 enzyme is involved in the last step of PGE2 biosynthesis, and its expression is stimulated by proinflammatory agents. The present study attempted to determine whether an upregulation of mPGES-1 gene expression may account for the immune-induced anorexic behavior. We focused our study on mPGES-1 expression in the hypothalamus and dorsal vagal complex, two structures strongly activated during peripheral inflammation and involved in the regulation of food intake. We showed that mPGES-1 gene expression was robustly upregulated in these structures after intraperitoneal and intracerebroventricular injections of anorexigenic doses of IL-1beta. This increase was correlated with the onset of anorexia. The concomitant reduction in food intake and central mPGES-1 gene upregulation led us to test the feeding behavior of mice lacking mPGES-1 during inflammation. Interestingly, IL-1beta failed to decrease food intake in mPGES-1(-/-) mice, although these animals developed anorexia in response to a PGE2 injection. Taken together, our results demonstrate that mPGES-1, which is strongly upregulated during inflammation in central structures involved in feeding control, is essential for immune anorexic behavior and thus may constitute a potential therapeutic target.

Stearoylethanolamide exerts anorexic effects in mice via down-regulation of liver stearoyl-coenzyme A desaturase-1 mRNA expression.

Given the recent demonstration that oleoylethanolamide (OEA), a cannabinoid receptor-inactive N-acylethanolamine, decreases food intake by activating the nuclear receptor PPARalpha (peroxisome proliferator-activated receptor alpha) in the periphery, we here evaluated the effects of both saturated and unsaturated C18 N-acylethanolamides (C18:0; C18:1; C18:2) in mice feeding behavior after overnight starvation. Our results show stearoylethanolamide (SEA, C18:0) exerts, unlike other unsaturated C18 homologs, a marked dose-dependent anorexic effect evident already at 2 h after its intraperitoneal administration. In addition, oral administration of SEA (25 mg/kg) was also effective in reducing food consumption, an effect ascribed to the molecule itself and not to its catabolites. Moreover, although the anorexic response to oral administered SEA was not associated with changes in the levels of various hematochemical parameters (e.g., glucose, cholesterol, triglycerides, leptin) nor in liver mRNA expression of peroxisome proliferator-activated receptors (PPARs) including PPARalpha, the anorexic effect of SEA was interestingly accompanied by a reduction in liver stearoyl-CoA desaturase-1 (SCD-1) mRNA expression. As SCD-1 has been recently proposed as a molecular target for the treatment of obesity, the novel observation provided here that SEA reduces food intake in mice in a structurally selective manner, in turn, correlated with downregulation of liver SCD-1 mRNA expression, has the potential of providing new insights on a class of lipid mediators with suitable properties for the pharmacological treatment of over-eating dysfunctions.

Involvement of protein kinase C and tyrosine kinase in lipopolysaccharide-induced anorexia.

Injections of lipopolysaccharide (LPS, 3 microg) into the lateral ventricle elicited anorexia with fever and also decreased body weight in rats. The LPS-induced anorexia was inhibited by intracerebroventicular (i.c.v.) injections of anti-interleukin (IL)-1beta antibody (Ab), chelerythrine, genistein and tyrphostin 46, but not by injections of indomethacin. Consecutive injections of orthovanadate and LPS (0.3 microg, a dose of LPS that did not show any effect on food intake, body weight or body temperature) reduced body weight, but did not induce anorexia. On the other hand, injections of IL-1beta (50 ng) did not influence food intake, although they decreased body weight and produced fever. The IL-1beta-induced decrease in body weight was inhibited by injections of genistein, but not by injections of chelerythrine or indomethacin. These findings suggest that the LPS-induced anorexia is independent of hyperthermia and involves IL-1beta generation, tyrosine kinase (TK) and protein kinase C (PKC). This is the first in vivo evidence that activation of TK and PKC induced by LPS is linked to anorexia.

Interleukin-1beta-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia.

Interleukin-1beta (IL-1beta) mediates many of the behavioral responses to infection and inflammation, and IL-1beta-converting enzyme (ICE) processes intracellular IL-1beta, leading to its maturation and secretion. Here we demonstrate that intracerebroventricular injections of lipopolysaccharide (LPS) produced a greater reduction in both food intake and food-motivated behavior in wild-type compared with ICE-deficient (ICE -/-) mice. This defect occurred although ICE -/- mice were able to fully respond to intracerebroventricular injections of IL-1beta. In contrast, ICE -/- mice remained fully responsive to intraperitoneal injections of LPS. These results indicate that brain, but not peripheral, IL-1beta plays a critical role in the depression in food intake that occurs during inflammation.

Differential expression of monoamine oxidase A, serotonin transporter, tyrosine hydroxylase and norepinephrine transporter mRNA by anorexia mutation and food deprivation.

The Anorexia (anx) mutation causes reduced food intake in preweanling mice, resulting in death from starvation within 3-4 weeks. We have found serotonin (5HT) hyperinnervation in the anx brain; altered noradrenergic (NE) innervation may also mediate eating disorders. We examined the expression of synthetic or catabolic monoamine enzyme genes in brainstem nuclei: serotonin transporter (5HTT) and monoamine oxidase A (MAOA) in the raphe nuclei (RN), and MAOA, norepinephrine transporter (NET), and tyrosine hydroxylase (TH) in the locus ceruleus (LC). We compared 3-week old anx with control and 24-h food-deprived wildtype littermates using in situ hybridization to measure mRNA levels by quantitative autoradiography. The anx mutation was correlated with decreased MAOA mRNA in the LC (but not RN), decreased 5HTT mRNA in the RN, and a trend towards lower NET mRNA in the LC. Food deprivation decreased MAOA mRNA in the LC (but not RN), increased TH mRNA in the LC, and did not alter NET or 5HTT mRNA levels. Thus, the effect of the anx mutation on MAOA expression in the LC paralleled the effect of food-deprivation, but the anx mutation and food-deprivation had differential effects on the expression of TH, NET, and 5HTT genes. Decreased 5HTT expression in the anx RN is consistent with upregulation of serotonergic neurotransmission that may accompany 5HT hyperinnervation. Central NE levels or innervation may be altered in anx mice by decreased expression of NET and MAOA and a lack of TH upregulation induced by food deprivation as in wild-type mice.

Correlation between serum creatine kinase activities and anorexia in cats.

There are no available biochemical analyses that will reliably identify malnourished cats or enable monitoring them during supportive alimentation. Studies in people indicate that creatine kinase (CK) activity is high in malnourished patients and may decrease in response to nutritional intervention. The purpose of this study was to determine the value of quantifying serum CK activities in anorectic cats and to assess the usefulness of this test in monitoring nutritional support in these patients. Serum CK activity was evaluated in nonanorectic cats (Group 1, n = 25), and in hospitalized, anorectic cats that received nutritional support through a nasoesophageal tube (Group 2, n = 25). Anorectic cats had a significantly higher serum CK activity (median = 2,529 U/ L, range 88 to 153,000 U/L) than the control group (median = 175 U/L, range 81 to 363 U/L, P < .001). There were significant positive correlations between serum CK and both aspartate transaminase (AST) (P < .05; r = .59) and lactate dehydrogenase (LDH) (P < .05; r = .41) activities. Serum CK activity was significantly lower in anorectic cats after 48 hours of nutritional support than at time 0 (P < .001) and eventually returned to normal with continued support. Serum CK activity may serve as a useful marker in assessing and monitoring nutritional status in cats.

Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate.

The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating). In skeletal muscle, a decreased proportion of PDH complex in the active, nonphosphorylated form (PDHa) limits glucose oxidation and promotes the conversion of pyruvate to lactate. Increased lactate formation with the accompanying hyperlactatemia is a frequent metabolic complication of sepsis. The time course for inactivation of the PDH complex in skeletal muscle during sepsis was contrasted with changes in PDHa during sterile inflammation 3,7, or 14 days following the implantation of the foreign body nidus. Total PDH complex activity was not altered in any of the conditions examined. Sepsis, but not sterile inflammation, caused a reduction in the muscle PDHa measured 3 or 7 days following induction of sepsis. The inhibition of the muscle PDHa during sepsis was associated with a sustained hyperlactatemia. PDH kinase activity measured in extracts of mitochondria was enhanced twofold during this period. Fourteen days after induction of sepsis, there were no differences in the PDHa or plasma lactate concentrations in septic rats compared with either control or sterile inflammation. Furthermore, the PDH kinase activity was decreased to values observed in control values. The results are consistent with the hypothesis that a reduced PDHa in skeletal muscle during sepsis is responsible, in part, for the hyperlactatemia characteristic of septic hypermetabolism. Furthermore, the results provide evidence that the decrease in PDHa results from a stable stimulation of PDH kinase activity.

Refractory hypothalamic adenylate cyclase in anorectic tumor-bearing rats: implications for NPY-induced feeding.

Although isoproterenol stimulated adenylate cyclase activity in hypothalamic membranes taken from freely-feeding, food-restricted or nonanorectic tumor-bearing rats, the response was greatly reduced in anorectic tumor-bearing rats. The addition of NPY to the membrane preparation inhibited adenylate cyclase activity in hypothalamus taken from freely-feeding and food-restricted rats, but NPY-inhibitory activity was significantly reduced in both groups of tumor-bearing rats. These results suggest that cyclic AMP formation is refractory in anorectic tumor-bearing rats, and that NPY-induced inhibition of hypothalamic adenylate cyclase is reduced in tumor-bearing rats prior to the onset of significant anorexia. Therefore, NPY-induced feeding may be reduced in tumor-bearing organisms due to a dysfunction in the cyclic AMP second messenger system.