RESUMO
OBJECTIVE: Anorexia nervosa (AN) is characterized by hyperactivation of the hypothalamic-pituitary-adrenal axis and cognitive deficits. However, little is known about the rapid non-genomic stress response involvement. This study investigates the molecular, structural and behavioral signatures of the anorexic phenotype induction in female rats on stress-related mechanisms in the hippocampus. METHOD: Female adolescent rats, exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, were sacrificed in the acute phase of the pathology (postnatal day [P]42) or following a 7-day recovery period (P49). RESULTS: ABA rats, in addition to body weight loss and increased wheel activity, alter their pattern of activity over days, showing increased food anticipatory activity, a readout of their motivation to engage in intense physical activity. Corticosterone plasma levels were enhanced at P42 while reduced at P49 in ABA rats. In the membrane fraction of the hippocampus, we found reduced glucocorticoid receptor levels together with reduced expression of caldesmon, n-cadherin and neuroligin-1, molecular markers of cytoskeletal stability and glutamatergic homeostasis. Accordingly, structural analyses revealed reduced dendritic spine density, a reduced number of mushroom-shaped spines, together with an increased number of thin-shaped spines. These events are paralleled by impairment in spatial memory measured in the spatial order object recognition test. These effects persisted even when body weight of ABA rats was restored. DISCUSSION: Our findings indicate that ABA induction orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.
Assuntos
Hipocampo , Animais , Feminino , Hipocampo/metabolismo , Ratos , Memória Espacial/fisiologia , Anorexia/metabolismo , Anorexia/fisiopatologia , Anorexia/patologia , Corticosterona/sangue , Estresse Psicológico/fisiopatologia , Estresse Psicológico/metabolismo , Transtornos da Memória/fisiopatologia , Transtornos da Memória/patologia , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Anorexia Nervosa/metabolismo , Anorexia Nervosa/fisiopatologia , Anorexia Nervosa/patologia , Modelos Animais de DoençasRESUMO
Anorexia nervosa is a feeding disorder involving intentional weight loss. Restricted dietary intake leads to disturbed bone metabolism due to various factors, notably endocrine, that affect bone microarchitecture and incur risk of fracture. Mild to moderate anorexia shows a paradoxical increase in bone marrow adipose tissue, whereas severe forms show gelatinous transformation known as serous atrophy of bone marrow (SABM). Imaging assessment of the mineralized and adipose components uses several techniques: dual-energy X-ray absorptiometry, computed tomography, chemical shift magnetic resonance imaging (MRI), and single-voxel MR spectroscopy. SABM induces MRI bone signal disturbances that can be hard to interpret and may hinder visualization of the fracture line.
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Anorexia Nervosa , Fraturas Ósseas , Humanos , Anorexia/diagnóstico por imagem , Anorexia/patologia , Medula Óssea , Anorexia Nervosa/diagnóstico por imagem , Anorexia Nervosa/patologia , Imageamento por Ressonância Magnética/métodos , Tecido Adiposo/patologia , Atrofia/patologia , Densidade ÓsseaRESUMO
Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunction in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assessment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have significantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.
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Anorexia , Sistema Nervoso Entérico , Animais , Anorexia/metabolismo , Anorexia/patologia , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Percepção da Dor , Modelos Animais , DorRESUMO
BACKGROUND: Global energy balance is a vital process tightly regulated by the brain that frequently becomes dysregulated during the development of cancer. Glioblastoma (GBM) is one of the most investigated malignancies, but its appetite-related disorders, like anorexia/cachexia symptoms, remain poorly understood. METHODS: We performed manganese enhanced magnetic resonance imaging (MEMRI) and subsequent diffusion tensor imaging (DTI), in adult male GBM-bearing (n = 13) or control Wistar rats (n = 12). A generalized linear model approach was used to assess the effects of fasting in different brain regions involved in the regulation of the global energy metabolism: cortex, hippocampus, hypothalamus and thalamus. The regions were selected on the contralateral side in tumor-bearing animals, and on the left hemisphere in control rats. An additional DTI-only experiment was completed in two additional GBM (n = 5) or healthy cohorts (n = 6) to assess the effects of manganese infusion on diffusion measurements. RESULTS: MEMRI results showed lower T1 values in the cortex (p-value < 0.001) and thalamus (p-value < 0.05) of the fed ad libitum GBM animals, as compared to the control cohort, consistent with increased Mn2+ accumulation. No MEMRI-detectable differences were reported between fed or fasting rats, either in control or in the GBM group. In the MnCl2-infused cohorts, DTI studies showed no mean diffusivity (MD) variations from the fed to the fasted state in any animal cohort. However, the DTI-only set of acquisitions yielded remarkably decreased MD values after fasting only in the healthy control rats (p-value < 0.001), and in all regions, but thalamus, of GBM compared to control animals in the fed state (p-value < 0.01). Fractional anisotropy (FA) decreased in tumor-bearing rats due to the infiltrate nature of the tumor, which was detected in both diffusion sets, with (p-value < 0.01) and without Mn2+ administration (p-value < 0.001). CONCLUSIONS: Our results revealed that an altered physiological brain response to fasting occurred in hunger related regions in GBM animals, detectable with DTI, but not with MEMRI acquisitions. Furthermore, the present results showed that Mn2+ induces neurotoxic inflammation, which interferes with diffusion MRI to detect appetite-induced responses through MD changes.
Assuntos
Glioblastoma , Masculino , Ratos , Animais , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Imagem de Tensor de Difusão/métodos , Manganês , Anorexia/patologia , Ratos Wistar , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/métodos , JejumRESUMO
Cachexia is a devastating, multifactorial and often irreversible systemic syndrome characterized by substantial weight loss (mainly of skeletal muscle and adipose tissue) that occurs in around 50-80% of patients with cancer. Although this condition mainly affects skeletal muscle (which accounts for approximately 40% of total body weight), cachexia is a multi-organ syndrome that also involves white and brown adipose tissue, and organs including the bones, brain, liver, gut and heart. Notably, cachexia accounts for up to 20% of cancer-related deaths. Cancer-associated cachexia is invariably associated with systemic inflammation, anorexia and increased energy expenditure. Understanding these mechanisms is essential, and the progress achieved in this area over the past decade could help to develop new therapeutic approaches. In this Review, we examine the currently available evidence on the roles of both the tumour macroenvironment and microenvironment in cancer-associated cachexia, and provide an overview of the novel therapeutic strategies developed to manage this syndrome.
Assuntos
Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Neoplasias/complicações , Neoplasias/patologia , Tecido Adiposo/patologia , Músculo Esquelético/patologia , Anorexia/complicações , Anorexia/patologia , Microambiente TumoralRESUMO
Cancer cachexia demonstrates the same pathology as cachexia found in patients with disease-associated malnutrition presenting with inflammation. In advanced cancer, a decrease in skeletal muscle mass progresses with an increase in cancer cell mass. Moreover, cancer cachexia causes systemic edema and cachexia, reduces the efficacy of chemotherapy, and negatively affects cancer prognosis. Early nutritional intervention and multidisciplinary care are essential to ensure sufficient nutritional requirements and minimize anabolic resistance factors. In addition, preventive care that minimizes deterioration of nutritional status and loss of skeletal muscle mass is required for the effective treatment of cachexia. Therefore, the current review sought to comprehensively describe the available evidence for the effective pharmaceutical treatment of cancer-associated cachexia. Steroids have traditionally been used for cachexia drug therapy. However, their effects are limited, and it is difficult to radically restore the highly reduced muscle mass inherent to cancer-associated cachexia. Recently, anamorelin hydrochloride, an endogenous ligand for the growth hormone release-promoting factor receptor, which has a similar pharmacological action to that of ghrelin, was developed to treat weight loss accompanied by anorexia. This medication also treats cachexia and was the first drug to be approved for this purpose. Anamorelin hydrochloride is expected to bring new advancements into the field of clinical oncology as an effective therapeutic drug for cancer cachexia, a devastating complication that, so far, has no definitive and effective treatment.
Assuntos
Desnutrição , Neoplasias , Humanos , Caquexia/tratamento farmacológico , Caquexia/etiologia , Neoplasias/complicações , Resultado do Tratamento , Anorexia/tratamento farmacológico , Anorexia/etiologia , Anorexia/patologiaRESUMO
OBJECTIVES: To study the clinical and gastroscopic features of children with cyclic vomiting syndrome. METHODS: A retrospective analysis was performed on the medical data of 63 children with cyclic vomiting syndrome who were hospitalized and followed up in Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University from August 2019 to March 2022. RESULTS: Among the 63 children, there were 30 boys and 33 girls, with a mean age of 6.11 years, a mean course of disease of 2.57 years, and a mean vomiting period of 4.04 days. The most common accompanying symptom was listlessness or somnolence (55/63, 87%), followed by anorexia (45/63, 71%), abdominal pain or abdominal discomfort (40/63, 63%), constipation (19/63, 30%), salivation (12/63, 19%), nausea (11/63, 17%), headache (11/63, 17%), fever (6/63, 10%), and rash (1/63, 2%). All 63 children underwent gastroscopy, among whom 3 had no marked abnormalities, 22 (35%) had chronic superficial gastritis or chronic non-atrophic gastritis alone, and 38 (60%) had other abnormal changes aside from chronic gastritis (16 children with reflux esophagitis, 12 with bile reflux gastritis, 13 with duodenitis, 10 with erosive gastritis, and 5 with gastric or duodenal ulcer). Among the 63 children, 42 underwent pathological examinations of gastric mucosa, among whom 5 had no marked abnormalities, 34 had mild chronic gastritis, 2 had moderate chronic gastritis, and 1 had severe chronic gastritis. Among the 63 children, 15 received 24-hour dynamic esophageal pH monitoring during the interictal period, among whom 9 children were found to have pathological acid reflux. CONCLUSIONS: In addition to recurrent vomiting, most children with cyclic vomiting syndrome also have the symptoms such as somnolence or listlessness, anorexia, and abdominal pain. The main manifestation on gastroscopy is chronic gastritis, and most children may also have reflux esophagitis, bile reflux gastritis, and erosive gastritis. Mild chronic gastritis is the main pathological change of gastric mucosa.
Assuntos
Refluxo Biliar , Esofagite Péptica , Gastrite , Masculino , Feminino , Humanos , Criança , Gastroscopia , Esofagite Péptica/patologia , Refluxo Biliar/patologia , Anorexia/patologia , Estudos Retrospectivos , Sonolência , Gastrite/diagnóstico , Gastrite/patologia , Mucosa Gástrica/patologia , Vômito/etiologia , Vômito/patologia , Dor AbdominalRESUMO
OBJECTIVE: Identifying risk factors that contribute to the development of anorexia nervosa (AN) is critical for the implementation of early intervention strategies. Anxiety, obsessive-compulsive behavior, and immune dysfunction may be involved in the development of AN; however, their direct influence on susceptibility to the condition remains unclear. Here, we used the activity-based anorexia (ABA) model to examine whether activity, anxiety-like behavior, compulsive behavior, and circulating immune markers predict the subsequent development of pathological weight loss. METHOD: Female Sprague-Dawley rats (n = 44) underwent behavioral testing before exposure to ABA conditions after which they were separated into susceptible and resistant subpopulations. Blood was sampled before behavioral testing and after recovery from ABA to screen for proinflammatory cytokines. RESULTS: Rats that were vulnerable to pathological weight loss differed significantly from resistant rats on all key ABA parameters. While the primary measures of anxiety-like or compulsive behavior were not shown to predict vulnerability to ABA, increased locomotion and anxiety-like behavior were both associated with the extent of weight loss in susceptible but not resistant animals. Moreover, the change in expression of proinflammatory markers IL-4 and IL-6 evoked by ABA was associated with discrete vulnerability factors. Intriguingly, behavior related to risk assessment was shown to predict vulnerability to ABA. DISCUSSION: We did not find undisputable behavioral or immune predictors of susceptibility to pathological weight loss in the ABA rat model. Future research should examine the role of cognition in the development of ABA, dysfunction of which may represent an endophenotype linking anorectic, anxiety-like and compulsive behavior. PUBLIC SIGNIFICANCE: Anorexia nervosa (AN) has among the highest mortality rates of all psychiatric disorders and treatment options remain limited in their efficacy. Understanding what types of risk factors contribute to the development of AN is essential for implementing early intervention strategies. This study describes how some of the most common psychological features of AN could be used to predict susceptibility to pathological weight loss in a well-established animal model.
Assuntos
Anorexia Nervosa , Anorexia , Adolescente , Animais , Anorexia/patologia , Anorexia Nervosa/diagnóstico , Biomarcadores , Modelos Animais de Doenças , Feminino , Humanos , Ratos , Ratos Sprague-Dawley , Redução de Peso/fisiologiaRESUMO
Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamento farmacológico , Ipilimumab/administração & dosagem , Carcinomatose Meníngea/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Anorexia/induzido quimicamente , Anorexia/mortalidade , Anorexia/patologia , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Colite/induzido quimicamente , Colite/mortalidade , Colite/patologia , Exantema/induzido quimicamente , Exantema/mortalidade , Exantema/patologia , Fadiga/induzido quimicamente , Fadiga/mortalidade , Fadiga/patologia , Feminino , Febre/induzido quimicamente , Febre/mortalidade , Febre/patologia , Hepatite/etiologia , Hepatite/mortalidade , Hepatite/patologia , Humanos , Ipilimumab/efeitos adversos , Masculino , Carcinomatose Meníngea/mortalidade , Carcinomatose Meníngea/patologia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/patologia , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/mortalidade , Náusea/patologia , Nivolumabe/efeitos adversos , Análise de SobrevidaRESUMO
Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.
Assuntos
Anorexia/metabolismo , Anorexia/microbiologia , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal , Mucosa Intestinal/microbiologia , Obesidade/microbiologia , Peptídeo YY/metabolismo , Receptores Odorantes/metabolismo , Animais , Anorexia/patologia , Células Cultivadas , Modelos Animais de Doenças , Células Enteroendócrinas/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologiaRESUMO
During its evolution, cancer induces changes in patients' energy metabolism that strongly affect the overall clinical state and are responsible for cancer-related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of "resistance" and "tolerance" typically involved in the human body response against stress, pathogens, or cancer. Indeed, in the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death.
Assuntos
Caquexia/genética , Metabolismo Energético/genética , Tolerância Imunológica/genética , Neoplasias/genética , Anorexia/genética , Anorexia/metabolismo , Anorexia/patologia , Caquexia/complicações , Caquexia/metabolismo , Caquexia/patologia , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Qualidade de VidaRESUMO
Sleep apnea syndrome (SAS) is a breathing disorder characterized by recurrent episodes of upper-airway collapse, resulting in intermittent hypoxia (IH) during sleep. Experimental studies with animals and cellular models have indicated that IH leads to attenuation of glucose-induced insulin secretion from pancreatic ß cells and to enhancement of insulin resistance in peripheral tissues and cells, such as the liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes), both of which could lead to obesity. Although obesity is widely recognized as a major factor in SAS, it is controversial whether the development of SAS could contribute directly to obesity, and the effect of IH on the expression of appetite regulatory genes remains elusive. Appetite is regulated appropriately by both the hypothalamus and the gut as a gut-brain axis driven by differential neural and hormonal signals. In this review, we summarized the recent epidemiological findings on the relationship between SAS and feeding behavior and focused on the anorexigenic effects of IH on the gut-brain axis by the IH-induced up-regulation of proopiomelanocortin and cocaine- and amphetamine-regulated transcript in neuronal cells and the IH-induced up-regulation of peptide YY, glucagon-like peptide-1 and neurotensin in enteroendocrine cells and their molecular mechanisms.
Assuntos
Anorexia/patologia , Eixo Encéfalo-Intestino , Hipóxia/complicações , Síndromes da Apneia do Sono/complicações , Animais , Apetite , Glucose/metabolismo , Humanos , Hipóxia/genéticaRESUMO
Estradiol (E2) enhances the anorectic action of apolipoprotein A-IV (apoA-IV), however, the intracellular mechanisms are largely unclear. Here we reported that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway was significantly activated by E2 and apoA-IV, respectively, in primary neuronal cells isolated from rat embryonic brainstem. Importantly, the combination of E2 and apoA-IV at their subthreshold doses synergistically activated the PI3K/Akt signaling pathway. These effects, however, were significantly diminished by the pretreatment with LY294002, a selective PI3K inhibitor. E2-induced activation of the PI3K/Akt pathway was through membrane-associated ERα, because the phosphorylation of Akt was significantly increased by PPT, an ERα agonist, and by E2-BSA (E2 conjugated to bovine serum albumin) which activates estrogen receptor on the membrane. Centrally administered apoA-IV at a low dose (0.5 µg) significantly suppressed food intake and increased the phosphorylation of Akt in the nucleus tractus solitarius (NTS) of ovariectomized (OVX) rats treated with E2, but not in OVX rats treated with vehicle. These effects were blunted by pretreatment with LY294002. These results indicate that E2's regulatory role in apoA-IV's anorectic action is through the ERα-PI3K pathway in the NTS. Manipulation of the PI3K/Akt signaling activation in the NTS may provide a novel therapeutic approach for the prevention and the treatment of obesity-related disorders in females.
Assuntos
Anorexia , Apolipoproteínas A/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Núcleo Solitário , Animais , Anorexia/induzido quimicamente , Anorexia/metabolismo , Anorexia/patologia , Feminino , Ratos , Ratos Long-Evans , Núcleo Solitário/metabolismo , Núcleo Solitário/patologiaRESUMO
Obesity-associated low-grade inflammation favors weight gain, whereas systemic infection frequently leads to anorexia. Thus, inflammatory signals can either induce positive or negative energy balance. In this study, we used whole-cell patch-clamp to investigate the acute effects of three important proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-6, and interleukin-1ß (IL-1ß) on the membrane excitability of agouti-related peptide (AgRP)- or proopiomelanocortin (POMC)-producing neurons. We found that both TNF-α and IL-1ß acutely inhibited the activity of 35-42% of AgRP-producing neurons, whereas very few POMC neurons were depolarized by TNF-α. Interleukin-6 induced no acute changes in the activity of AgRP or POMC neurons. Our findings indicate that the effect of TNF-α and IL-1ß, especially on the activity of AgRP-producing neurons, may contribute to inflammation-induced anorexia observed during acute inflammatory conditions.
Assuntos
Proteína Relacionada com Agouti/genética , Inflamação/genética , Interleucina-1beta/genética , Obesidade/genética , Fator de Necrose Tumoral alfa/genética , Animais , Anorexia/genética , Anorexia/metabolismo , Anorexia/patologia , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Metabolismo Energético , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/genética , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeo Y/genética , Obesidade/metabolismo , Obesidade/patologia , Técnicas de Patch-Clamp , Pró-Opiomelanocortina/genéticaRESUMO
The LPBN (lateral parabrachial nucleus) plays an important role in feeding control. CGRP (calcitonin gene-related peptide) LPBN neurons activation mediates the anorectic effects of different gut-derived peptides, including amylin. Amylin and its long acting analog sCT (salmon calcitonin) exert their anorectic actions primarily by directly activating neurons located in the area postrema (AP). A large proportion of projections from the AP and the adjacent nucleus of the solitary tractNTS to the LPBN, are noradrenergic (NA), and amylin-activated NAAP neurons are critical in mediating amylin's hypophagic effects. Here, we determine the functional role of NAAP amylin activated neurons to activate CGRP and non-CGRP LPBN neurons. To this end, NA was specifically depleted in the rat LPBN through a stereotaxic microinfusion of 6-OHDA, a neurotoxic agent that destroys NA terminals. While amylin (50 µg/kg) and sCT (5 µg/kg) reduced eating in sham-lesioned rats, no reduction in feeding occurred in NA-depleted animals. Further, the amylin-induced c-Fos response in the LPBN and c-Fos/CGRP colocalization were reduced in NA-depleted animals compared to controls. We conclude that AP â LPBN NA signaling, through the activation of LPBN CGRP neurons, mediates part of amylin's hypophagic effect.
Assuntos
Anorexia/tratamento farmacológico , Calcitonina/metabolismo , Ingestão de Alimentos/fisiologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Neurônios/efeitos dos fármacos , Norepinefrina/farmacologia , Núcleos Parabraquiais/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Agonistas dos Receptores da Amilina/farmacologia , Animais , Anorexia/metabolismo , Anorexia/patologia , Calcitonina/genética , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Núcleos Parabraquiais/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15. Pica, a marker of visceral malaise, is present at all anorectic GDF15 doses. Moreover, malaise induced by GDF15 does not decline over time, suggesting the lack of an improved tolerance after prolonged exposure. One association between GDF15 and novel food conditions a disgust/aversive response that persists beyond GDF15 acute action. Delayed GE is not a requirement for GDF15-induced anorexia. Clinical studies are required to evaluate whether GDF15's aversive-state-based anorexia will be contraindicated as an obesity treatment.
Assuntos
Anorexia/induzido quimicamente , Fator 15 de Diferenciação de Crescimento/administração & dosagem , Obesidade/tratamento farmacológico , Redução de Peso/efeitos dos fármacos , Animais , Anorexia/metabolismo , Anorexia/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagemRESUMO
Neuropeptide K (NPK) induces satiety in birds and mammals. We demonstrated that in birds this effect was associated with the hypothalamus, but beyond this little is known in any species regarding the central mechanism of action. Thus, this study was designed to identify hypothalamic molecular mechanisms associated with the food intake-inhibiting effects of NPK in chicks. In Experiment 1, intracerebroventricular (ICV) injection of 1.0 and 3.0â¯nmol of NPK reduced food intake and we identified an effective dose for microinjection. In Experiment 2, food intake was reduced when NPK was microinjected into the PVN. In Experiment 3, whole hypothalamus was collected from chicks at 1â¯h post-ICV NPK injection. The abundance of corticotropin-releasing factor (CRF) and agouti-related peptide (AgRP) mRNA was reduced in NPK-injected chicks. In Experiment 4, within the isolated paraventricular nucleus (PVN) there was less CRF mRNA, and within the arcuate nucleus (ARC) there was less AgRP mRNA, in NPK- than vehicle-treated chicks at 1â¯h post-injection. We conclude that there are first order neurons for NPK that reside within the PVN, and the anorexigenic effect of NPK is associated with a decrease in AgRP in the ARC.
Assuntos
Anorexia/tratamento farmacológico , Depressores do Apetite/farmacologia , Ingestão de Alimentos/genética , Taquicininas/farmacologia , Proteína Relacionada com Agouti/genética , Animais , Anorexia/genética , Anorexia/patologia , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Galinhas , Hormônio Liberador da Corticotropina/genética , Modelos Animais de Doenças , Ingestão de Líquidos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Infusões Intraventriculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , RNA Mensageiro/genética , Taquicininas/genéticaRESUMO
Central administration of neuropeptide K (NPK), a 36-amino acid peptide, is associated with anorexigenic effects in rodents and chickens. The mechanisms underlying the potent anorexigenic effects of NPK are still poorly understood. Thus, the aim of the present study was to identify the hypothalamic nuclei and neuropeptides that mediate anorexic effects of NPK in 7â¯day-old Japanese quail (Coturnix japonica). After a 6â¯h fast, intracerebroventricular (ICV) injection of NPK decreased food and water intake for 180â¯min post-injection. Quail injected with NPK had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), lateral hypothalamus, and paraventricular nucleus (PVN) compared to the birds that were injected with the vehicle. In the ARC of NPK-injected quail, there was decreased neuropeptide Y (NPY), NPY receptor sub-type 1, and agouti-related peptide mRNA, and increased CART, POMC, and neurokinin receptor 1 mRNA. NPK-injected quail expressed greater amounts of corticotropin-releasing factor (CRF), CRF receptor sub-type 2, melanocortin receptors 3 and 4, and urocortin 3 mRNA in the PVN. In conclusion, results provide insights into understanding NPK-induced changes in hypothalamic physiology and feeding behavior, and suggest that the anorexigenic effects of NPK involve the ARC and PVN, with increased CRF and melanocortin and reduced NPY signaling.
Assuntos
Anorexia/genética , Coturnix/metabolismo , Hipotálamo/metabolismo , Taquicininas/farmacologia , Animais , Anorexia/induzido quimicamente , Anorexia/metabolismo , Anorexia/patologia , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Coturnix/genética , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Infusões Intraventriculares , Proteínas do Tecido Nervoso/genética , Neuropeptídeo Y/genética , Pró-Opiomelanocortina/genética , Proteínas Proto-Oncogênicas c-fos/genética , Receptores de Melanocortina/genética , Taquicininas/metabolismo , Urocortinas/genéticaRESUMO
BACKGROUND/AIM: Treatments for controlling delayed nausea after chemotherapy are inadequate, potentially inciting malnutrition. We sought to determine the incidence of nausea, anorexia, and food intake after chemotherapy. PATIENTS AND METHODS: Subjects were females with gynecological cancers who underwent chemotherapy between 2008 and 2013. Nausea, anorexia, and food intake in the acute (day 1) and delayed phases (days 2 and 3) were retrospectively evaluated. RESULTS: Subjects included 156 females. Chemotherapies were highly (HEC; n=24) and moderately emetogenic (MEC; n=132). There were no significant between-group differences for anorexia control during either the acute or the delayed phase and both groups demonstrated significantly worse control of nausea during the delayed phase. In the HEC group, food intake was significantly reduced on days 2 and 3 compared with day 1. CONCLUSION: Rates of nausea, anorexia, and food intake significantly worsened over time, particularly in the MEC group. Current supportive therapies appear inadequate and should be improved.
Assuntos
Anorexia/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Ingestão de Alimentos , Neoplasias dos Genitais Femininos/tratamento farmacológico , Adulto , Idoso , Anorexia/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/patologia , Humanos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/epidemiologia , Náusea/patologia , Vômito/induzido quimicamente , Vômito/epidemiologia , Vômito/patologiaRESUMO
BACKGROUND: The optimal prognostic factors in patients with advanced cancer are not known, as a comparison of these is lacking. The aim of the present study was to determine the optimal prognostic factors by comparing validated factors. MATERIALS AND METHODS: A multicenter, prospective observational cohort study recruited patients over 18 years with advanced cancer. The following were assessed: clinician-predicted survival (CPS), Eastern Cooperative Oncology Group performance status (ECOG-PS), patient reported outcome measures (anorexia, cognitive impairment, dyspnea, global health), metastatic disease, weight loss, modified Glasgow Prognostic Score (mGPS) based on C-reactive protein and albumin, lactate dehydrogenase (LDH), and white (WCC), neutrophil (NC), and lymphocyte cell counts. Survival at 1 and 3 months was assessed using area under the receiver operating curve and logistic regression analysis. RESULTS: Data were available on 478 patients, and the median survival was 4.27 (1.86-7.03) months. On univariate analysis, the following factors predicted death at 1 and 3 months: CPS, ECOG-PS, mGPS, WCC, NC (all p < .001), dyspnea, global health (both p ≤ .001), cognitive impairment, anorexia, LDH (all p < .01), and weight loss (p < .05). On multivariate analysis ECOG-PS, mGPS, and NC were independent predictors of survival at 1 and 3 months (all p < .01). CONCLUSION: The simple combination of ECOG-PS and mGPS is an important novel prognostic framework which can alert clinicians to patients with good performance status who are at increased risk of having a higher symptom burden and dying at 3 months. From the recent literature it is likely that this framework will also be useful in referral for early palliative care with 6-24 months survival. IMPLICATIONS FOR PRACTICE: This large cohort study examined all validated prognostic factors in a head-to-head comparison and demonstrated the superior prognostic value of the Eastern Cooperative Oncology Group performance status (ECOG-PS)/modified Glasgow Prognostic Score (mGPS) combination over other prognostic factors. This combination is simple, accurate, and also relates to quality of life. It may be useful in identifying patients who may benefit from early referral to palliative care. It is proposed ECOG-PS/mGPS as the new prognostic domain in patients with advanced cancer.