Current advancements in pharmacotherapy for cancer cachexia.

INTRODUCTION: Cancer cachexia is a multifactorial metabolic syndrome associated with a pathophysiology intertwined with increased inflammatory response, anorexia, metabolic dysregulation, insulin resistance, and hormonal alterations, which together generate a negative energy balance in favor of catabolism. The development of therapeutic strategies to treat cancer cachexia has always been related to clinical interventions with increased food intake/supplementation, physical exercise regimens, and/or medication to attenuate catabolism and increase the anabolic response. However, the approval of drugs by regulatory agencies has always been a challenge. AREAS COVERED: This review outlines the main pharmacotherapy findings in cancer cachexia as well as the ongoing clinical trials that have evaluated changes in body composition and muscle function. The National Library of Medicine (PubMed) was used as search tool. EXPERT OPINION: The pharmacological therapy for cachexia should be focused on improving body composition, muscle function, and mortality, although none of the compounds used so far was able to demonstrate positive results beyond increased appetite and improvements in body composition. Ponsegromab (GDF15 inhibitor), a new compound that has just entered a phase II clinical trial, is a promising candidate to treat cancer cachexia and may produce exciting results if the study can be conducted as planned.

Anorexia disrupts glutamate-glutamine homeostasis associated with astroglia in the prefrontal cortex of young female rats.

Anorexia nervosa (AN) is an eating disorder characterized by self-starvation and excessive weight loss with a notorious prevalence in young women. The neurobiology of AN is unknown but murine models, like dehydration induced anorexia (DIA), reproduce weight loss and avoidance of food despite its availability. Astrocytes are known to provide homeostatic support to neurons, but it is little explored if anorexia affects this function. In this study, we tested if DIA disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex (PFC) of young female rats. Our results showed that anorexia reduced the redox state, as well as endogenous glutamate and glutamine. These effects correlated with a reduced expression of the glutamate transporters (GLT-1 and GLAST) and glutamine synthetase, all of them are preferentially expressed by astrocytes. Accordingly, the expression of GFAP was reduced. Anorexia reduced the astrocyte density, promoted a de-ramified morphology, and augmented the de-ramified/ramified astrocyte ratio in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC), but not in the motor cortex (M2). The increase of a de-ramified phenotype correlated with increased expression of vimentin and nestin. Based on these results, we conclude that anorexia disrupts glutamate-glutamine homeostasis and the redox state associated with astrocyte dysfunction.

Tumor Necrosis Factor α and Interleukin-1ß Acutely Inhibit AgRP Neurons in the Arcuate Nucleus of the Hypothalamus.

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.

Role of parathyroid hormone in anorexia on maintenance hemodialysis patients.

BACKGROUND AND AIM: Anorexia, which is a common condition in patients on hemodialysis (HD), is characterized by impaired appetite, a subjective condition that hinders anorexia diagnosis. Anorexia is frequently associated with protein energy wasting and inflammation, increasing morbidity and mortality risk. The aim of the study was to evaluate the association between appetite and nutritional, inflammatory, hormonal, and dietary intake parameters in patients on maintenance HD. METHODS: Cross-sectional study with clinical, laboratory, and anthropometric parameters, body composition, muscle function, and dietary intake assessment. To evaluate appetite, a three simple questions questionnaire previously validated was used. After appetite classification, the sample was dichotomized in "normal appetite" and "impaired appetite" and compared. Multiple logistic regression was used to identify association between variables and outcome. RESULTS: 125 patients on HD were included, aged 60.6 ± 14.12 years old, median HD vintage 35.5 months. In dichotomized sample, 78.4% patients showed "normal appetite", and 21.6% "impaired appetite". "Impaired appetite" was independently associated with increased serum PTH (OR 1.001; 95% CI 1.000-1.002; p = 0.03), low zinc intake (OR 0.860; 95% CI 0.746-0.991; p = 0.03) and lower urea serum (OR 0.982; 95% CI 0.965-0.999; p = 0.04). Both groups showed insufficient dietary intake. CONCLUSIONS: Appetite was independently associated with increased serum of PTH, low serum concentration of urea, and low zinc intake which may infer association of appetite with mineral bone disease, protein intake and zinc deficiency.

Anorexia increases microglial density and cytokine expression in the hippocampus of young female rats.

Anorexia by osmotic dehydration is an adaptive response to hypernatremia and hyperosmolaemia induced by ingestion of a hypertonic solution. Dehydration-induced anorexia (DIA) reproduces weight loss and avoidance of food, despite its availability. By using this model, we previously showed increased reactive astrocyte density in the rat dorsal hippocampus, suggesting a pro-inflammatory environment where microglia may play an important role. However, whether such anorexic condition increases a pro-inflammatory response is unknown. The aim of this study was to test if DIA increases microglial density in the dorsal hippocampus, as well as the expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1ß) in the hippocampus of young female rats. Our results showed that DIA significantly increased microglial density in CA2-CA3 and dentate gyrus (DG) but not in CA1. However, forced food restriction (FFR) only increased microglial density in the DG. Accordingly, the activated/resting microglia ratio was significantly increased in CA2-CA3 and DG, in DIA and FFR groups. Finally, western blot analysis showed increased expression of IBA1, TNF-α, IL-6 and IL-1ß in the hippocampus of both experimental groups. We conclude that anorexia triggers increased reactive microglial density and expression of TNF-α, IL-6 and IL-1ß; this environment may result in hippocampal neuroinflammation.

Anorexia Reduces GFAP+ Cell Density in the Rat Hippocampus.

Anorexia nervosa is an eating disorder observed primarily in young women. The neurobiology of the disorder is unknown but recently magnetic resonance imaging showed a volume reduction of the hippocampus in anorexic patients. Dehydration-induced anorexia (DIA) is a murine model that mimics core features of this disorder, including severe weight loss due to voluntary reduction in food intake. The energy supply to the brain is mediated by astrocytes, but whether their density is compromised by anorexia is unknown. Thus, the aim of this study was to estimate GFAP+ cell density in the main regions of the hippocampus (CA1, CA2, CA3, and dentate gyrus) in the DIA model. Our results showed that GFAP+ cell density was significantly reduced (~20%) in all regions of the hippocampus, except in CA1. Interestingly, DIA significantly reduced the GFAP+ cells/nuclei ratio in CA2 (-23%) and dentate gyrus (-48%). The reduction of GFAP+ cell density was in agreement with a lower expression of GFAP protein. Additionally, anorexia increased the expression of the intermediate filaments vimentin and nestin. Accordingly, anorexia increased the number of reactive astrocytes in CA2 and dentate gyrus more than twofold. We conclude that anorexia reduces the hippocampal GFAP+ cell density and increases vimentin and nestin expression.

Hypothalamic inflammation and the central nervous system control of energy homeostasis.

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.

Pielonefrite contagiosa bovina em vaca holandesa: relato de caso / Contagious bovine pyelonephritis in Holstein cow: a case report / Pielonefritis bovina constagiosa en vaca holandesa - Relato de caso

O presente estudo foi conduzido com o objetivo de relatar um caso de pielonefrite contagiosa na espécie bovina. Uma fêmea bovina holandesa de 600 kg e que havia parido há 20 dias apresentava sinais clínicos de apatia, anorexia, sialorreia, normoquesia, disúria, diminuição da ingestão de água e bruxismo. No exame físico apresentou taquipneia, taquicardia e temperatura retal elevada. Foi realizada uma ruminotomia para descartar reticuloperitonite. Na laparotomia exploratória notou-se o rim esquerdo hiperatrofiado com ausência de lobulação, dor à palpação e espessamento da parede da bexiga. O tratamento instituído foi com o antibiótico penicilina. O diagnóstico presuntivo foi pielonefrite contagiosa, sendo concluído com base nos sinais clínicos e na resposta imediata ao tratamento, corroborando com o caso descrito.

This study was conducted in order to report a case of contagious pyelonephritis in cattle. A 600-kg female Holstein cow, calved 20 days before, presented clinical signs of lethargy, anorexia, drooling, normoquesia, dysuria, decreased water intake and bruxism. On physical examination, it showed tachypnea, tachycardia and pyrexia. Ruminotomia was performed to rule out a diagnosis of reticuloperitonite. During an exploratory laparotomy, hypertrophy in the left kidney with no lobulation, pain on palpation and thickening of the bladder wall was noticed. The treatment was performed with penicillin. The presumptive diagnosis was contagious pyelonephritis, and it was completed based on the clinical signs and the immediate response to treatment, supporting the case described.

Este estudio se realizó con el objetivo de informar un caso de pielonefritis bovina contagiosa. Una hembra bovina holandesa de 600 kg y que había parido hacía 20 días presentaba signos clínicos de apatía, anorexia, salivación, normoquesia, disuria, disminución de ingestión de agua y bruxismo. En la exploración física presentó taquipnea, taquicardia y fiebre. Se realizó ruminotomia para descartar reticuloperitonitis. En la laparotomía exploradora se observó el riñón izquierdo hipertrofico sin lobulación, dolor a la palpación y engrosamiento de la pared vesical. El tratamiento fue con penicilina. El diagnóstico presuntivo fue pielonefritis contagiosa, que se completó con base en los signos clínicos y en la respuesta inmediata al tratamiento, corroborando con el caso descrito.

MCT2 expression and lactate influx in anorexigenic and orexigenic neurons of the arcuate nucleus.

Hypothalamic neurons of the arcuate nucleus control food intake, releasing orexigenic and anorexigenic neuropeptides in response to changes in glucose concentration. Several studies have suggested that the glucosensing mechanism is governed by a metabolic interaction between neurons and glial cells via lactate flux through monocarboxylate transporters (MCTs). Hypothalamic glial cells (tanycytes) release lactate through MCT1 and MCT4; however, similar analyses in neuroendocrine neurons have yet to be undertaken. Using primary rat hypothalamic cell cultures and fluorimetric assays, lactate incorporation was detected. Furthermore, the expression and function of MCT2 was demonstrated in the hypothalamic neuronal cell line, GT1-7, using kinetic and inhibition assays. Moreover, MCT2 expression and localization in the Sprague Dawley rat hypothalamus was analyzed using RT-PCR, in situ hybridization and Western blot analyses. Confocal immunohistochemistry analyses revealed MCT2 localization in neuronal but not glial cells. Moreover, MCT2 was localized to ∼90% of orexigenic and ~60% of anorexigenic neurons as determined by immunolocalization analysis of AgRP and POMC with MCT2-positives neurons. Thus, MCT2 distribution coupled with lactate uptake by hypothalamic neurons suggests that hypothalamic neurons control food intake using lactate to reflect changes in glucose levels.

Pielonefrite contagiosa bovina em vaca holandesa - Relato de caso / Contagious bovine pyelonephritis in Holstein cow - A case report / Pielonefritis bovina constagiosa en vaca holandesa - Relato de caso

O presente estudo foi conduzido com o objetivo de relatar um caso de pielonefrite contagiosa na espécie bovina. Uma fêmea bovina holandesa de 600 kg e que havia parido há 20 dias apresentava sinais clínicos de apatia, anorexia, sialorreia, normoquesia, disúria, diminuição da ingestão de água e bruxismo. No exame físico apresentou taquipneia, taquicardia e temperatura retal elevada. Foi realizada uma ruminotomia para descartar reticuloperitonite. Na laparotomia exploratória notou-se o rim esquerdo hiperatrofiado com ausência de lobulação, dor à palpação e espessamento da parede da bexiga. O tratamento instituído foi com o antibiótico penicilina. O diagnóstico presuntivo foi pielonefrite contagiosa, sendo concluído com base nos sinais clínicos e na resposta imediata ao tratamento, corroborando com o caso descrito.(AU)

This study was conducted in order to report a case of contagious pyelonephritis in cattle. A 600-kg female Holstein cow, calved 20 days before, presented clinical signs of lethargy, anorexia, drooling, normoquesia, dysuria, decreased water intake and bruxism. On physical examination, it showed tachypnea, tachycardia and pyrexia. Ruminotomia was performed to rule out a diagnosis of reticuloperitonite. During an exploratory laparotomy, hypertrophy in the left kidney with no lobulation, pain on palpation and thickening of the bladder wall was noticed. The treatment was performed with penicillin. The presumptive diagnosis was contagious pyelonephritis, and it was completed based on the clinical signs and the immediate response to treatment, supporting the case described.(AU)

Este estudio se realizó con el objetivo de informar un caso de pielonefritis bovina contagiosa. Una hembra bovina holandesa de 600 kg y que había parido hacía 20 días presentaba signos clínicos de apatía, anorexia, salivación, normoquesia, disuria, disminución de ingestión de agua y bruxismo. En la exploración física presentó taquipnea, taquicardia y fiebre. Se realizó ruminotomia para descartar reticuloperitonitis. En la laparotomía exploradora se observó el riñón izquierdo hipertrofico sin lobulación, dolor a la palpación y engrosamiento de la pared vesical. El tratamiento fue con penicilina. El diagnóstico presuntivo fue pielonefritis contagiosa, que se completó con base en los signos clínicos y en la respuesta inmediata al tratamiento, corroborando con el caso descrito.(AU)

Hypothyroidism reduces ObRb-STAT3 leptin signalling in the hypothalamus and pituitary of rats associated with resistance to leptin acute anorectic action.

Leptin has been shown to regulate the hypothalamus-pituitary-thyroid axis, acting primarily through the STAT3 pathway triggered through the binding of leptin to the long-chain isoform of the leptin receptor, ObRb. We previously demonstrated that although hyperthyroid rats presented leptin effects on TSH secretion, those effects were abolished in hypothyroid rats. We addressed the hypothesis that changes in the STAT3 pathway might explain the lack of TSH response to leptin in hypothyroidism by evaluating the protein content of components of leptin signalling via the STAT3 pathway in the hypothalamus and pituitary of hypothyroid (0·03% methimazole in the drinking water/21 days) and hyperthyroid (thyroxine 5 µg/100 g body weight /5 days) rats. Hypothyroid rats exhibited decreased ObRb and phosphorylated STAT3 (pSTAT3) protein in the hypothalamus, and in the pituitary gland they exhibited decreased ObRb, total STAT3, pSTAT3 and SOCS3 (P<0·05). Except for a modest decrease in pituitary STAT3, no other alterations were observed in hyperthyroid rats. Moreover, unlike euthyroid rats, the hypothyroid rats did not exhibit a reduction in food ingestion after a single injection of leptin (0·5 mg/kg body weight). Therefore, hypothyroidism decreased ObRb-STAT3 signalling in the hypothalamus and pituitary gland, which likely contributes to the loss of leptin action on food intake and TSH secretion, as previously observed in hypothyroid rats.

Changes in blood metabolic parameters during the development of Walker-256 tumour-induced cachexia in rats are not caused by decreased food intake.

Blood metabolic parameters of Walker-256 tumour-bearing rats, on days 5, 8, 11 and 14 after implantation of tumour, were compared with those of rats without tumour fed ad libitum (free-fed control) or with reduced feeding (pair-fed control), similar to the anorexic tumour-bearing rats. Cachexia parameters and tumour mass also were investigated. In general, especially on day 14 after implantation of tumour, there was reduction of body mass, gastrocnemius muscle mass, food intake and glycemia and increase of blood triacylglycerol, free fatty acids, lactate and urea, compared with free-fed controls rats. These changes did not occur in pair-fed control, except a slight reduction of glycemia. Pair-fed control showed no significant changes in blood cholesterol and glycerol in comparison with free-fed control, although there was reduction of cholesterol and increase of blood glycerol on day 14 after tumour implantation compared with pair-fed control. The results demonstrate that, besides the characteristic signs of the cachexia syndrome such as anorexia, weight loss and muscle catabolism, Walker-256 tumour-bearing rats show several blood metabolic alterations, some of which begin as early as day 5 after implantation of tumour, and are accentuated during the development of cachexia. Evidence that the alterations of blood metabolic parameters of tumour-bearing rats were not found in pair-fed control indicate that they were not caused by decreased food intake. These changes were probably mediated by factors produced by tumour or host tissue in response to the presence of tumour.

Defeito de septo atrial em cão idoso / Atrial septal defect in an elderly dog

Atendeu-se uma cadela de 11 anos de idade, em hospital veterinário escola, apresentando anorexia, pulso jugular, taquipnéia e ascite. As radiografias torácicas mostraram efusão pleural. O exame ecocardiográfico identificou comunicação interatrial (CIA) grande, espessamento e insuficiência das valvas atrioventriculares. O tratamento foi realizado sem que houvesse melhora clínica significativa. O exame necroscópico confirmou a comunicação interatrial do tipo ostium secundum. Acredita-se que a apresentação dos sinais clínicos em cão idoso foi devido ao aumento do fluxo errático pelo defeito, secundário à degeneração da valva mitral. Conclui-se que a CIA pode causar sinais clínicos em animais adultos.

Defeito de septo atrial em cão idoso / Atrial septal defect in an elderly dog

Atendeu-se uma cadela de 11 anos de idade, em hospital veterinário escola, apresentando anorexia, pulso jugular, taquipnéia e ascite. As radiografias torácicas mostraram efusão pleural. O exame ecocardiográfico identificou comunicação interatrial (CIA) grande, espessamento e insuficiência das valvas atrioventriculares. O tratamento foi realizado sem que houvesse melhora clínica significativa. O exame necroscópico confirmou a comunicação interatrial do tipo ostium secundum. Acredita-se que a apresentação dos sinais clínicos em cão idoso foi devido ao aumento do fluxo errático pelo defeito, secundário à degeneração da valva mitral. Conclui-se que a CIA pode causar sinais clínicos em animais adultos.(AU)

Oxidative stress, l-arginine-nitric oxide and arginase pathways in platelets from adolescents with anorexia nervosa.

Anorexia nervosa (AN) is associated with high cardiovascular mortality. Nitric oxide (NO) inhibits platelet function and regulates the cardiovascular homeostasis. The aim of this study was to investigate the l-arginine-NO-GMPc and arginase pathways and oxidative stress in platelets from patients with AN. Intraplatelet l-arginine transport, NOS expression and activity, cGMP levels, platelet aggregation, arginase expression and oxidative stress were measured in adolescent patients with AN (n=11) and healthy controls (n=12). Plasma l-arginine levels were significantly reduced in AN. l-arginine transport, NOS activity and cGMP basal levels were reduced in platelets associated with unchanged platelet aggregability. The expression of NOS isoforms was not affected. TBARS production was diminished, while the activity of superoxide dismutase was elevated in AN patients. There was an overexpression of arginase II in AN. Alterations of l-arginine-NO-GMPc and arginase pathways in platelets can be early predictors of the incidence of cardiovascular disease into adult life in AN.

Prepro-orexin and feeding-related peptide receptor expression in dehydration-induced anorexia.

Food-restricted animals present metabolic adaptations that facilitate food-seeking behavior and decelerate energy utilization by reducing the hypothalamus-pituitary-thyroid (HPT) axis function. Stress by dehydration induces an anorexic behavior in rats, loss of weight and reduced food intake when compared to ad libitum fed animals, however these alterations are accompanied by HPT axis changes such as increased serum thyrotropin levels and enhanced expression of thyrotropin-releasing hormone (TRH) in the paraventricular nucleus of the hypothalamus, which is considered as anorexigenic peptide. In contrast, a pair-fed group conformed by forced-food-restricted animals (FFR) (eating the exact same amount of food as dehydration-induced anorexic rats--DIA rats) present decreased TRH mRNA levels. NPY synthesis in the arcuate nucleus and orexin-expressing neurons from the lateral hypothalamic area (LHA) are activated during food restriction. These brain structures project into PVN, suggesting that NPY and orexins are possible factors involved in TRHergic neuron activation in DIA rats. Leptin signaling is another likely factor to be involved in TRH differential expression. Therefore, to gain more insight into the regulation of the feeding behavior in the experimental models, we analyzed Y1, Y5, Ox1-R and Ob-R(b) mRNA levels in PVN and prepro-orexin in LHA, since their signaling to the PVN might be altering TRH synthesis and feeding in DIA animals. Prepro-orexinergic cells were activated in FFR animals; Ox1-R and Y1 expression was reduced in FFR vs. controls or DIA group. Compensatory changes in PVN receptor expression of some feeding-related peptides in anorexic rats may alter TRHergic neural response to energy demands.

Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats.

Corticotrophin-releasing factor (CRF) and alpha-melanocyte-stimulating hormone (alpha-MSH), both of which are synthesized by hypothalamic neurons, play an essential role in the control of energy homeostasis. Neuroendocrine and behavioural responses induced by lipopolyssacharide (LPS) have been shown to involve prostaglandin-mediated pathways. This study investigated the effects of prostaglandin on CRF and alpha-MSH neuronal activities in LPS-induced anorexia. Male Wistar rats were pretreated with indomethacin (10 mg kg(-1); i.p.) or vehicle; 15 min later they received LPS (500 microg kg(-1); i.p.) or saline injection. Food intake, hormone responses and Fos-CRF and Fos-alpha-MSH immunoreactivity in the paraventricular and arcuate nuclei, respectively, were evaluated. In comparison with saline treatment, LPS administration induced lower food intake and increased plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF and Fos-alpha-MSH double-labelled neurons in vehicle-pretreated rats. In contrast, indomethacin treatment partly reversed the hypophagic effect, blunted the hormonal increase and blocked the Fos-CRF and Fos-alpha-MSH hypothalamic double labelling increase in response to the LPS stimulus. These data demonstrate that the activation of pro-opiomelanocortin and CRF hypothalamic neurons following LPS administration is at least partly mediated by the prostaglandin pathway and is likely to be involved in the modulation of feeding behaviour during endotoxaemia.

Peptide YY: a gut hormone associated with anorexia during infectious diarrhea in children.

OBJECTIVE: To evaluate the effects of diarrhea on appetite among Peruvian children age 12 to 71 months and to assess whether elevated plasma levels of peptide YY, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta contribute to anorexia in this population. STUDY DESIGN: A total of 46 Peruvian children with diarrhea and 46 healthy controls underwent an observed feeding trial that was repeated when cases were healthy. Blood samples were obtained from 30 cases and 30 controls at the first trial and from 30 cases at the second trial and assayed for peptide YY, TNF-alpha, and IL-1beta. RESULTS: In the cases, mean consumption was less when sick than when healthy. The mean plasma level of peptide YY was higher for cases than controls and higher for cases when sick than when healthy. TNF-alpha levels were higher in cases than controls at visit 1 and also higher in cases when sick than when healthy. There were no differences in IL-1beta levels between cases and controls or between cases when sick and healthy. Peptide YY levels in children with diarrhea correlated with the likelihood of them eating less when sick than when healthy. CONCLUSIONS: Elevated serum peptide YY may be a mechanism for anorexia in children with diarrhea.

Adrenalectomy enhances endotoxemia-induced hypophagia: higher activation of corticotrophin-releasing-factor and proopiomelanocortin hypothalamic neurons.

Inflammatory and infectious processes evoke neuroendocrine and behavioral changes known as acute-phase response that includes activation of the hypothalamo-pituitary-adrenal (HPA) axis and reduction of food intake. Besides its action as the most important ACTH secretagogue, corticotrophin-releasing factor (CRF), synthesized in the paraventricular nucleus (PVN), is also involved in the control of food intake. Alpha-melanocyte stimulating hormone (alpha-MSH) in the arcuate nucleus also plays a role in the energy homeostasis, possessing anorexigenic effects. To investigate the participation of neuropeptides involved in the regulation of food intake during endotoxemia, we administrated lipopolysaccharide (LPS) in sham-operated and adrenalectomized (ADX) male Wistar rats to evaluate food intake, hormone responses and Fos-CRF and Fos-alpha-MSH immunoreactivity in the PVN and arcuate nucleus, as well as CRF and POMC mRNA expression in these hypothalamic nuclei. In sham-operated rats, treatment with LPS (100 microg/kg) showed lower food intake, higher plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF double labeled neurons and CRF mRNA expression in the PVN, with no changes in Fos-alpha-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to saline treated rats. After LPS treatment, ADX rats showed further increase in plasma ACTH levels, marked decrease of food intake, higher Fos-CRF immunoreactive neurons in the PVN and CRF mRNA expression, as well as an increase in Fos-alpha-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to sham-operated rats treated with LPS. In conclusion, the present data indicate that the marked hypophagia during endotoxemia following ADX is associated with an increased activation of CRF and POMC neurons in the hypothalamus and an increased mRNA expression of these neuropeptides.

AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus.

Adiponectin exerts an insulin-sensitizing effect, improving insulin action in peripheral tissues and restraining insulin resistance. Here, we explore the hypothesis that adiponectin can reproduce some of the actions of insulin/leptin in the hypothalamus. The presence of AdipoR1 and AdipoR2 was mapped to the arcuate and lateral hypothalamic nuclei. Icv adiponectin reduced food intake, which was accompanied by activation/engagement of IRS1/2, ERK, Akt, FOXO1, JAK2 and STAT3. All these actions were dependent on AdipoR1, since inhibition of this receptor, and not of AdipoR2, completely reversed the effects described above. Thus, adiponectin acts in the hypothalamus, activating elements of the canonical insulin and leptin signaling pathways and promoting reduction of food intake.