Neonatal resveratrol treatment in cerebral palsy model recovers neurodevelopment impairments by restoring the skeletal muscle morphology and decreases microglial activation in the cerebellum.

Cerebral Palsy (CP) is the main motor disorder in childhood resulting from damage to the developing brain. Treatment perspectives are required to reverse the primary damage caused by the early insult and consequently to recover motor skills. Resveratrol has been shown to act as neuroprotection with benefits to skeletal muscle. This study aimed to investigate the effects of neonatal resveratrol treatment on neurodevelopment, skeletal muscle morphology, and cerebellar damage in CP model. Wistar rat pups were allocated to four experimental groups (n = 15/group) according CP model and treatment: Control+Saline (CS), Control+Resveratrol (CR), CP + Saline (CPS), and CP + Resveratrol (CPR). CP model associated anoxia and sensorimotor restriction. CP group showed delay in the disappearance of the palmar grasp reflex (p < 0.0001) and delay in the appearance of reflexes of negative geotaxis (p = 0.01), and free-fall righting (p < 0.0001), reduced locomotor activity and motor coordination (p < 0.05) than CS group. These motor skills impairments were associated with a reduction in muscle weight (p < 0.001) and area and perimeter of soleus end extensor digitorum longus muscle fibers (p < 0.0001), changes in muscle fibers typing pattern (p < 0.05), and the cerebellum showed signs of neuroinflammation due to elevated density and percentage of activated microglia in the CPS group compared to CS group (p < 0.05). CP animals treated with resveratrol showed anticipation of the appearance of negative geotaxis and free-fall righting reflexes (p < 0.01), increased locomotor activity (p < 0.05), recovery muscle fiber types pattern (p < 0.05), and reversal of the increase in density and the percentage of activated microglia in the cerebellum (p < 0.01). Thus, we conclude that neonatal treatment with resveratrol can contribute to the recovery of the delay neurodevelopment resulting from experimental CP due to its action in restoring the skeletal muscle morphology and reducing neuroinflammation from cerebellum.

Creatine supplementation increases postnatal growth and strength and prevents overexpression of pro-inflammatory interleukin 6 in the hippocampus in an experimental model of cerebral palsy.

ABSTRACTObjectives: The aim of this study was thus to evaluate the effect of Cr supplementation on morphological changes and expression of pro-inflammatory cytokines in the hippocampus and on developmental parameters. Methods: Male Wistar rat pups were submitted to an experimental model of CP. Cr was administered via gavage from the 21st to the 28th postnatal day, and in water after the 28th, until the end of the experiment. Body weight (BW), food consumption (FC), muscle strength, and locomotion were evaluated. Expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry in the hippocampal hilus. Results: Experimental CP caused increased density and activation of microglial cells, and overexpression of IL-6. The rats with CP also presented abnormal BW development and impairment of strength and locomotion. Cr supplementation was able to reverse the overexpression of IL-6 in the hippocampus and mitigate the impairments observed in BW, strength, and locomotion. Discussion: Future studies should evaluate other neurobiological characteristics, including changes in neural precursor cells and other cytokines, both pro- and anti-inflammatory.

Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

Motor deficits are associated with increased glial cell activation in the hypothalamus and cerebellum of young rats subjected to cerebral palsy.

Cerebral palsy (CP) is a syndrome characterized by a wide range of sensory and motor damage, associated with behavioral and cognitive deficits. The aim of the present study was to investigate the potential of a model of CP using a combination of perinatal anoxia and sensorimotor restriction of hind paws to replicate motor, behavioral and neural deficits. A total of 30 of male Wistar rats were divided into Control (C, n = 15), and CP (CP, n = 15) groups. The potential of the CP model was assessed by evaluating food intake, the behavioral satiety sequence, performance on the CatWalk and parallel bars, muscle strength, and locomotor activity. The weight of the encephalon, soleus, and extensor digitorum longus (EDL) muscles, and the activation of glial cells (microglia and astrocytes) were also measured. The CP animals showed delayed satiety, impaired locomotion on the CatWalk and open field test, reduced muscle strength, and reduced motor coordination. CP also reduced the weight of the soleus and muscles, brain weight, liver weight, and quantity of fat in various parts of the body. There was also found to be an increase in astrocyte and microglia activation in the cerebellum and hypothalamus (arcuate nucleus, ARC) of animals subjected to CP.

Neonatal kaempferol exposure attenuates gait and strength deficits and prevents altered muscle phenotype in a rat model of cerebral palsy.

Cerebral palsy (CP) is characterized by brain damage at a critical period of development of the central nervous system, and, as a result, motor, behavioural and learning deficits are observed in those affected. Flavonoids such as kaempferol have demonstrated potential anti-inflammatory and neuroprotective properties for neurological disorders. This study aimed to assess the effects of neonatal treatment with kaempferol on the body development, grip strength, gait performance and morphological and biochemical phenotype of skeletal muscle in rats subjected to a model of CP. The groups were formed by randomly allocating male Wistar rats after birth to four groups as follows: C = control treated with vehicle, K = control treated with kaempferol, CP = CP treated with vehicle and CPK = CP treated with kaempferol. The model of CP involved perinatal anoxia and sensorimotor restriction of the hind paws during infancy, from the second to the 28th day of postnatal life. Treatment with kaempferol (1 mg/kg) was performed intraperitoneally during the neonatal period. Body weight and length, muscle strength, gait kinetics and temporal and spatial parameters were evaluated in the offspring. On the 36th day of postnatal life, the animals were euthanized for soleus muscle dissection. The muscle fibre phenotype was assessed using the myofibrillar ATPase technique, and the muscle protein expression was measured using the Western blot technique. A reduction in the impact of CP on body phenotype was observed, and this also attenuated deficits in muscle strength and gait. Treatment also mitigated the impact on muscle phenotype by preventing a reduction in the proportion of oxidative fibres and in the histomorphometric parameters in the soleus muscle of rats in the CP group. The results demonstrate that neonatal treatment with kaempferol attenuated gait deficits and impaired muscle strength and muscle maturation in rats subjected to a model of CP.

Dietary flavonoid kaempferol reduces obesity-associated hypothalamic microglia activation and promotes body weight loss in mice with obesity.

BACKGROUND: Obesity results from an unbalance in the ingested and burned calories. Energy balance (EB) is critically regulated by the hypothalamic arcuate nucleus (ARC) by promoting appetite or anorectic actions. Hypothalamic inflammation, driven by high activation of the microglia, has been reported as a key mechanism involved in the development of diet-induced obesity. Kaempferol (KF), a flavonoid-type polyphenol present in a large number of fruits and vegetables, was shown to regulate both energy metabolism and inflammation. OBJECTIVES: In this work, we studied the effects of both the central and peripheral treatment with KF on hypothalamic inflammation and EB regulation in mice with obesity. METHODS: Obese adult mice were chronically (40 days) treated with KF (0.5 mg/kg/day, intraperitoneally). During the treatment, body weight, food intake (FI), feed efficiency (FE), glucose tolerance, and insulin sensitivity were determined. Analysis of microglia activation in the ARC of the hypothalamus at the end of the treatment was also performed. Body weight, FI, and FE changes were also evaluated in response to 5µg KF, centrally administrated. RESULTS: Chronic administration of KF decreased ∼43% of the density, and ∼30% of the ratio, of activated microglia in the arcuate nucleus. These changes were accompanied by body weight loss, decreased FE, reduced fasting blood glucose, and a tendency to improve insulin sensitivity. Finally, acute central administration of KF reproduced the effects on EB triggered by peripheral administration. CONCLUSION: These findings suggest that KF might fight obesity by regulating central processes related to EB regulation and hypothalamic inflammation.

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.

Effects of flavonols on emotional behavior and compounds of the serotonergic system: A preclinical systematic review.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates multiple psychophysiological functions. An imbalance of 5-HT in the brain can modulate emotional behavior such as depression and anxiety. Substances, such as flavonols, naturally found in some plants and foods have beneficial effects on psychiatric disorders, have been studied. The aim of this systematic review was to investigate the effects of flavonols on morphological, physiological, and cellular aspects of the serotonergic system as well as on some behaviors modulated by this system. Literature searches were performed in the LILACS, Web of Science, Scopus, PubMed and Sigle via Open Grey databases, from which 1725 studies were found. Using a predefined protocol registered on the CAMARADES website, 18 studies were chosen for qualitative synthesis. Internal validity was assessed using the SYRCLE's risk of bias tool. The Kappa index was also measured to analyze agreement among the reviewers. The results of this systematic review showed that flavonols have been reported to modify physiological aspects of the serotonergic system, increasing levels of serotonin and decreasing levels of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and promoting antioxidant effects in encephalic regions. Moreover, the results showed that flavonols can also modulate of the serotonergic system, being associated with antidepressant and anxiolytic activities. Additionally, flavonols were found to not have psychostimulant effect; they can, however, reverse damage to locomotor activity.

The role of vitamin B12 in viral infections: a comprehensive review of its relationship with the muscle-gut-brain axis and implications for SARS-CoV-2 infection.

This comprehensive review establishes the role of vitamin B12 as adjunct therapy for viral infections in the treatment and persistent symptoms of COVID-19, focusing on symptoms related to the muscle-gut-brain axis. Vitamin B12 can help balance immune responses to better fight viral infections. Furthermore, data from randomized clinical trials and meta-analysis indicate that vitamin B12 in the forms of methylcobalamin and cyanocobalamin may increase serum vitamin B12 levels, and resulted in decreased serum methylmalonic acid and homocysteine concentrations, and decreased pain intensity, memory loss, and impaired concentration. Among studies, there is much variation in vitamin B12 doses, chemical forms, supplementation time, and administration routes. Larger randomized clinical trials of vitamin B12 supplementation and analysis of markers such as total vitamin B12, holotranscobalamin, total homocysteine and methylmalonic acid, total folic acid, and, if possible, polymorphisms and methylation of genes need to be conducted with people with and without COVID-19 or who have had COVID-19 to facilitate the proper vitamin B12 form to be administered in individual treatment.

Mucuna pruriens treatment shows anti-obesity and intestinal health effects in obese rats.

This study evaluated the anti-obesity effect and intestinal health of obese rats treated with Mucuna pruriens (MP), focusing on food consumption and somatic, biochemical, and histological parameters. A total of 32 adult male Wistar rats were initially randomized into a healthy group (HG, n = 16) which consumed a control diet and an obese group (OG, n = 16) which consumed a cafeteria diet for eight weeks. They were then subdivided into four groups: healthy (HG, n = 8); healthy treated with MP (HGMP, n = 8); obese (OG, n = 8); obese treated with MP (OGMP, n = 8), with consumption of their respective diets continuing for another eight weeks; the treated groups received 750 mg kg-1 of MP extract via gavage. Food consumption and body weight were monitored weekly. Glucose and insulin tolerance tests were performed, and feces were collected for bacterial count and quantification of organic acids. The rats were euthanized, their blood was collected for biochemical analysis, organs and adipose tissue for histological analysis and carcasses for body composition. The obsese rats showed a preference for processed meat, stuffed biscuits, popcorn, hot dog sausages, Bologna and ham. The OGMP exhibited lower caloric intake (17%), body weight (14%), fat mass (44%), triglycerides (68%), insulin (58%), leptin (40%), C-reactive protein (75%) and alpha1-glycoprotein acid (62%) and increased HDL (45%) compared to the OG. Moreover, MP reversed changes in liver and adipose tissues induced by obesity and increased counts of lactic acid bacteria and organic acids in feces. The MP treatment demonstrated an anti-obesity effect with improvement in body composition, biochemical profile, and intestinal health of obese rats.

Hypothalamic bile acid-TGR5 signaling protects from obesity.

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.

A systematic review of neurogenesis in animal models of early brain damage: Implications for cerebral palsy.

Brain damage during early life is the main factor in the development of cerebral palsy (CP), which is one of the leading neurodevelopmental disorders in childhood. Few studies, however, have focused on the mechanisms of cell proliferation, migration, and differentiation in the brain of individuals with CP. We thus conducted a systematic review of preclinical evidence of structural neurogenesis in early brain damage and the underlying mechanisms involved in the pathogenesis of CP. Studies were obtained from Embase, Pubmed, Scopus, and Web of Science. After screening 2329 studies, 29 studies, covering a total of 751 animals, were included. Prenatal models based on oxygen deprivation, inflammatory response and infection, postnatal models based on oxygen deprivation or hypoxic-ischemia, and intraventricular hemorrhage models showed varying neurogenesis responses according to the nature of the brain damage, the time period during which the brain injury occurred, proliferative capacity, pattern of migration, and differentiation profile in neurogenic niches. Results mainly from rodent studies suggest that prenatal brain damage impacts neurogenesis and curbs generation of neural stem cells, while postnatal models show increased proliferation of neural precursor cells, improper migration, and reduced survival of new neurons.

Calcitonin Gene-Related Peptide-Induced Phosphorylation of STAT3 in Arcuate Neurons Is a Link in the Metabolic Benefits of Portal Glucose.

INTRODUCTION: Intestinal gluconeogenesis (IGN) exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. OBJECTIVE: The aim of this work was to determine central mechanisms involved in the effects of IGN on the control of energy homeostasis. METHODS: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient Ob/Ob and calcitonin gene-related peptide (CGRP)-deficient mice. RESULTS: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3 phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient Ob/Ob mice. We hypothesized that the portal glucose effects could require CGRP, a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP-deficient mice. CONCLUSIONS: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

Mucuna pruriens Administration Minimizes Neuroinflammation and Shows Anxiolytic, Antidepressant and Slimming Effects in Obese Rats.

This study evaluated the effect of Mucuna pruriens (MP) administration on neuroinflammation and behavioral and murinometric parameters in obese rats. Proximate composition, oligosaccharide and phenolic compound profile of MP were determined. Wistar adult male rats were randomized into healthy (HG) and obese group (OG). The HG consumed a control chow diet while OG consumed a cafeteria diet for eight weeks. Then, they were subdivided into: Healthy (HG); Healthy with MP administration (HGMP); Obese (OG); Obese with MP administration (OGMP), with the consumption of the respective diets remaining for another eight weeks, in addition to gavage with MP extract to supplemented groups (750 mg/kg weight). MP presented a composition rich in proteins and phenolic compounds, especially catechin, in addition to 1-kestose and levodopa. Supplementation reduced food intake, body weight, and thoracic and abdominal circumferences in obese rats. MP showed anxiolytic and antidepressant effects and reduced morphological damage and expression of interleukin 6 in the hippocampus of obese rats. MP treatment showed satietogenic, slimming, anxiolytic and antidepressant effects, besides to minimizing hippocampal neuroinflammation in obese rats. Our results demonstrated the potential anti-obesity of MP which are probably related to the high content of bioactive compounds present in this plant extract.

Central administration of REV-ERBα agonist promotes opposite responses on energy balance in fasted and fed states.

The REV-ERBα receptor has a recognised role in the regulation of the circadian rhythm system. However, recent evidence suggests that it also contributes to energy balance regulation. Both expression and function of REV-ERBα can be influenced by the energy status of the body. Considering the possibility of the involvement of REV-ERBα in the regulation of energy balance, which is critically regulated by the hypothalamus, and based on the impact of intermittent fasting, the present study evaluated the effects of central administration of REV-ERBα agonist on energy balance in rats exposed to 24 hours of fasting or ad lib. feeding conditions. Initially, 24-hour fasted rats received an acute i.c.v. administration of agonist at doses of 1, 5, 10 or 15 µg per rat and feed efficiency was evaluated. Because 10 µg was a sufficient dose to affect feed efficiency, subsequent experiments used this dose to assess effects of agonist on the following parameters: energy expenditure induced by physical activity and locomotor activity, time spent in physical activity over 24 hours, and glucose and insulin tolerance. In fasted rats, the agonist promoted increased food intake and feed efficiency, with a greater body weight gain associated with less time spent in locomotor activity, suggesting a reduction in energy expenditure induced by physical activity. Furthermore, a reduction in glucose tolerance was noted. By contrast, free-fed rats exhibited reduced food intake and feed efficiency with decreased body weight gain along with an increase in locomotor activity and physical activity-dependent energy expenditure. Thus, i.c.v. administration of REV-ERBα agonist regulates energy balance depending on the energy status of the organism; that is, it promotes a positive energy balance in the fasted state and a negative energy balance in the fed state. These results may be useful in understanding the underlying mechanisms of energy balance disorders and intermittent fasting for body weight control.

NPV-BSK805, an Antineoplastic Jak2 Inhibitor Effective in Myeloproliferative Disorders, Causes Adiposity in Mice by Interfering With the Action of Leptin.

The pathophysiology of body weight gain that is observed in patients suffering from myeloproliferative neoplasms treated with inhibitors of the janus kinase (Jak) 1 and 2 pathway remains unknown. Here we hypothesized that this class of drugs interferes with the metabolic actions of leptin, as this hormone requires functional Jak2 signaling. To test this, C57BL/6J chow-fed mice received either chronic intraperitoneal (ip) or repeated intracerebroventricular (icv) administration of the selective Jak2 inhibitor NVP-BSK805, which was proven efficacious in treating polycythemia in rodents. Changes in food intake, body weight and body composition were recorded. Icv NVP-BSK805 was combined with ip leptin to evaluate ability to interfere with the action of this hormone on food intake and on induction of hypothalamic phosphorylation of signal transducer and activator of transcription 3 (STAT3). We found that chronic peripheral administration of NVP-BSK805 did not alter food intake, but increased fat mass and feed efficiency. The increase in fat mass was more pronounced during repeated icv administration of the compound, suggesting that metabolic effects were related to molecular interference in brain structures regulating energy balance. Accordingly, acute icv administration of NVP-BSK805 prevented the ability of leptin to decrease food intake and body weight by impeding STAT3 phosphorylation within the hypothalamus. Consequently, acute icv administration of NVP-BSK805 at higher dose induced hyperphagia and body weight gain. Our results provide evidence for a specific anabolic effect exerted by antineoplastic drugs targeting the Jak2 pathway, which is due to interference with the actions of leptin. Consequently, assessment of metabolic variables related to increased fat mass gain should be performed in patients treated with Jak2 inhibitors.

mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin.

OBJECTIVE: Nutrient availability modulates reactive oxygen species (ROS) production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal activity and feeding behavior. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important cellular integrator of the action of nutrients and hormones. Here we tested the hypothesis that modulation of mTORC1 activity, particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the cellular and behavioral effects of ROS. METHODS: C57BL/6J mice or controls and their knockout (KO) littermates deficient either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1 (S6K1) or for the mTORC1 component Rptor specifically in POMC neurons (POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or, respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1 activator leptin. Oxidant-related signal in POMC neurons was assessed using dihydroethidium (DHE) fluorescence. RESULTS: Icv administration of H2O2 decreased food intake, while co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant levels in POMC neurons, an effect that hinged on functional mTORC1 in these neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit food intake. CONCLUSIONS: Our results demonstrate that ROS and leptin require mTORC1 pathway activity in POMC neurons to increase oxidant levels in POMC neurons and consequently decrease food intake.