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White, beige, and brown adipose tissues play a crucial role in maintaining energy homeostasis. Due to the heterogeneous and diffuse nature of fat pads, this balance requires a fine and coordinated control of many actors and therefore permanent dialogues between these tissues and the central nervous system. For about two decades, many studies have been devoted to describe the neuro-anatomical and functional complexity involved to ensure this dialogue. Thus, if it is now clearly demonstrated that there is an efferent sympathetic innervation of different fat depots controlling plasticity as well as metabolic functions of the fat pad, the crucial role of sensory innervation capable of detecting local signals informing the central nervous system of the metabolic state of the relevant pads is much more recent. The purpose of this review is to provide the current state of knowledge on this subject.
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Tecido Adiposo Marrom , Tecido Adiposo , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático , Homeostase , Adiposidade , Termogênese , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Bege/metabolismoRESUMO
Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.
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Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation of Ucp1 gene expression, the role of lactate transporters on beige adipocytes' ongoing metabolic activity remains poorly understood. To explore the function of the lactate-transporting monocarboxylate transporters (MCTs), we used a combination of primary cell culture studies, 13C isotopic tracing, laser microdissection experiments, and in situ immunofluorescence of murine adipose fat pads. Dissecting white adipose tissue heterogeneity revealed that the MCT1 is expressed in inducible beige adipocytes as the emergence of uncoupling protein 1 after cold exposure was restricted to a subpopulation of MCT1-expressing adipocytes suggesting MCT1 as a marker of inducible beige adipocytes. We also observed that MCT1 mediates bidirectional and simultaneous inward and outward lactate fluxes, which were required for efficient utilization of glucose by beige adipocytes activated by the canonical ß3-adrenergic signaling pathway. Finally, we demonstrated that significant lactate import through MCT1 occurs even when glucose is not limiting, which feeds the oxidative metabolism of beige adipocytes. These data highlight the key role of lactate fluxes in finely tuning the metabolic activity of beige adipocytes according to extracellular metabolic conditions and reinforce the emerging role of lactate metabolism in the control of energy homeostasis.
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Adipócitos Bege/metabolismo , Regulação da Expressão Gênica , Ácido Láctico/metabolismo , Células-Tronco Mesenquimais/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Adipócitos Bege/citologia , Animais , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ácidos Monocarboxílicos/genética , Transdução de Sinais , Simportadores/genética , TermogêneseRESUMO
OBJECTIVES: Protein-energy wasting is a risk factor for mortality and morbidity in hemodialysis patients (HD patients). Food intake could be modified by HD-related changes in the food reward system (i.e., liking and wanting of specific macronutrients). In HD patients on days with and without dialysis, we evaluated (1) the reward system for protein-, fat-, and carbohydrate-rich foods, plasma hormones, and metabolite changes; and (2) the spontaneous ad libitum intake of macronutrients. (DESIGN AND) METHODS: Twenty-four HD patients evaluated their liking and wanting of macronutrients at 7:30 AM and 11:30 AM on a day with and a day without dialysis. Concentrations of hormones and plasma amino acids were determined. An additional 18 HD patients ate what they wanted from a buffet lunch comprising 8 dishes on a day with and a day without dialysis. Healthy subjects, age-, sex-, and body mass index-matched, served as controls. RESULTS: At 11:30 AM, wanting for protein-rich foods was higher on the day with than on the day without dialysis (P < .01), bringing wanting levels close to those of healthy subjects. This increase correlated with changes in the concentrations of plasma amino acids (P < .01). HD patients ate more protein from the buffet on the day with than on the day without dialysis (P < .01) and more than healthy subjects (P < .01). CONCLUSIONS: In HD patients, wanting and spontaneous intake of protein-rich foods increase immediately after dialysis. This increase correlated with decreased concentrations of plasma amino acids. Thus, in clinical practice, protein-rich foods should be recommended during and after dialysis in patients with protein-energy wasting.
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Diálise Renal , Insuficiência Renal Crônica , Índice de Massa Corporal , Ingestão de Energia , Humanos , Insuficiência Renal Crônica/terapia , RecompensaRESUMO
Opioids are regarded as among the most effective analgesic drugs and their use for the management of pain is considered standard of care. Despite their systematic administration in the peri-operative period, their impact on tissue repair has been studied mainly in the context of scar healing and is only beginning to be documented in the context of true tissue regeneration. Indeed, in mammals, growing evidence shows that opioids direct tissue repair towards scar healing, with a loss of tissue function, instead of the regenerative process that allows for recovery of both the morphology and function of tissue. Here, we review recent studies that highlight how opioids may prevent a regenerative process by silencing nociceptive nerve activity and a powerful anti-inflammatory effect. These data open up new perspectives for inducing tissue regeneration and argue for opioid-restricted strategies for managing pain associated with tissue injury.
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Analgésicos Opioides/uso terapêutico , Manejo da Dor , Dor/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Humanos , Dor/metabolismo , Dor/patologiaRESUMO
Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.
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Aminoácidos de Cadeia Ramificada/sangue , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Aminoácidos de Cadeia Ramificada/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Ansiedade/sangue , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Depressão/sangue , Depressão/tratamento farmacológico , Depressão/psicologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
There is some evidence of specific oro-detection of FFAs in rodents and humans. The aim of this study was to record gustatory evoked potentials (GEPs) in response to FFA solutions and to compare GEPs in response to linoleic acid solution with GEPs obtained after stimulation with sweet and salty tastants. Eighteen healthy men were randomly stimulated with fatty (linoleic acid), sweet (sucrose), and salty (NaCl) solutions at two concentrations in the first experiment. Control recordings (n = 14) were obtained during stimulation by a paraffin oil mixture without FFA or by water. In the second experiment, 28 men were randomly stimulated with five FFA solutions and a paraffin emulsion. GEPs were recorded with electroencephalographic electrodes at Cz, Fz, and Pz. GEPs were observed in response to FFA in all participants. GEP characteristics did not differ according to the quality and the concentration of the solutions in the first experiment and according to the FFA in the second experiment. This study describes for the first time GEPs in response to FFA and demonstrates that the presence of FFA in the mouth triggers an activation of the gustatory cortex. These data reinforce the concept that fat taste could be the sixth primary taste.
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Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Potenciais Evocados/efeitos dos fármacos , Ácidos Graxos não Esterificados/farmacologia , Percepção Gustatória/efeitos dos fármacos , Percepção Gustatória/fisiologia , Adulto , Encéfalo/citologia , Humanos , Ácido Linoleico/farmacologia , Masculino , Filosofia , Adulto JovemRESUMO
Glucose, fructose, and sucrose are important carbohydrates in Western diets with particular sweetness intensity and metabolisms. No study has compared their cerebral detection and their taste perception. Gustatory evoked potentials (GEPs), taste detection thresholds, intensity perception, and pleasantness were compared in response to glucose, fructose, and sucrose solutions at similar sweetness intensities and at identical molar concentrations. Twenty-three healthy subjects were randomly stimulated with 3 solutions of similar sweetness intensity (0.75 M of glucose, 0.47 M of fructose and 0.29 M of sucrose - sit. A), and with an identical molar concentration (0.29 M - sit. B). GEPs were recorded at gustatory cortex areas. Intensity perception and hedonic values of each solution were evaluated as were gustatory thresholds of the solutions. No significant difference was observed concerning the GEP characteristics of the solutions according to their sweetness intensities (sit. A) or their molar concentration (sit. B). In sit. A, the 3 solutions were perceived to have similar intensities and induced similar hedonic sensations. In sit. B, the glucose solution was perceived to be less intense and pleasant than the fructose and the sucrose solutions (P < 0.001) and the fructose solution was perceived to be less intense and pleasant than the sucrose (P < 0.001). Since GEP recordings were similar for glucose, fructose, and sucrose solutions whatever the concentrations, activation of same taste receptor induces similar cortical activation, even when the solutions were perceived differently. Sweet taste perception seems to be encoded by a complex chemical cerebral neuronal network.
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Córtex Cerebral/metabolismo , Frutose/análise , Glucose/análise , Sacarose/análise , Percepção Gustatória/fisiologia , Adulto , Feminino , Humanos , Masculino , Soluções , Adulto JovemRESUMO
High time resolution is required to reliably measure neuronal activity in the gustatory cortex in response to taste stimuli. Hedonic aspects of gustatory processing have never been explored using gustatory evoked potentials (GEPs), a high-time-resolution technique. Our aim was to study cerebral processing of hedonic taste in humans using GEPs in response to sucrose solutions in subjects with different ratings of pleasantness regarding sucrose. In this exploratory study, 30 healthy volunteers were randomly stimulated with 3 sucrose solutions. The sucrose stimulus was presented to the tongue for 1s 20 times. GEPs were recorded from 9 cortical sites with EEG sensors at Cz, Fz, Pz, C3, C4, F3, F4, Fp1, and Fp2 (10/20 system). The main result was that subjects who preferred the high-concentration (20g/100mL) sucrose solution had higher GEP amplitudes on the Pz, Cz, and Fz electrodes than did subjects who preferred the low-concentration (5g/100mL) or the moderate-concentration (10g/100mL) solutions regardless of stimulus intensity. The difference in P1N1 amplitude on the Pz, Cz, and Fz electrodes according to sucrose preference of the subjects was described with stronger significance with stimulation by the 20 g-sucrose solution than by the 5 and 10g sucrose solutions. Using the reliable and safe GEP technique, we provide an original demonstration of variability of the gustatory response on the Pz, Cz, and Fz electrodes according to a sweet preference in humans. Further studies are needed to correlate the electric signal recorded by surface electrodes to the neural generator.
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Córtex Cerebral , Preferências Alimentares/fisiologia , Sacarose/química , Percepção Gustatória/fisiologia , Adulto , Feminino , Humanos , Masculino , Soluções , Adulto JovemRESUMO
Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from amyloid-positive individuals, before any sign of cognitive decline, to distinguish individuals who progressed to cognitive decline from those who remained cognitively intact. A plasma-derived metabolite signature was developed from Supercritical Fluid chromatography coupled with high-resolution mass spectrometry (SFC-HRMS) and nuclear magnetic resonance (NMR) metabolomics. The 2 metabolomics data sets were analyzed by Data Integration Analysis for Biomarker discovery using Latent approaches for Omics studies (DIABLO), to identify a minimum set of metabolites that could describe cognitive decline status. NMR or SFC-HRMS data alone cannot predict cognitive decline. However, among the 320 metabolites identified, a statistical method that integrated the 2 data sets enabled the identification of a minimal signature of 9 metabolites (3-hydroxybutyrate, citrate, succinate, acetone, methionine, glucose, serine, sphingomyelin d18:1/C26:0 and triglyceride C48:3) with a statistically significant ability to predict cognitive decline more than 3 years before decline. This metabolic fingerprint obtained during this exploratory study may help to predict amyloid-positive individuals who will develop cognitive decline. Due to the high prevalence of brain amyloid-positivity in older adults, identifying adults who will have cognitive decline will enable the development of personalized and early interventions.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Vida Independente , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Disfunção Cognitiva/metabolismo , Encéfalo/metabolismo , Metabolômica , Proteínas Amiloidogênicas , Peptídeos beta-Amiloides/metabolismo , BiomarcadoresRESUMO
Leptin is an adipocyte-derived hormone that controls energy balance by acting primarily in the CNS, but its action is lost in common forms of obesity due to central leptin resistance. One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation. Ample studies have confirmed the important role of Socs3 in leptin resistance and obesity. However, the degree to which Socs3 participates in the regulation of energy homeostasis in nonobese conditions remains largely undetermined. In this study, using adult mice maintained under standard diet, we demonstrate that Socs3 deficiency in the mediobasal hypothalamus (MBH) reduces food intake, protects against body weight gain, and limits adiposity, suggesting that Socs3 is necessary for normal body weight maintenance. Mechanistically, MBH Socs3-deficient mice display increased hindbrain sensitivity to endogenous, meal-related satiety signals, mediated by oxytocin signaling. Thus, oxytocin signaling likely mediates the effect of hypothalamic leptin on satiety circuits of the caudal brainstem. This provides an anatomical substrate for the effect of leptin on meal size, and more generally, a mechanism for how the brain controls short-term food intake as a function of the energetic stores available in the organism to maintain energy homeostasis. Any dysfunction in this pathway could potentially lead to overeating and obesity.
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Hipotálamo/metabolismo , Ocitocina/metabolismo , Rombencéfalo/metabolismo , Resposta de Saciedade/fisiologia , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Devazepida/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Antagonistas de Hormônios/farmacologia , Hipotálamo/efeitos dos fármacos , Leptina/metabolismo , Camundongos , Receptores da Colecistocinina/antagonistas & inibidores , Rombencéfalo/efeitos dos fármacos , Resposta de Saciedade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticity-driven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases.
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Adaptação Fisiológica/fisiologia , Núcleo Arqueado do Hipotálamo/fisiologia , Gorduras na Dieta/administração & dosagem , Pró-Opiomelanocortina/fisiologia , Ácidos Siálicos/fisiologia , Animais , Ingestão de Energia/genética , Metabolismo Energético/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Rede Nervosa/fisiologia , Plasticidade Neuronal/genética , Técnicas de Cultura de Órgãos , Pró-Opiomelanocortina/metabolismo , Sialiltransferases/deficiência , Sialiltransferases/genética , Transdução de Sinais/genética , Aumento de Peso/genéticaRESUMO
Aims: Part of hypothalamic (mediobasal hypothalamus [MBH]) neurons detect changes in blood glucose levels that in turn coordinate the vagal control of insulin secretion. This control cascade requires the production of mitochondrial reactive oxygen species (mROS), which is altered in models of obesity and insulin resistance. Obese, insulin-resistant Zücker rats are characterized by hypothalamic hypersensitivity to glucose. This initiates an abnormal vagus-induced insulin secretion, associated with an overproduction of mROS in response to a low glucose dose. Here, we hypothesized that ghrelin, known to buffer reactive oxygen species (ROS) via mitochondrial function, may be a major component of the hypothalamic glucose hypersensitivity in the hypoghrelinemic obese Zücker rat. Results: Hypothalamic glucose hypersensitivity-induced insulin secretion of Zücker obese rats was reversed by ghrelin pretreatment. The overproduction of MBH mROS in response to a low glucose load no longer occurred in obese rats that had previously received the cerebral ghrelin infusion. This decrease in mROS production was accompanied by a normalization of oxidative phosphorylation (OXPHOS). Conversely, blocking the action of ghrelin with a growth hormone secretagogue receptor antagonist in a model of hyperghrelinemia (fasted rats) completely restored hypothalamic glucose sensing-induced insulin secretion that was almost absent in this physiological situation. Accordingly, ROS signaling and mitochondrial activity were increased by the ghrelin receptor antagonist. Innovation: These results demonstrate for the first time that ghrelin addressed only to the brain could have a protective effect on the defective control of insulin secretion in the insulin-resistant, hypoghrelinemic obese subject. Conclusions: Ghrelin, through its action on OXPHOS, modulates mROS signaling in response to cerebral hyperglycemia and the consequent vagal control of insulin secretion. In insulin-resistant obese states, brain hypoghrelinemia could be responsible for the nervous defect in insulin secretion.
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Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate physiological aging and do not capture the full complexity of inter-parameter interactions. Machine learning (ML) is promising, but its black box nature eludes direct understanding, substantially limiting physician confidence and clinical usage. Using a broad population dataset from the National Health and Nutrition Examination Survey (NHANES) study including routine biological variables and after selection of XGBoost as the most appropriate algorithm, we created an innovative explainable ML framework to determine a Personalized physiological age (PPA). PPA predicted both chronic disease and mortality independently of chronological age. Twenty-six variables were sufficient to predict PPA. Using SHapley Additive exPlanations (SHAP), we implemented a precise quantitative associated metric for each variable explaining physiological (i.e., accelerated or delayed) deviations from age-specific normative data. Among the variables, glycated hemoglobin (HbA1c) displays a major relative weight in the estimation of PPA. Finally, clustering profiles of identical contextualized explanations reveal different aging trajectories opening opportunities to specific clinical follow-up. These data show that PPA is a robust, quantitative and explainable ML-based metric that monitors personalized health status. Our approach also provides a complete framework applicable to different datasets or variables, allowing precision physiological age estimation.
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Algoritmos , Nível de Saúde , Inquéritos Nutricionais , Aprendizado de MáquinaRESUMO
Obesity results from a temporary or prolonged positive energy balance due to an alteration in the homeostatic feedback of energy balance. Food, with its discriminative and hedonic qualities, is a key element of reward-based energy intake. An alteration in the brain reward system for highly palatable energy-rich foods, comprised of fat and carbohydrates, could be one of the main factors involved in the development of obesity by increasing the attractiveness and consumption of fat-rich foods. This would induce, in turn, a decrease in the taste of fat. A better understanding of the altered reward system in obesity may open the door to a new era for the diagnosis, management and treatment of this disease.
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Obesidade , Paladar , Metabolismo Energético , Homeostase , Humanos , RecompensaRESUMO
OBJECTIVE: The ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here, we investigated the importance of the autophagy-related gene Atg7 in Sf1-expressing neurons of the VMH in control and fasted conditions. METHODS: We generated Sf1-Cre; Atg7loxP/loxP mice and examined their metabolic and cellular response to fasting. RESULTS: Fasting induces autophagy in the VMH, and mice lacking Atg7 in Sf1-expressing neurons display altered leptin sensitivity and impaired energy expenditure regulation in response to fasting. Moreover, loss of Atg7 in Sf1 neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice. CONCLUSION: Together, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.
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Autofagia , Jejum , Mitocôndrias/metabolismo , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Metabolismo Energético , Feminino , Homeostase , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , TranscriptomaRESUMO
Tissue repair after injury in adult mammals, usually results in scarring and loss of function in contrast to lower vertebrates such as the newt and zebrafish that regenerate. Understanding the regulatory processes that guide the outcome of tissue repair is therefore a concerning challenge for regenerative medicine. In multiple regenerative animal species, the nerve dependence of regeneration is well established, but the nature of the innervation required for tissue regeneration remains largely undefined. Using our model of induced adipose tissue regeneration in adult mice, we demonstrate here that nociceptive nerves promote regeneration and their removal impairs tissue regeneration. We also show that blocking the receptor for the nociceptive neuropeptide calcitonin gene-related peptide (CGRP) inhibits regeneration, whereas CGRP administration induces regeneration. These findings reveal that peptidergic nociceptive neurons are required for adult mice tissue regeneration.
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Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.
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The sugar transporter GLUT2, present in several tissues of the gut-brain axis, has been reported to be involved in the control of food intake. GLUT2 is a sugar transporter sustaining energy production in the cell, but it can also function as a receptor for extracellular glucose. A glucose-signaling pathway is indeed triggered, independently of glucose metabolism, through its large cytoplasmic loop domain. However, the contribution of the receptor function over the transporter function of GLUT2 in the control of food intake remains to be determined. Thus, we generated transgenic mice that express a GLUT2-loop domain, blocking the detection of glucose but leaving GLUT2-dependent glucose transport unaffected. Inhibiting GLUT2-mediated glucose detection augmented daily food intake by a mechanism that increased the meal size but not the number of meals. Peripheral hormones (ghrelin, insulin, leptin) were unaffected, leading to a focus on central aspects of feeding behavior. We found defects in c-Fos activation by glucose in the arcuate nucleus and changes in the amounts of TRH and orexin neuropeptide mRNA, which are relevant to poorly controlled meal size. Our data provide evidence that glucose detection by GLUT2 contributes to the control of food intake by the hypothalamus. The sugar transporter receptor, i.e., "transceptor" GLUT2, may constitute a drug target to treat eating disorders and associated metabolic diseases, particularly by modulating its receptor function without affecting vital sugar provision by its transporter function.
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Ingestão de Alimentos/fisiologia , Transportador de Glucose Tipo 2/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Análise de Variância , Animais , Transporte Biológico/fisiologia , Peso Corporal/fisiologia , Contagem de Células , Metabolismo Energético , Comportamento Alimentar/fisiologia , Grelina/sangue , Transportador de Glucose Tipo 2/genética , Homeostase/fisiologia , Imuno-Histoquímica , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leptina/sangue , Camundongos , Camundongos Transgênicos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Orexinas , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Hormônio Liberador de Tireotropina/genética , Hormônio Liberador de Tireotropina/metabolismoRESUMO
Treatment of cancer using radiation can be significantly compromised by the development of severe acute and late damage to normal tissue. Treatments that either reduce the risk and severity of damage or that facilitate the healing of radiation injuries are being developed, including autologous adipose tissue grafts to repair tissue defects or involutional disorders that result from tumor resection. Adipose tissue is specialized in energy storage and contains different cell types, including preadipocytes, which could be used for autologous transplantation. It has long been considered a poorly proliferative connective tissue; however, the acute effects of ionizing radiation on adipose tissue have not been investigated. Therefore, the aim of this study was to characterize the alterations induced in adipose tissue by total body irradiation. A severe decrease in proliferating cells, as well as a significant increase in apoptotic cells, was observed in vivo in inguinal fat pads following irradiation. Additionally, irradiation altered the hematopoietic population. Decreases in the proliferation and differentiation capacities of non-hematopoietic progenitors were also observed following irradiation. Together, these data demonstrate that subcutaneous adipose tissue is very sensitive to irradiation, leading to a profound alteration of its developmental potential. This damage could also alter the reconstructive properties of adipose tissue and, therefore, calls into question its use in autologous fat transfer following radiotherapy.