RESUMO
Obesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. While the TLR4 activation by dietary fats is a well-characterized pathway involved in the neuronal and glial inflammation, the role of its accessory proteins in diet-induced hypothalamic inflammation remains unknown. Here, we demonstrate that the knockdown of TLR4-interactor with leucine-rich repeats (Tril), a functional component of TLR4, resulted in reduced hypothalamic inflammation, increased whole-body energy expenditure, improved the systemic glucose tolerance and protection from diet-induced obesity. The POMC-specific knockdown of Tril resulted in decreased body fat, decreased white adipose tissue inflammation and a trend toward increased leptin signaling in POMC neurons. Thus, Tril was identified as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental obesity and its inhibition in the hypothalamus may represent a novel target for obesity treatment.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Neurônios/metabolismo , Obesidade/etiologia , Pró-Opiomelanocortina/genética , Receptor 4 Toll-Like/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Hipotálamo/patologia , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Obesidade/metabolismo , Obesidade/patologia , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.
Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/complicações , Gliose , Hipotálamo , Obesidade , Feminino , Gliose/diagnóstico por imagem , Gliose/patologia , Humanos , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Imageamento por Ressonância Magnética , Obesidade/complicações , Obesidade/cirurgia , Resultado do TratamentoRESUMO
AIMS: This study aimed to evaluate the effect of pioglitazone on brown adipose tissue function and hypothalamic gliosis in humans. Brown adipose tissue and the hypothalamus are regarded as important potential pharmacological targets to metabolic diseases, and defining the impact of current therapies on their structure and/or function could provide therapeutic advance in this field. METHODS: Six patients with type 2 diabetes were treated for 24 weeks with pioglitazone 30 mg/day as an add-on therapy. Brown adipose tissue glucose uptake and volume were determined using 18F-FDG PET/CT scans; hypothalamic gliosis was determined using MRI scans; blood was collected for hormone and biochemistry measurements. All tests were performed at inclusion and six months after pioglitazone introduction. RESULTS: Pioglitazone treatment led to a significant 3% body mass increase. There were neither changes in cold-induced brown adipose tissue glucose uptake and volume nor changes in hypothalamic gliosis. CONCLUSIONS: This is a proof-of-concept study that provides clinical evidence for a lack of action of a thiazolidinedione, pioglitazone, to promote homogeneous and measurable changes in brown adipose tissue volume and also in hypothalamic gliosis after 6 months of treatment.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliose/prevenção & controle , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Pioglitazona/farmacologia , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/patologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Quimioterapia Combinada , Feminino , Fluordesoxiglucose F18 , Gliose/diagnóstico , Gliose/patologia , Humanos , Hipotálamo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Sobrepeso/complicações , Sobrepeso/diagnóstico , Sobrepeso/tratamento farmacológico , Sobrepeso/patologia , Pioglitazona/administração & dosagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudo de Prova de Conceito , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologiaRESUMO
BACKGROUND: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. METHODS: Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. FINDINGS: IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet-induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. INTERPRETATION: Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation. FUND: Sao Paulo Research Foundation grants 2013/07607-8 (LAV) and 2017/02983-2 (JDJ); NIH grants R01DK083567 (YBK).
Assuntos
Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hipotálamo/metabolismo , Obesidade/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Peso Corporal , Linhagem Celular , Biologia Computacional/métodos , Modelos Animais de Doenças , Ingestão de Energia , Metabolismo Energético , Jejum/metabolismo , Humanos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Fenótipo , Análise de Sequência de RNARESUMO
Hypothalamic sphingosine-1-phosphate receptor 1 (S1PR1), the G protein-coupled receptor 1 of sphingosine-1-phosphate, has been described as a modulator in the control of energy homeostasis in rodents. However, this mechanism is still unclear. Here, we evaluate the role of interleukin 6 (IL-6) associated with acute physical exercise in the control of the hypothalamic S1PR1-signal transducer and activator of transcription 3 (STAT3) axis. Acute exercise session and an intracerebroventricular IL-6 injection increased S1PR1 protein content and STAT3 phosphorylation in the hypothalamus of lean and obese mice accompanied by a reduction in food consumption. Transcriptome analysis indicated a strong positive correlation between Il-6 and S1pr1 messenger RNA in several tissues of genetically diverse BXD mice strains and humans, including in the hypothalamus. Interestingly, exercise failed to stimulate the S1PR1-STAT3 axis in IL-6 knockout mice and the disruption of hypothalamic-specific IL-6 action blocked the anorexigenic effects of exercise. Taken together, our results indicate that physical exercise modulates the S1PR1 protein content in the hypothalamus, through the central action of IL-6.
Assuntos
Hipotálamo/metabolismo , Interleucina-6/metabolismo , Condicionamento Físico Animal , Receptores de Lisoesfingolipídeo/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Humanos , Injeções Intraventriculares , Interleucina-6/administração & dosagem , Interleucina-6/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Esfingosina-1-FosfatoRESUMO
Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of ß-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of ß-endorphin levels, is the earliest hypothalamic defect leading to obesity.