RESUMO
Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.
Assuntos
Núcleo Arqueado do Hipotálamo , Leptina , Camundongos , Animais , Feminino , Leptina/metabolismo , Estradiol/farmacologia , Pró-Opiomelanocortina/metabolismo , Hipotálamo/metabolismo , Obesidade/metabolismoRESUMO
In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.
Assuntos
Proteínas Sanguíneas/análise , Náusea/sangue , Náusea/terapia , Efeito Placebo , Terapia por Acupuntura , Adulto , Terapia por Estimulação Elétrica , Feminino , Humanos , Masculino , Enjoo devido ao Movimento/sangue , Enjoo devido ao Movimento/terapia , Proteômica , Adulto JovemRESUMO
Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism.
Assuntos
Hipotálamo/metabolismo , Melanocortinas/metabolismo , Neurônios/metabolismo , Proteínas com Domínio T/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Peso Corporal , Metabolismo Energético , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Hipotálamo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/genética , RNA Mensageiro/genética , Proteínas com Domínio T/genéticaRESUMO
Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep ob mice respond with a decrease in food intake and body weight, adult Lep db and Lep ob mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Proteína Desacopladora 1/metabolismo , Redução de Peso/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Metabolismo Energético/efeitos dos fármacos , Camundongos Knockout , Obesidade/genética , Triterpenos Pentacíclicos , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Desacopladora 1/genéticaRESUMO
Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I-/-) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I-/- compared with apoA-I+/+ mice and was associated with compromised mitochondrial function. apoA-I-/- mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I+/+ controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I-/- mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.
Assuntos
Apolipoproteína A-I/metabolismo , Gliose/metabolismo , Gliose/patologia , Hipotálamo/patologia , Lipoproteínas HDL/sangue , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores/metabolismo , Gliose/sangue , Glicólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Fosforilação Oxidativa , FenótipoRESUMO
OBJECTIVE: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. METHODS: We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM). RESULTS: We found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet. CONCLUSIONS: Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.
Assuntos
Gorduras na Dieta/metabolismo , Açúcares da Dieta/metabolismo , Gliose/metabolismo , Hipotálamo/metabolismo , Molécula de Adesão de Leucócito Ativado/genética , Animais , Gorduras na Dieta/efeitos adversos , Açúcares da Dieta/efeitos adversos , Gliose/etiologia , Produtos Finais de Glicação Avançada/metabolismo , Hipotálamo/patologia , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Receptor para Produtos Finais de Glicação Avançada/deficiência , Receptor para Produtos Finais de Glicação Avançada/genéticaRESUMO
Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.
Assuntos
Astrócitos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Obesidade/etiologia , Obesidade/metabolismo , Animais , Astrócitos/citologia , Peso Corporal/fisiologia , Ceramidas/metabolismo , Citometria de Fluxo , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Teste de Tolerância a Glucose , Humanos , Hipotálamo/citologia , Imuno-Histoquímica , Hibridização In Situ , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.
Assuntos
Astrócitos/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Transdução de Sinais , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Barreira Hematoencefálica , Retículo Endoplasmático/metabolismo , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Homeostase , Camundongos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMO
Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.
Assuntos
Hipotálamo/metabolismo , Leptina/metabolismo , Animais , Glicemia , Linhagem Celular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Teste de Tolerância a Glucose , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Infusões Intraventriculares , Resistência à Insulina , Microdissecção e Captura a Laser , Leptina/genética , Masculino , Hormônios Estimuladores de Melanócitos/farmacologia , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Neurônios/fisiologia , Ratos , Ratos WistarRESUMO
Although food intake is necessary to provide energy for all bodily activities, considering food intake as a motivated behavior is complex. Rather than being a simple unconditioned reflex to energy need, eating is mediated by diverse factors. These include homeostatic signals such as those related to body fat stores, to food available and being eaten, and to circulating energy-rich compounds like glucose and fatty acids. Eating is also greatly influenced by non-homeostatic signals that convey information related to learning and experience, hedonics, stress, the social situation, opportunity, and many other factors. Recent developments identifying the intricate nature of the relationships between homeostatic and non-homeostatic influences significantly add to the complexity underlying the neural basis of the motivation to eat. The future of research in the field of food intake would seem to lie in the identification of the neural circuitry and interactions between homeostatic and non-homeostatic influences.
Assuntos
Encéfalo/fisiopatologia , Comportamento Alimentar/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Motivação/fisiologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Colecistocinina/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Homeostase , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Insulina/metabolismo , Leptina/metabolismo , Saciação/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
The most effective treatment for obesity is bariatric surgery. However, there is increasing concern that bariatric surgery can cause nutrient deficiencies that translate into metabolic bone disease. Whether this is true for all surgery types is not yet clear. We therefore investigated the effects of 2 commonly applied bariatric surgeries (Roux-en-Y gastric bypass [RYGB] and vertical sleeve gastrectomy) on energy and bone metabolism in rats 60 days after surgery. Both surgeries resulted in similar reductions of body weight, body fat, and food intake. Glucose tolerance was improved to a similar extent after both surgeries and was accompanied by increased postprandial secretion of glucose-dependent insulinotropic peptide. Using microcomputed tomography, we found that, relative to sham-operated rats, bone volume was significantly reduced after RYGB but not vertical sleeve gastrectomy. RYGB rats also had markedly reduced lipid absorption from the intestine and significantly lower serum 25-hydroxyvitamin D and calcium levels. Importantly, dietary supplementation with calcium and vitamin D could not fully rescue the reduced bone volume after RYGB surgery. Both surgeries resulted in a significant increase in stomach pH, which may have worsened the malabsorption in RYGB rats. Our findings suggest that bone loss in RYGB rats is not exclusively driven by calcium and vitamin D malabsorption but also by additional factors that may not be rescuable by dietary supplementation. These data point toward important similarities and differences between bariatric procedures that should be considered in clinical settings as guidance for which procedure will be best for specific patient populations.
Assuntos
Densidade Óssea , Metabolismo Energético , Gastrectomia/métodos , Derivação Gástrica/métodos , Tecido Adiposo , Animais , Peso Corporal , Cálcio/administração & dosagem , Cálcio/sangue , Cálcio da Dieta/administração & dosagem , Suplementos Nutricionais , Ingestão de Alimentos , Fêmur/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Lipídeos/farmacocinética , Masculino , Ratos , Ratos Long-Evans , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/sangue , Microtomografia por Raio-XRESUMO
The focus of this overview is on the animal models of obesity most commonly utilized in research. The models include monogenic models in the leptin pathway, polygenic diet-dependent models, and, in particular for their historical perspective, surgical and chemical models of obesity. However, there are far too many models to consider all of them comprehensively, especially those caused by selective molecular genetic approaches modifying one or more genes in specific populations of cells. Further, the generation and use of inducible transgenic animals (induced knock-out or knock-in) is not covered, even though they often carry significant advantages compared to traditional transgenic animals, e.g., influences of the genetic modification during the development of the animals can be minimized. The number of these animal models is simply too large to be covered in this unit.
Assuntos
Dieta/efeitos adversos , Modelos Animais de Doenças , Obesidade/etiologia , Animais , Núcleo Arqueado do Hipotálamo/cirurgia , Cricetinae , Feminino , Hipotálamo/cirurgia , Leptina/genética , Lipodistrofia/complicações , Masculino , Mesocricetus , Doenças Metabólicas/complicações , Camundongos , Camundongos Transgênicos , Mutação/genética , Obesidade/genética , Ovariectomia , Phodopus , Ratos , Ratos Transgênicos , Receptores para Leptina/genética , Estações do AnoRESUMO
Vertical sleeve gastrectomy (VSG) is a restrictive procedure that reduces food intake to produce weight loss. Here we assess volume and nutrient effects on the ingestive behavior of VSG and sham surgery animals. Rats given access to Ensure or pelleted chow were used to determine if liquid foods would adversely affect weight loss after surgery. Volume effects were studied by altering the caloric density of Ensure, and dietary preferences for fat and carbohydrate (sucrose) were assessed using a two-bottle test. c-Fos was used to measure neuronal activation in the nucleus of the solitary tract and area postrema in response to intragastric infusions of water, sucrose, or Intralipid. The degree of colocalization with catecholaminergic neurons was also assessed. VSG rats did not show the expected preference for a liquid diet over chow and lacked dietary preferences for fat seen in shams. Preferences for carbohydrate/sucrose solutions were unaffected by surgery. Meal size was reduced by VSG; however, VSG rats were able to alter their volume of intake to compensate for changes in caloric density, and intragastric infusions of water produced similar levels of neuronal activation among VSG, sham, and pair-fed rats. In comparison, nutrient-induced c-Fos activation was substantially increased by VSG. Colocalization between c-Fos and catecholaminergic-expressing neurons was similar among rats treated with water, sucrose, or Intralipid. VSG alters nutrient sensing in a manner that lowers the threshold for satiety and reduces fat preference to induce and maintain weight loss.
Assuntos
Preferências Alimentares/fisiologia , Gastrectomia/métodos , Resposta de Saciedade/fisiologia , Animais , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Dopamina beta-Hidroxilase/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Emulsões/farmacologia , Alimentos Formulados , Mucosa Gástrica/metabolismo , Imuno-Histoquímica , Intubação Gastrointestinal , Masculino , Fosfolipídeos/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Long-Evans , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Óleo de Soja/farmacologia , Estômago/citologia , Estômago/efeitos dos fármacos , Sacarose/farmacologia , Água/farmacologiaRESUMO
Although obesity rates are rapidly rising, caloric restriction remains one of the few safe therapies. Here we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue as opposed to excess dietary lipids. Fat mass (FM) of lean C57B6 mice fed a high-fat diet (HFD; FMC mice) was "clamped" to match the FM of mice maintained on a low-fat diet (standard diet [SD] mice). FMC mice displayed improved glucose and insulin tolerance as compared with ad libitum HFD mice (P < 0.001) or SD mice (P < 0.05). These improvements were associated with fewer signs of inflammation, consistent with the less-impaired metabolism. In follow-up studies, diet-induced obese mice were food restricted for 5 weeks to achieve FM levels identical with those of age-matched SD mice. Previously, obese mice exhibited improved glucose and insulin tolerance but showed markedly increased fasting-induced hyperphagia (P < 0.001). When mice were given ad libitum access to the HFD, the hyperphagia of these mice led to accelerated body weight gain as compared with otherwise matched controls without a history of obesity. These results suggest that although caloric restriction on a HFD provides metabolic benefits, maintaining those benefits may require lifelong continuation, at least in individuals with a history of obesity.
Assuntos
Tecido Adiposo Branco/metabolismo , Restrição Calórica/efeitos adversos , Metabolismo Energético , Adiposidade , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Redutora/efeitos adversos , Regulação da Expressão Gênica , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Intolerância à Glucose/imunologia , Intolerância à Glucose/metabolismo , Hiperfagia/etiologia , Hipotálamo/metabolismo , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/dietoterapia , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , Distribuição Aleatória , Prevenção Secundária , Aumento de PesoRESUMO
Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipotálamo/patologia , Inflamação/patologia , Inflamação/prevenção & controle , Condicionamento Físico Animal/fisiologia , Animais , Peso Corporal/fisiologia , Calorimetria Indireta , Teste de Tolerância a Glucose , Homeostase/fisiologia , Imuno-Histoquímica , Ativação de Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Microglia/fisiologia , Resistência Física/fisiologia , Receptores de LDL/genética , Corrida/fisiologiaRESUMO
The mediobasal hypothalamic arcuate nucleus (ARC), with its relatively 'leaky' blood-brain barrier that allows more circulating molecules to enter the brain, has emerged as a key sensor of blood-borne signals. In both the ARC and white adipose tissue (WAT), consumption of a high-fat diet (HFD) rapidly induces infiltration of microglia (ARC) or macrophages (WAT). Animals with HFD-induced obesity (DIO) and insulin resistance additionally accumulate B cells in WAT, increasing the local production of pathogenic antibodies. We therefore investigated whether DIO mice or genetically obese ob/ob mice have increased IgG in the ARC, analogous to the recent observations in WAT. Following 16 weeks of exposure to a HFD, wild-type (WT) mice had significantly increased IgG-immunoreactivity (ir) signaling that was specific to the ARC and was exclusively concentrated in microglia. By contrast, IgG-ir of age-matched obese ob/ob mice fed standard chow had ARC IgG levels comparable with those in chow-fed WT control mice. However, following 2 weeks of HFD exposure, ob/ob mice also had a significant increase of IgG-ir in the ARC. In summary, our findings reveal a novel pathophysiological phenomenon, specific for the hypothalamic ARC, that is induced by exposure to a HFD and can be enhanced, but not caused, by genetic obesity.
Assuntos
Dieta Hiperlipídica , Hipotálamo/metabolismo , Imunoglobulina G/metabolismo , Microglia/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Densitometria , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Hipotálamo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microglia/patologia , Aumento de PesoRESUMO
Physiological reactions to psychological stress are positively associated with several important chronic conditions including cardiovascular and neurodegenerative diseases and are linked to increased mortality. As such, the identification of cellular and molecular pathways that act to reduce stress responding may represent important targets for therapeutic intervention. Here we report that acute treatment with the peroxisome-proliferator activated receptor-γ (PPARγ) agonist rosiglitazone (RSG) blunts systemic responses to acute psychological stress in rats. Rats that had previously received oral RSG for 5 d exhibited a 40% reduction in the initial heart rate response to an acute restraint stress, compared with vehicle-treated controls, suggesting that increased PPARγ signaling blunts the acute autonomic response to stress. Rats previously treated with RSG likewise had a blunted hormonal response to this stressor, exhibiting a 30% reduction in peak corticosterone levels compared with controls. Moreover, stress-induced expression of c-Fos, a marker of early neuronal activation, was similarly reduced in the paraventricular hypothalamus, a key site for brain stress integration, facilitating both autonomic and hypothalamic-pituitary-adrenocortical responses to stress. Taken as a whole, these data suggest that PPARγ stimulation potently inhibits physiological responses to psychological stress, prescribing a novel role for PPARγ signaling in the regulation of brain stress integration.
Assuntos
PPAR gama/agonistas , Estresse Psicológico/tratamento farmacológico , Tiazolidinedionas/farmacologia , Administração Oral , Animais , Doenças Cardiovasculares/metabolismo , Corticosterona/farmacologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipotálamo/metabolismo , Imuno-Histoquímica/métodos , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Long-Evans , Rosiglitazona , Transdução de Sinais , Tiazolidinedionas/administração & dosagemRESUMO
Genome-wide association studies (GWAS) are a powerful tool for revealing genes associated with common human obesity. New loci associated with obesity have recently been reported, but their function and metabolic implications remain to be elucidated. In order to begin identifying the role of some of these obesity-related loci, the closest genes to the polymorphism of each locus were selected and their expression was compared in the hypothalamus, adipose tissue, liver, soleus muscle, and extensor digitorum longus muscle (EDL) of Long-Evans rats maintained on chow or a high-fat diet (HFD) for 6 weeks. From a total of 19 genes analyzed, seven genes (ETV5, FTO, GNPDA2, KCTD15, TMEM18, MC4R, and SH2B1) were down-regulated in the hypothalamus of HFD compared to chow-fed rats. In adipose tissue of rats fed on HFD, the mRNA levels of BCDIN3, KCTD15, and SULT1A1 were down-regulated, whereas those of MTCH2, PTER, and TUFM were up-regulated. In the liver, three genes were up-regulated (PTER, SULT1A1, and TUFM) in HFD relative to chow-fed rats, and TMEM18 was down-regulated. Finally, in soleus muscle of HFD-fed rats, BCDIN3, BDNF, and TMEM18 were down-regulated, and in the EDL muscle SH2B1 and TUFM were up-regulated. mRNA levels in the hypothalamus were compared between fed and fasted states, and only KCTD15 was down-regulated during fasting when fed a chow diet. In conclusion, novel genes found to be associated with obesity are regulated by a HFD and the mRNA levels of KCTD15 is dependent on the nutritional status. These results suggest a potential role of these genes in the regulation of energy balance.
Assuntos
Tecido Adiposo/metabolismo , Hipotálamo/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Obesidade/genética , Animais , Dieta Hiperlipídica , Estudo de Associação Genômica Ampla , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Ratos , Ratos Long-EvansRESUMO
Recent tremendous advances in our understanding of the regulation of food intake are expected to contribute to the treatment of obesity in the near future. The hypothalamus is a center for regulation of food intake and NPY/AgRP and POMC neurons are key regulators of food intake in the arcuate nucleus. The level of energy in the body is monitored by energy sensors in the hypothalamus. A variety of signals originating from peripheral organs to sense the status of energy converge on the hypothalamus and diverse neurons in the hypothalamus are involved in determining the output of signal to regulate food intake. Therefore, it is important to understand the signals and energy sensors in the hypothalamus. In this review, we describe the potential role of Akt/PKB signaling as an energy sensor that regulates food intake.
Assuntos
Ingestão de Alimentos/fisiologia , Hipotálamo/fisiologia , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Humanos , Hipotálamo/enzimologia , Neurônios/enzimologia , Transdução de SinaisRESUMO
Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and ß(3)-adrenergic receptor expression in brown adipose tissue and ß3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.