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1.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484128

RESUMO

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Assuntos
COVID-19/metabolismo , Cardiomiopatias/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/imunologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação , Gordura Intra-Abdominal/patologia , Obesidade/complicações , Obesidade/imunologia , Obesidade/patologia , Pericárdio , Prognóstico , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445634

RESUMO

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called "hunger" hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.


Assuntos
Corpo Estriado/patologia , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Neurônios/patologia , Obesidade/patologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Grelina/metabolismo , Animais , Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Grelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores de Grelina/genética , Transdução de Sinais , Regulação para Cima
3.
Adipocyte ; 10(1): 408-411, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34402717

RESUMO

Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Resveratrol/administração & dosagem , Tecido Adiposo/citologia , Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , COVID-19/virologia , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/patologia , Efeito Placebo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Resveratrol/farmacologia , SARS-CoV-2/isolamento & purificação
4.
Nat Commun ; 12(1): 4725, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354051

RESUMO

Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antibacterianos/administração & dosagem , Ceco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Termogênese/fisiologia , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
5.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34350941

RESUMO

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/patologia , Obesidade/imunologia , Obesidade/patologia , Humanos , Inflamação/patologia , Obesidade/epidemiologia , Fatores de Risco , SARS-CoV-2/imunologia
6.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360816

RESUMO

Hypothalamic dysfunction is an initial event following diet-induced obesity, primarily involving areas regulating energy balance such as arcuate nucleus (Arc) and median eminence (ME). To gain insights into the early hypothalamic diet-induced alterations, adult CD1 mice fed a high-fat diet (HFD) for 6 weeks were studied and compared with normo-fed controls. Transmission and scanning electron microscopy and histological staining were employed for morphological studies of the ME, while Raman spectroscopy was applied for the biochemical analysis of the Arc-ME complex. In HFD mice, ME ß2-tanycytes, glial cells dedicated to blood-liquor crosstalk, exhibited remarkable ultrastructural anomalies, including altered alignment, reduced junctions, degenerating organelles, and higher content of lipid droplets, lysosomes, and autophagosomes. Degenerating tanycytes also displayed an electron transparent cytoplasm filled with numerous vesicles, and they were surrounded by dilated extracellular spaces extending up to the subependymal layer. Consistently, Raman spectroscopy analysis of the Arc-ME complex revealed higher glycogen, collagen, and lipid bands in HFD mice compared with controls, and there was also a higher band corresponding to the cyanide group in the former compared to the last. Collectively, these data show that ME ß2-tanycytes exhibit early structural and chemical alterations due to HFD and reveal for the first-time hypothalamic cyanide presence following high dietary lipids consumption, which is a novel aspect with potential implications in the field of obesity.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Eminência Mediana/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/patologia , Metabolismo Energético , Masculino , Eminência Mediana/patologia , Camundongos , Obesidade/patologia
7.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360563

RESUMO

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the "modern" Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin-GH-IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin-GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/patologia , Hiperinsulinismo/complicações , Resistência à Insulina , Neoplasias/patologia , Obesidade/patologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Neoplasias/etiologia
8.
Lancet Diabetes Endocrinol ; 9(8): 515-524, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34217404

RESUMO

BACKGROUND: Nutritional deficiencies, such as iron and vitamin B12 deficiencies, are potential adverse consequences of bariatric surgery. Long-term data on anaemia after bariatric surgery are largely lacking. We aimed to investigate the risk of anaemia, iron and vitamin B12 deficiency anaemia, and vitamin B12 deficiency over 20 years in individuals who had bariatric surgery or received usual obesity care. METHODS: The prospective, controlled Swedish Obese Subjects study recruited people with obesity via recruitment campaigns in the mass media and at primary health-care centres, and was done at 480 primary health-care centres and in 25 surgical departments in Sweden. Eligible participants were aged 37-60 years and had a BMI of either 34 kg/m2 or more (for men) or 38 kg/m2 or more (for women). Participants were excluded if they had undergone previous bariatric surgery or had contraindicating conditions. Two main groups were formed: those who chose bariatric surgery, the type of which was determined by the operating surgeon, and a contemporaneously matched control group, created by use of 18 matching variables, who received usual non-surgical obesity care that ranged from lifestyle advice to no treatment. Haemoglobin concentration was measured during examination visits at baseline and at 1 year, 2 years, 3 years, 4 years, 6 years, 8 years, 10 years, 15 years, and 20 years of follow-up. Anaemia was defined as a haemoglobin concentration of less than 120 g/L for women and 130 g/L for men. The primary, non-specified outcome was the incidence of anaemia, and was assessed in the as-treated population, which comprised only patients who received the actual treatment. The associations between treatment type and anaemia are expressed as unadjusted hazard ratios (HRs) and HRs adjusted for age, sex, BMI, menopausal status, education, diabetes, and hypertension, with 95% CIs. This study is registered in ClinicalTrials.gov, NCT01479452, and is closed to new participants, with follow-up ongoing. FINDINGS: Between Sept 1, 1987, and Jan 31, 2001, 6905 individuals were assessed for eligibility, of whom 5335 were eligible. Of these, we included 2007 patients who chose bariatric surgery (266 in the gastric bypass group, 1365 in the vertical-banded gastroplasty group, and 376 in the gastric banding group) and 2040 matched controls who received usual obesity care. During a maximum of 20 years and a median of 10 years (IQR 3-20) of follow-up, there were 133 anaemia events in the gastric bypass group, 359 in the vertical-banded gastroplasty group, 101 in the gastric banding group, and 261 in the control group. Compared with the control group (13 cases per 1000 person-years, 95% CI 11-14), the incidence of anaemia was higher in the gastric bypass group (64 cases per 1000 person-years, 53-74; HR 5·05, 95% CI 3·94-6·48; p<0·0001), the vertical-banded gastroplasty group (23 cases per 1000 person-years, 21-26; 2·67, 2·25-3·18; p<0·0001), and the gastric banding group (26 per 1000 person-years, 21-31; 2·76, 2·15-3·52; p<0·0001). These associations remained after adjustment. INTERPRETATION: Our findings highlight the increased risk of anaemia after bariatric surgery and the importance of long-term compliance to nutritional supplementation and monitoring to enable prevention and early detection of serious nutritional deficiencies after bariatric surgery. FUNDING: Swedish Research Council, the Swedish state under the agreement between the Swedish Government and the county councils, the Swedish Diabetes Foundation, the Swedish Heart-Lung Foundation, and the Novo Nordisk Foundation.


Assuntos
Anemia/etiologia , Cirurgia Bariátrica/efeitos adversos , Obesidade/cirurgia , Adulto , Anemia/epidemiologia , Anemia/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Prognóstico , Estudos Prospectivos , Suécia/epidemiologia
9.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208002

RESUMO

The aging of human populations, including those in Europe, is an indisputable fact. The challenge for the future is not simply prolonging human life at any cost or by any means but rather extending self-sufficiency and quality of life. Even in the most advanced societies, the eternal questions remain. Who will take care of the older generations? Will adult children's own circumstances be sufficient to support family members as they age? For a range of complex reasons, including socioeconomic conditions, adult children are often unable or unwilling to assume responsibility for the care of older family members. For this reason, it is imperative that aging adults maintain their independence and self-care for as long as possible. Movement is an important part of self-sufficiency. Moreover, movement has been shown to improve patients' clinical status. At a time when the coronavirus pandemic is disrupting the world, older people are among the most vulnerable. Our paper explores current knowledge and offers insights into the significant benefits of movement for the elderly, including improved immunity. We discuss the biochemical processes of aging and the counteractive effects of exercise and endogenous substances, such as vitamin D.


Assuntos
Envelhecimento , Exercício Físico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Humanos , Obesidade/patologia , SARS-CoV-2/isolamento & purificação , Sarcopenia/patologia , Estresse Psicológico , Vitamina D/administração & dosagem
10.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199596

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Mitocôndrias/genética , Obesidade/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adipócitos/metabolismo , Tecido Adiposo Branco/fisiologia , Restrição Calórica , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Obesidade/patologia , Biogênese de Organelas
11.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299338

RESUMO

Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called "exhausted phenotype", which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.


Assuntos
Armadilhas Extracelulares/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Armadilhas Extracelulares/imunologia , Glicólise , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Obesidade/imunologia , Obesidade/patologia , Via de Pentose Fosfato , Sepse/metabolismo
12.
FASEB J ; 35(8): e21759, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245608

RESUMO

Life-style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity. Here, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre-existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low-fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet-switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of ß3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of ß3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer-lasting benefits in obesity.


Assuntos
Receptores de Ativinas Tipo I/deficiência , Adipócitos/metabolismo , Ingestão de Alimentos , Lipólise , Obesidade/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Adipócitos/patologia , Animais , Camundongos , Camundongos Transgênicos , Obesidade/genética , Obesidade/patologia , Salicilatos/farmacologia
13.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201099

RESUMO

Astrocytes are a type of glial cell anatomically and functionally integrated into the neuronal regulatory circuits for the neuroendocrine control of metabolism. Being functional integral compounds of synapses, astrocytes are actively involved in the physiological regulatory aspects of metabolic control, but also in the pathological processes that link neuronal dysfunction and obesity. Between brain areas, the hypothalamus harbors specialized functional circuits that seem selectively vulnerable to metabolic damage, undergoing early cellular rearrangements which are thought to be at the core of the pathogenesis of diet-induced obesity. Such changes in the hypothalamic brain region consist of a rise in proinflammatory cytokines, the presence of a reactive phenotype in astrocytes and microglia, alterations in the cytoarchitecture and synaptology of hypothalamic circuits, and angiogenesis, a phenomenon that cannot be found elsewhere in the brain. Increasing evidence points to the direct involvement of hypothalamic astrocytes in such early metabolic disturbances, thus moving the study of these glial cells to the forefront of obesity research. Here we provide a comprehensive review of the most relevant findings of molecular and pathophysiological mechanisms by which hypothalamic astrocytes might be involved in the pathogenesis of obesity.


Assuntos
Astrócitos/patologia , Hipotálamo/patologia , Sistemas Neurossecretores/patologia , Obesidade/patologia , Animais , Astrócitos/metabolismo , Humanos , Hipotálamo/metabolismo , Sistemas Neurossecretores/metabolismo , Obesidade/metabolismo
14.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201257

RESUMO

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain's ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.


Assuntos
Diabetes Mellitus/patologia , Hipotálamo/patologia , Neurônios/patologia , Obesidade/patologia , Fator Esteroidogênico 1/metabolismo , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Humanos , Hipotálamo/metabolismo , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo
15.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281182

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 2.7 million lives globally. Obesity has been associated with increased severity and mortality of COVID-19. However, the molecular mechanisms by which obesity exacerbates COVID-19 pathologies are not well-defined. The levels of free fatty acids (FFAs) are elevated in obese subjects. This study was therefore designed to examine how excess levels of different FFAs may affect the progression of COVID-19. Biological molecules associated with palmitic acid (PA) and COVID-19 were retrieved from QIAGEN Knowledge Base, and Ingenuity Pathway Analysis tools were used to analyze these datasets and explore the potential pathways affected by different FFAs. Our study found that one of the top 10 canonical pathways affected by PA was the coronavirus pathogenesis pathway, mediated by key inflammatory mediators, including PTGS2; cytokines, including IL1ß and IL6; chemokines, including CCL2 and CCL5; transcription factors, including NFκB; translation regulators, including EEF1A1; and apoptotic mediators, including BAX. In contrast, n-3 fatty acids may attenuate PA's activation of the coronavirus pathogenesis pathway by inhibiting the activity of such mediators as IL1ß, CCL2, PTGS2, and BAX. Furthermore, PA may modulate the expression of ACE2, the main cell surface receptor for the SARS-CoV-2 spike protein.


Assuntos
COVID-19/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Obesidade/metabolismo , Ácido Palmítico/metabolismo , SARS-CoV-2/patogenicidade , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/patologia , Quimiocinas/metabolismo , Biologia Computacional/métodos , Citocinas/metabolismo , Bases de Dados Factuais , Ácidos Graxos não Esterificados/sangue , Humanos , Mediadores da Inflamação/metabolismo , Obesidade/patologia , Pandemias , SARS-CoV-2/isolamento & purificação
16.
Nat Commun ; 12(1): 4434, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290249

RESUMO

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Período Pós-Prandial/fisiologia , Tecido Adiposo/citologia , Animais , HDL-Colesterol/metabolismo , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Lisossomos/metabolismo , Macrófagos/citologia , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Ativação Transcricional , Proteínas de Transporte Vesicular/metabolismo
17.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298894

RESUMO

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Adiponectina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Receptores para Leptina/metabolismo
18.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
19.
Front Immunol ; 12: 649359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220807

RESUMO

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.


Assuntos
COVID-19/patologia , Leptina/imunologia , Obesidade/patologia , SARS-CoV-2/imunologia , Adipócitos/metabolismo , Células Apresentadoras de Antígenos/imunologia , COVID-19/mortalidade , Citocinas/imunologia , Suscetibilidade a Doenças/patologia , Humanos , Leptina/sangue , Monócitos/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Células Th1/imunologia
20.
Nature ; 595(7866): 266-271, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34163066

RESUMO

Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown1. Hair follicles-mini-epithelial organs that grow hair-are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs)2. Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.


Assuntos
Alopecia/patologia , Alopecia/fisiopatologia , Folículo Piloso/patologia , Obesidade/fisiopatologia , Células-Tronco/patologia , Animais , Comunicação Autócrina , Contagem de Células , Diferenciação Celular , Linhagem da Célula , Senescência Celular , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Estresse Oxidativo , Comunicação Parácrina , Receptores de Interleucina-1/metabolismo
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