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White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.
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Tecido Adiposo Branco , Atlas como Assunto , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Doenças Metabólicas , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Adiposidade , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Camundongos , Obesidade/metabolismoRESUMO
Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite)1. It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications2,3. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals4. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.
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Adipócitos/metabolismo , Núcleo Celular/genética , RNA-Seq , Análise de Célula Única , Termogênese/genética , Acetatos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Adulto , Idoso , Família Aldeído Desidrogenase 1/genética , Família Aldeído Desidrogenase 1/metabolismo , Animais , Separação Celular , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Metabolismo Energético , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Comunicação Parácrina , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Adulto JovemRESUMO
PURPOSE OF REVIEW: Along with the marked increase in the population of older adults with obesity is the need for effective strategies to treat aging- and obesity-related complications. This review highlights recent progress in obesity management in older adults. RECENT FINDINGS: Although calorie restriction is needed to significantly reduce fat mass, an exercise protocol is crucial to ameliorate functional outcomes. The addition of a resistance exercise protocol improves the response of muscle protein synthesis to anabolic stimuli, preventing the calorie restriction-induced reduction in muscle and bone mass. The addition of an aerobic exercise protocol improves cardiorespiratory fitness and cognitive function. However, the addition of both aerobic and resistance exercise protocols to calorie restriction provides the greatest improvements in myocellular quality, frailty, and cardiometabolic and cognitive outcomes, translating into the greatest improvement in quality of life. Such comprehensive lifestyle intervention effectively improves glucometabolic control and age-relevant outcomes in older adults with diabetes. When combined with testosterone therapy, such lifestyle intervention also preserves muscle and bone mass in older, men with obesity and hypogonadism. SUMMARY: We conclude that calorie restriction among older adults with obesity should be prescribed in combination with both aerobic and resistance exercise to maximize benefits on overall health.
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Restrição Calórica , Qualidade de Vida , Masculino , Humanos , Idoso , Obesidade/complicações , Obesidade/terapia , Exercício Físico/fisiologia , Terapia por ExercícioRESUMO
BACKGROUND: Preliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19). METHODS: We performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied. RESULTS: Although there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects' lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed. CONCLUSIONS: This study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.
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COVID-19 , Embolia Gordurosa , COVID-19/complicações , Teste para COVID-19 , Células Endoteliais/metabolismo , Humanos , Hialina/metabolismo , Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Lipídeos , Pulmão , Obesidade/metabolismo , SARS-CoV-2RESUMO
INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM. METHODS: This was a secondary analysis of baseline data from 169 male participants, aged 35-65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography. RESULTS: At the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively). CONCLUSION: Poor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality.
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Diabetes Mellitus Tipo 2 , Absorciometria de Fóton , Densidade Óssea , Osso e Ossos , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas , Humanos , Masculino , Osteocalcina , TíbiaRESUMO
Obesity is a complex, multifactorial, and relapsing disease whose prevalence has tripled during the last decades and whose incidence is expected to further increase. For these reasons, obesity is considered as a real pandemic, deeply burdening the global health-care systems. From a pathophysiological standpoint obesity is the result of a chronic-positive energy balance which in turn leads to an excessive accumulation of lipids, not only within the adipose organ, but also in different cytotypes, a phenomenon leading to lipotoxicity that deeply compromises several cellular and organs functions. Obesity is therefore associated with over 200 medical complications, including insulin resistance and type 2 diabetes mellitus (T2DM) and represents the fifth leading cause of death worldwide. In this review, we describe the main pathophysiological mechanisms linking obesity-induced adipose organ dysfunction to insulin resistance and T2DM.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Metabolismo Energético , Humanos , Resistência à Insulina/fisiologia , Obesidade/complicaçõesRESUMO
The mammary gland (MG) is an exocrine gland present in female mammals responsible for the production and secretion of milk during the process of lactation. It is mainly composed by epithelial cells and adipocytes. Among the features that make the MG unique there are 1) its highly plastic properties displayed during pregnancy, lactation and involution (all steps belonging to the lactation cycle) and 2) its requirement to grow in close association with adipocytes which are absolutely necessary to ensure MG's proper development at puberty and remodeling during the lactation cycle. Although MG adipocytes play such a critical role for the gland development, most of the studies have focused on its epithelial component only, leaving the role of the neighboring adipocytes largely unexplored. In this review we aim to describe evidences regarding MG's adipocytes role and properties in physiologic conditions (gland development and lactation cycle), obesity and breast cancer, emphasizing the existing gaps in the literature which deserve further investigation.
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Neoplasias da Mama , Glândulas Mamárias Humanas , Adipócitos , Animais , Feminino , Humanos , Lactação , Glândulas Mamárias Animais , Obesidade , GravidezRESUMO
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.
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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/patologiaRESUMO
PURPOSE: Due to COVID-19 pandemic, the Italian population lived in quarantine from March to May 2020 (lockdown phase I). Restrictions impacted individuals' psychological health, especially in those with eating disorders (ED). Healthcare providers (HCPs) treating ED provided assistance by telemedicine and/or in walk-in clinics. We hypothesize that social restrictions represented a great stressor for ED patients and HCPs, negatively impacted their therapeutic alliance, and affected the frequency of dysfunctional behaviors. METHODS: This cross-sectional study consisted of an online survey investigating the experience of HCPs involved in ED treatment, with a specific focus on difficulties concerning the therapeutic efficacy. Questionnaire (n. 18 questions) was formulated ad hoc by our research team and sent by e-mail to Italian HCPs registered on online platforms. HCPs included ED experts specialized in psychology, nutrition or medicine. Data were collected during lockdown phase I and referred to patients with Anorexia Nervosa-(AN), Bulimia Nervosa (BN)-and Binge-Eating Disorder-(BED). RESULTS: One-hundred questionnaires were collected; 84 and 76 were included in our qualitative and quantitative analyses, respectively. Thirty-six% of HCPs felt their therapeutic intervention was unsuccessful, 37% complained compromised therapeutic alliance. Changes in frequency of compensatory behaviors (increased in 41% AN and 49,5% BN; reduced in 14,6% AN and 21,8% BN) and binge-eating episodes (increased in 53,3% BN and 30,5% BED; reduced in 30,7% BN and 24,7% BED) were experienced and ascribed to augmented patient's anxiety. Disorders switches and variation in dysfunctional conducts frequency were both significantly related to ED category (p < 0.05 for all). Concentration techniques were recognized as useful to offset such negative outcomes. CONCLUSION: According to HCPs, social restrictions affected the frequency of dysfunctional behaviors in ED patients and the efficacy of their therapeutic intervention. Further long-term studies are needed to confirm our data in a larger sample size. LEVEL IV: Novel results from a cross-sectional study.
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Anorexia Nervosa , Transtorno da Compulsão Alimentar , Bulimia Nervosa , COVID-19 , Transtornos da Alimentação e da Ingestão de Alimentos , Controle de Doenças Transmissíveis , Estudos Transversais , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Pessoal de Saúde , Humanos , Itália/epidemiologia , Pandemias , SARS-CoV-2RESUMO
Although hypogonadism is a risk factor for bone loss and fractures, the different etiopathophysiology and hormonal profile of classical and obesity-induced hypogonadism may lead to differences in musculoskeletal profile. This is a cross-sectional study of hypogonadal men between 40 and 74 years old. Our outcomes include: areal bone mineral density (aBMD) and body composition by dual-energy X-ray absorptiometry; volumetric BMD (vBMD) and soft tissue composition of the tibia by peripheral quantitative computed tomography. Fracture risk assessment tool (FRAX) scores were evaluated. Testosterone, estradiol, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin, C-telopeptide, osteocalcin, and sclerostin were measured. We divided the population into subgroups of BMI: group 1: BMI < 30; group 2: BMI ≥30 to <35 and group 3: BMI ≥ 35 kg/m2. One-hundred five men were enrolled. Spine and hip aBMD, and total and trabecular vBMD at the 4% tibia significantly increased with increasing BMI. Cortical thickness (330.7 ± 53.2, 343.3 ± 35.4, and 358.7 ± 38.2 mm, p = 0.04; groups 1, 2 and 3, respectively) and cortical area (5.3 ± 0.7, 5.5 ± 0.6, and 5.7 ± 0.6 mm, p = 0.01; groups 1, 2 and 3, respectively) at 38% tibia increased with increasing BMI. While absolute lean mass increased with increasing BMI, % lean mass and muscle density (70.2 ± 5.0, 71.3 ± 6.4, and 67.1 ± 5.1 mg/cm3; groups 1, 2 and 3, respectively) were lowest in group 3. Although severely obese hypogondal men have better BMD and bone quality, they have reduced muscle density, the significance of which remains to be determined.
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Densidade Óssea , Hipogonadismo/complicações , Músculo Esquelético/patologia , Adulto , Idoso , Índice de Massa Corporal , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/etiologia , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Sarcopenia/epidemiologia , Sarcopenia/etiologiaRESUMO
OBJECTIVE: Fat mass and obesity-associated (FTO) gene polymorphisms have been reported to be associated with differences in BMI, obesity, and type 2 diabetes. However, previous studies have been predominantly conducted in younger individuals across a spectrum of body weights, whereas little information is available on the older population. We examined the association of FTO gene polymorphisms with cardiometabolic risks among adults who were both obese (BMI≥30 kg/m) and older (age≥65 years). METHODS: A total of 165 frail, obese older adults were genotyped for FTO (rs9939609 and rs8050136) single nucleotide polymorphisms and studied for associations with body weight and body composition, components and prevalence of the metabolic syndrome, insulin response to an oral glucose tolerance test, and levels of adipocytokines (e.g. leptin) and vitamin D. RESULTS: Carriers of the A allele (CA/AA) of the FTO single nucleotide polymorphism rs8050136 had lower body weight, BMI, body fat, and trunk fat than those without the A allele (CC genotype; all P's<0.05). Moreover, genotype CA/AA was associated with lower levels of triglycerides and higher levels of high-density lipoprotein-cholesterol and carriers of this genotype showed a trend toward a lower waist circumference, resulting in a lower prevalence of metabolic syndrome than in CC genotype carriers. The insulin area under the curve during the oral glucose tolerance test was lower for genotype CA/AA. Despite the lower insulin levels, the glucose area under the curve was unchanged, resulting in a higher insulin sensitivity index. Leptin levels were also lower and adiponectin and 25-hydroxyvitamin levels tended to be higher for genotype CA/AA than for genotype CC. No differences were observed for rs9939609. CONCLUSION: Unlike the results from studies in younger individuals, the risk A allele may confer a favorable cardiometabolic risk profile in obese older adults, suggesting selective survival of obese adults into old age. If confirmed in a larger sample of surviving obese older adults, these findings may have implications in the clinical approach to obesity in this population.
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OBJECTIVE: Polymorphisms in the CYP19A1 (aromatase) gene influence disease-free survival and bone loss in patients taking aromatase inhibitors (AIs) for estrogen receptor-positive (ER+) breast cancers. Because AI use results in severe estrogen deficiency that may lead to changes in body composition, the aim of this study was to determine the effect of the rs700518 polymorphism in the CYP19A1 gene on the changes in body composition among postmenopausal women who were treated with AIs for ER+ breast cancer. PATIENTS AND METHODS: This was a 1-year prospective study of changes in body composition in postmenopausal women who were initiated on third-generation AIs for ER+ breast cancer. Body composition was measured by dual-energy absorptiometry at 6 and 12 months, serum estradiol by radioimmunoassay, and genotyping by a TaqMan single-nucleotide polymorphism allelic discrimination assay. RESULTS: Eighty-two women could provide at least one follow-up body composition measurement. Women with the GG genotype for the rs700518 (G/A at Val80) developed a significant increase in truncal fat mass index (P=0.03) and a significant decrease in fat-free mass index (P=0.01) at 12 months relative to patients carrying the A allele (GA/AA). There was no significant difference in the changes in estradiol levels among the genotypes. CONCLUSION: Patients with the GG genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for significant loss of fat-free mass and increase in truncal fat with AI therapy. Whether there are associated metabolic abnormalities and whether changes would persist with long-term AI therapy need to be confirmed in a larger study with a longer duration of follow-up.
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Inibidores da Aromatase/uso terapêutico , Aromatase/genética , Composição Corporal/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although there is an evidence of correlation between irisin and osteoporotic fractures, previous studies have not elucidated the relationship between irisin and either lean or fat mass. The main aim of this study is to investigate the relationship between irisin and body composition in postmenopausal women with osteoporosis and the impact of irisin levels on fragility vertebral fractures. METHODS: In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by an X-ray vertebral morphometry and 36 overweight nonosteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 h. RESULTS: No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels of irisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (P = 0·032), and the difference in irisin levels remained significant after adjustment for creatinine (P = 0·037), vitamin D (P = 0·046), lean mass (P = 0·02), lumbar BMD (P = 0·023) and femoral BMD (P = 0·032). CONCLUSION: Our data confirm an inverse correlation between irisin levels and vertebral fragility fractures, but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD but further studies are needed to clarify the relationship between irisin and bone metabolism.
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Fibronectinas/sangue , Osteoporose Pós-Menopausa/fisiopatologia , Absorciometria de Fóton , Idoso , Composição Corporal , Densidade Óssea , Estudos Transversais , Feminino , Fibronectinas/fisiologia , Humanos , Vértebras Lombares/patologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Sobrepeso , Pós-Menopausa , Fraturas da Coluna Vertebral/sangueRESUMO
Subcutaneous adipocytes are crucial for mammary gland epithelial development during pregnancy. Our and others' previous data have suggested that adipo-epithelial transdifferentiation could play a key role in the mammary gland alveolar development. In this study, we tested whether adipo-epithelial transdifferentiation occurs in vitro. Data show that, under appropriate co-culture conditions with mammary epithelial organoids (MEOs), mature adipocytes lose their phenotype and acquire an epithelial one. Interestingly, even in the absence of MEOs, extracellular matrix and diffusible growth factors are able to promote adipo-epithelial transdifferentiation. Gene and protein expression studies indicate that transdifferentiating adipocytes exhibit some characteristics of milk-secreting alveolar glands, including significantly higher expression of milk proteins such as whey acidic protein and ß-casein. Similar data were also obtained in cultured human multipotent adipose-derived stem cell adipocytes. A miRNA sequencing experiment on the supernatant highlighted mir200c, which has a well-established role in the mesenchymal-epithelial transition, as a potential player in this phenomenon. Collectively, our data show that adipo-epithelial transdifferentiation can be reproduced in in vitro models where this phenomenon can be investigated at the molecular level.
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Adipócitos , Transdiferenciação Celular , Células Epiteliais , Humanos , Feminino , Adipócitos/citologia , Adipócitos/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/citologia , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Organoides/citologia , Organoides/metabolismo , Técnicas de Cocultura , Camundongos , Modelos BiológicosRESUMO
Gremlin-1 is a secreted bone morphogenetic protein (BMP) antagonist playing a pivotal role in the regulation of tissue formation and embryonic development. Since its first identification in 1997, gremlin-1 has been shown to be a multifunctional factor involved in wound healing, inflammation, cancer and tissue fibrosis. Among others, the activity of gremlin-1 is mediated by its interaction with BMPs or with membrane receptors such as the vascular endothelial growth factor receptor 2 (VEGFR2) or heparan sulfate proteoglycans (HSPGs). Growing evidence has highlighted a central role of gremlin-1 in the homeostasis of the adipose tissue (AT). Of note, gremlin-1 is involved in AT dysfunction during type 2 diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) metabolic disorders. In this review we discuss recent findings on gremlin-1 involvement in AT biology, with particular attention to its role in metabolic diseases, to highlight its potential as a prognostic marker and therapeutic target.
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Diabetes Mellitus Tipo 2 , Fator A de Crescimento do Endotélio Vascular , Humanos , Proteínas Morfogenéticas ÓsseasRESUMO
One of cannabis' most iconic effects is the stimulation of hedonic high-calorie eating-the "munchies"-yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis' intoxicating constituent, Δ9-tetrahydrocannabinol (THC), to adolescent male mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and impaired cold- and ß-adrenergic receptor-stimulated lipolysis. Further analyses revealed that this phenotype is associated with molecular anomalies in the adipose organ, including ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring "pseudo-lean" state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.
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Dronabinol , Obesidade , Camundongos , Masculino , Animais , Dronabinol/farmacologia , Adiposidade , Ingestão de Energia , HomeostaseRESUMO
Obesity disease results from a dysfunctional modulation of the energy balance whose master regulator is the central nervous system. The neural circuitries involved in such function complete their maturation during early postnatal periods, when the brain is highly plastic and profoundly influenced by the environment. This phenomenon is considered as an evolutionary strategy, whereby metabolic functions are adjusted to environmental cues, such as food availability and maternal care. In this timeframe, adverse stimuli may program the body metabolism to maximize energy storage abilities to cope with hostile conditions. Consistently, the prevalence of obesity is higher among individuals who experienced early life stress (ELS). Oxytocin, a hypothalamic neurohormone, regulates the energy balance and modulates social, emotional, and eating behaviors, exerting both central and peripheral actions. Oxytocin closely cooperates with leptin in regulating energy homeostasis. Both oxytocin and leptin impact the neurodevelopment during critical periods and are affected by ELS and obesity. In this review article, we report evidence from the literature describing the effect of postnatal ELS (specifically, disorganized/inconstant maternal care) on the vulnerability to obesity with a focus on the role of oxytocin. We emphasize the existing research gaps and highlight promising directions worthy of exploration. Based on the available data, alterations in the oxytocin system may in part mediate the ELS-induced susceptibility to obesity.
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Experiências Adversas da Infância , Obesidade , Ocitocina , Ingestão de Alimentos , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Ocitocina/fisiologiaRESUMO
The Brown Adipose Tissue (BAT) is composed by mitochondrial rich, multilocular adipocytes, in strict topographical and functional relation with vasculature and noradrenergic nerves. Brown adipocytes are able to dissipate energy to produce heat, in a process known as non-shivering thermogenesis. Due to its contribution to energy expenditure, BAT is intensely studied for its potential to counteract metabolic diseases such as obesity, type 2 diabetes, dyslipidemia and cardiovascular diseases. BAT displays specific morphological characteristics that allow to assess its functional state. In this chapter we describe methodologies to properly dissect BAT depots, evaluate their gross anatomy, and assess its activation by light microscopy using peroxidase immunostaining and by laser scanning confocal microscopy using immunofluorescence. We also describe methodologies to study BAT ultrastructure by transmission and scanning electron microscopy, to visualize peroxidase immunostaining reactions at an ultrastructural level and to perform immunofluorescence reactions on paraffin-embedded samples, more often available in the clinical setting (due to the possibility to store them long-term) as opposed to fresh samples. The described techniques can be employed to study BAT morphology and activation in response to various stimuli (e.g., cold exposure; specific dietary composition) and in different pathological conditions (e.g., obesity; type 2 diabetes).
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Tecido Adiposo Marrom , Diabetes Mellitus Tipo 2 , Adipócitos Marrons , Tecido Adiposo Marrom/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Humanos , Roedores , TermogêneseRESUMO
Context: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy. Objective: The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl. Methods: This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA). Results: Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed. Conclusion: T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.