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2.
Sci Immunol ; 6(61)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330814

RESUMO

IL-33-associated type 2 innate immunity has been shown to support beige fat formation and thermogenesis in subcutaneous inguinal white adipose tissue (iWAT), but little is known about how it is regulated in iWAT. Chemerin, as a newly identified adipokine, is clinically associated with obesity and metabolic disorders. We here show that cold exposure specifically reduces chemerin and its receptor chemerin chemokine-like receptor 1 (CMKLR1) expression in iWAT. Lack of chemerin or adipocytic CMKLR1 enhances cold-induced thermogenic beige fat via potentiating type 2 innate immune responses. Mechanistically, we identify adipocytes, particularly beige adipocytes, as the main source for cold-induced IL-33, which is restricted by the chemerin-CMKLR1 axis via dampening cAMP-PKA signaling, thereby interrupting a feed-forward circuit between beige adipocytes and type 2 innate immunity that is required for cold-induced beige fat and thermogenesis. Moreover, specific deletion of adipocytic IL-33 inhibits cold-induced beige fat and type 2 innate immune responses. Last, genetic blockade of adipocytic CMKLR1 protects against diet-induced obesity and enhances the metabolic benefits of cold stimulation in preestablished obese mice. Thus, our study identifies the chemerin-CMKLR1 axis as a physiological negative regulator of thermogenic beige fat via interrupting adipose-immune communication and suggests targeting adipose CMKLR1 as a potential therapeutic strategy for obesity-related metabolic disorders.

3.
EBioMedicine ; 69: 103471, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34229277

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is highly related to the excessive accumulation of visceral adipose tissue (VAT). Quantitative measurements of VAT are commonly applied in clinical practice for measurement of metabolic risks; however, it remains largely unknown whether the texture of VAT can evaluate visceral adiposity, stratify MetS and predict surgery-induced weight loss effects. METHODS: 675 Chinese adult volunteers and 63 obese patients (with bariatric surgery) were enrolled. Texture features were extracted from VATs of the computed tomography (CT) scans and machine learning was applied to identify significant imaging biomarkers associated with metabolic-related traits. FINDINGS: Combined with sex, ten VAT texture features achieved areas under the curve (AUCs) of 0.872, 0.888, 0.961, and 0.947 for predicting the prevalence of insulin resistance, MetS, central obesity, and visceral obesity, respectively. A novel imaging biomarker, RunEntropy, was identified to be significantly associated with major metabolic outcomes and a 3.5-year follow-up in 338 volunteers demonstrated its long-term effectiveness. More importantly, the preoperative imaging biomarkers yielded high AUCs and accuracies for estimation of surgery responses, including the percentage of excess weight loss (%EWL) (0.867 and 74.6%), postoperative BMI group (0.930 and 76.1%), postoperative insulin resistance (0.947 and 88.9%), and excess visceral fat loss (the proportion of visceral fat reduced over 50%; 0.928 and 84.1%). INTERPRETATION: This study shows that the texture features of VAT have significant clinical implications in evaluating metabolic disorders and predicting surgery-induced weight loss effects. FUNDING: The complete list of funders can be found in the Acknowledgement section.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Gordura Intra-Abdominal/diagnóstico por imagem , Doenças Metabólicas/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Perda de Peso , Adulto , Feminino , Humanos , Masculino
4.
Andrology ; 9(6): 1872-1878, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34197044

RESUMO

BACKGROUND: Obesity in men is also shown to be associated with reduced reproductive potential, and this particular subtype was described as male obesity-associated secondary hypogonadism (MOSH). Recent studies showing the influence of sleep disorders on testosterone levels suggested a potential role of sleep disorders in determining the development of MOSH. OBJECTIVES: To assess the association between night-time sleep duration and day napping and the prevalence of MOSH. MATERIALS AND METHODS: In this cross-sectional study, 226 obese male participants aged 18-30 years were enrolled. Daytime napping and night-time sleep duration data were collected using a standardized self-reported Chinese-language questionnaire. MOSH was defined as obese men (BMI ≥ 30 kg/m2 ) with hypogonadal symptoms and decreased total testosterone level and/or free testosterone level, excluding other causes of hypogonadism. RESULTS: The overall prevalence of MOSH was 48.2% in this study. An inverse association was observed between night sleep duration and the risk of prevalent MOSH. Men who reported fewer than 6 h of night-time sleep had reduced total testosterone and free testosterone levels and an increased risk of MOSH. Further regression analysis revealed that after adjustment for potential confounders, the odds ratio of MOSH for the short night-time sleep group (<6 h vs. 6-8 h) was 6.17 (p = 0.040). No significant association was observed between day napping status and prevalence of MOSH. DISCUSSION AND CONCLUSION: Short night sleep duration was associated with an increased risk of MOSH in the young obese Chinese population. Chronic sleep curtailment has a negative effect on obese men's health in terms of hypogonadism.

5.
J Bone Miner Res ; 36(10): 2017-2026, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34131944

RESUMO

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Tecido Adiposo , Metabolismo Energético , Tecido Adiposo/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Osteoblastos/metabolismo
6.
J Bone Miner Res ; 36(8): 1605-1620, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33950533

RESUMO

Lgr4, a G-protein-coupled receptor, is associated with various physiological and pathological processes including oncogenesis, energy metabolism, and bone remodeling. However, whether Lgr4 is involved in osteoblasts' metabolism is not clear. Here we uncover that in preosteoblast cell line, lacking Lgr4 results in decreased osteogenic function along with reduced glucose consumption, glucose uptake, and lactate production in the presence of abundant oxygen, which is referred to as aerobic glycolysis. Activating canonical Wnt/ß-catenin signaling rescued the glycolytic dysfunction. Lgr4 promotes the expression of pyruvate dehydrogenase kinase 1 (pdk1) and is abolished by interfering canonical Wnt/ß-catenin signaling. Mice lacking Lgr4 specifically in osteoblasts (Lgr4osb-/- ) exhibit decreased bone mass and strength due to reduced bone formation. Additionally, glycolysis of osteoblasts is impaired in Lgr4osb-/- mice. Our study reveals a novel function of Lgr4 in regulating the cellular metabolism of osteoblasts. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Via de Sinalização Wnt , beta Catenina , Animais , Diferenciação Celular , Glicólise , Camundongos , Osteoblastos/metabolismo , Receptores Acoplados a Proteínas G/genética , beta Catenina/metabolismo
7.
J Clin Endocrinol Metab ; 106(9): e3619-e3633, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-33950216

RESUMO

CONTEXT: Vertical sleeve gastrectomy (VSG) is becoming a prioritized surgical intervention for obese individuals; however, the brain circuits that mediate its effective control of food intake and predict surgical outcome remain largely unclear. OBJECTIVE: We investigated VSG-correlated alterations of the gut-brain axis. METHODS: In this observational cohort study, 80 patients with obesity were screened. A total of 36 patients together with 26 normal-weight subjects were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire (TFEQ), MRI scanning, plasma intestinal hormone analysis, and fecal sample sequencing. Thirty-two patients underwent VSG treatment and 19 subjects completed an average of 4-month follow-up evaluation. Data-driven regional homogeneity (ReHo) coupled with seed-based connectivity analysis were used to quantify VSG-related brain activity. Longitudinal alterations of body weight, eating behavior, brain activity, gastrointestinal hormones, and gut microbiota were detected and subjected to repeated measures correlation analysis. RESULTS: VSG induced significant functional changes in the right putamen (PUT.R) and left supplementary motor area, both of which correlated with weight loss and TFEQ scores. Moreover, postprandial levels of active glucagon-like peptide-1 (aGLP-1) and Ghrelin were associated with ReHo of PUT.R; meanwhile, relative abundance of Clostridia increased by VSG was associated with improvements in aGLP-1 secretion, PUT.R activity, and weight loss. Importantly, VSG normalized excessive functional connectivities with PUT.R, among which baseline connectivity between PUT.R and right orbitofrontal cortex was related to postoperative weight loss. CONCLUSION: VSG causes correlated alterations of gut-brain axis, including Clostridia, postprandial aGLP-1, PUT.R activity, and eating habits. Preoperative connectivity of PUT.R may represent a potential predictive marker of surgical outcome in patients with obesity.


Assuntos
Encéfalo/fisiopatologia , Gastrectomia/métodos , Hormônios Gastrointestinais/sangue , Microbioma Gastrointestinal , Obesidade/metabolismo , Obesidade/cirurgia , Adulto , Peso Corporal , Córtex Cerebral/fisiopatologia , Estudos de Coortes , Ingestão de Alimentos , Feminino , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Motor/fisiopatologia , Obesidade/microbiologia , Putamen/fisiopatologia , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
8.
Front Endocrinol (Lausanne) ; 12: 634191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776928

RESUMO

Objective: The Iroquois homeobox 3 (IRX3) gene was recently reported to be a functional downstream target of a common polymorphism in the FTO gene, which encodes an obesity-associated protein; however, the role of IRX3 in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant-negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that IRX3 knockdown impaired the browning program of primary preadipocytes in vitro. In this study, we aimed to further clarify the effects of overexpressing human IRX3 (hIRX3) on brown/beige adipose tissues in vivo. Methods: Brown/beige adipocyte-specific hIRX3-overexpressing mice were generated and the browning program of white adipose tissues was induced by both chronic cold stimulation and CL316,243 injection. Body weight, fat mass, lean mass, and energy expenditure were measured, while morphological changes and the expression of thermogenesis-related genes in adipose tissue were analyzed. Moreover, the browning capacity of primary preadipocytes derived from hIRX3-overexpressing mice was assessed. RNA sequencing was also employed to investigate the effect of hIRX3 on the expression of thermogenesis-related genes. Results: hIRX3 overexpression in embryonic brown/beige adipose tissues (Rosa26 h IRX3 ;Ucp1-Cre) led to increased energy expenditure, decreased fat mass, and a lean body phenotype. After acute cold exposure or CL316,243 stimulation, brown/beige tissue hIRX3-overexpressing mice showed an increase in Ucp1 expression. Consistent with this, induced hIRX3 overexpression in adult mice (Rosa26 h IRX3 ;Ucp1-CreERT2) also promoted a moderate increase in Ucp1 expression. Ex vitro experiments further revealed that hIRX3 overexpression induced by Ucp1-driven Cre recombinase activity upregulated brown/beige adipocytes Ucp1 expression and oxygen consumption rate (OCR). RNA sequencing analyses indicated that hIRX3 overexpression in brown adipocytes enhanced brown fat cell differentiation, glycolysis, and gluconeogenesis. Conclusion: Consistent with the in vitro findings, brown/beige adipocyte-specific overexpression of hIRX3 promoted Ucp1 expression and thermogenesis, while reducing fat mass.

9.
Diabetes Ther ; 12(1): 289-300, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33216280

RESUMO

INTRODUCTION: East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of ß-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes. METHODS: Exome variants of 80 Chinese early-onset diabetes patients (onset age < 35 years) after the exclusion of type 1 diabetes (T1D) were detected by a customized gene panel covering 32 known diabetes-associated genes. Then, 229 subjects with early-onset diabetes (T1D excluded) and 1679 controls from the Chinese population were genotyped to validate the association of PAX4 R192H/S with early-onset diabetes and related phenotypes. RESULTS: The gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37-2.60, P = 8.41 × 10-5; R192S: OR 1.71, 95% CI 1.17-2.51, P = 0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels (P = 0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) (P = 0.040); R192S carriers had lower fasting C-peptide (FCP) (P = 0.011) and 2 h C-peptide levels (P = 0.033) in OGTT than non-variant carriers. CONCLUSIONS: The ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01938365).

10.
Diabetes Care ; 44(2): 499-510, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33355246

RESUMO

OBJECTIVE: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS: We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. RESULTS: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid (P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adulto , Ácidos e Sais Biliares , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Jejum , Humanos , Pessoa de Meia-Idade
11.
Obesity (Silver Spring) ; 29(2): 327-336, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33342076

RESUMO

OBJECTIVE: Adipose tissue macrophages (ATMs) play critical roles in obesity-associated inflammation that contributes to metabolic dysfunction. Talabostat (TB) exerts some therapeutic effects on tumors and obesity. However, it remains unknown whether the metabolic benefits of TB on obesity is dependent on ATM-mediated adipose inflammation. METHODS: Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet for 12 weeks, and mice were orally administered TB daily at a low dose (0.5 mg/kg). RESULTS: Administration of TB to mice fed a high-fat diet significantly improved adiposity and obesity-associated metabolic dysfunction, including glucose intolerance and insulin resistance, hyperlipidemia and hepatic steatosis, which were accompanied by increased whole-body energy expenditure. RNA sequencing analysis revealed extensive alterations in the transcriptome profiles associated with lipid metabolism and immune responses in adipose tissue of obese mice. Notably, TB treatment led to a significant reduction in ATM accumulation and a shift of the activation state of ATMs from the proinflammatory M1-like to the anti-inflammatory M2-like phenotype. Moreover, depletion of ATMs significantly abolished the TB-induced metabolic benefits. CONCLUSIONS: Our study demonstrates that TB at a low dose could increase energy expenditure and control ATM-mediated adipose inflammation in obese mice, thereby alleviating obesity and its associated metabolic dysfunction.


Assuntos
Tecido Adiposo , Ácidos Borônicos/farmacologia , Dipeptídeos/farmacologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Obesidade/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Front Cell Dev Biol ; 8: 572459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33251209

RESUMO

Background: Thermogenic adipocytes, including beige and brown adipocytes, are critical for thermogenesis and energy homeostasis. Identification of functional cell surface markers of thermogenic adipocytes is of significance for potential application in biological and clinical practices. Methods: With a combination of RNA-sequencing of in vivo and in vitro models, we identified transferrin receptor (Tfr1), a receptor specialized for cellular iron uptake, as a previously unappreciated cell surface molecule for thermogenic adipocytes compared to white adipocytes. The alternation of Tfr1 levels under physiological and pathological stimuli was assessed, and the mitochondria functionality, browning capacity, and iron metabolism of mature adipocytes were examined with Tfr1 knockdown. Results: Tfr1 was expressed predominantly in thermogenic adipocytes versus white adipocyte, and its expression levels were tightly correlated with the activation or inhibition status of thermogenic adipocytes under external stimuli. Besides, Tfr1 gene deficiency in thermogenic adipocytes led to reduced thermogenic gene programs and mitochondrial integrity. Conclusion: Tfr1 functionally marks thermogenic adipocytes and could serve as a potential thermogenic adipocyte surface marker.

13.
Elife ; 92020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32749219

RESUMO

R-spondin1 (Rspo1) has been featured as a Wnt agonist, serving as a potent niche factor for stem cells in many tissues. Here we unveil a novel role of Rspo1 in promoting estrogen receptor alpha (Esr1) expression, hence regulating the output of steroid hormone signaling in the mouse mammary gland. This action of Rspo1 relies on the receptor Lgr4 and intracellular cAMP-PKA signaling, yet is independent of Wnt/ß-catenin signaling. These mechanisms were reinforced by genetic evidence. Luminal cells-specific knockout of Rspo1 results in decreased Esr1 expression and reduced mammary side branches. In contrast, luminal cells-specific knockout of Wnt4, while attenuating basal cell Wnt/ß-catenin signaling activities, enhances Esr1 expression. Our data reveal a novel Wnt-independent role of Rspo1, in which Rspo1 acts as a bona fide GPCR activator eliciting intracellular cAMP signaling. The identification of Rspo1-ERα signaling axis may have a broad implication in estrogen-associated diseases.


Assuntos
Receptor alfa de Estrogênio/genética , Regulação da Expressão Gênica , Trombospondinas/genética , Via de Sinalização Wnt , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Trombospondinas/metabolismo
14.
Circ Res ; 127(8): 953-973, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32600176

RESUMO

RATIONALE: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. OBJECTIVE: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. METHODS AND RESULTS: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated c-Fos, Fosl1, and Fosb transactivation. CONCLUSIONS: Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Animais , Apoptose , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo
15.
EMBO J ; 39(7): e103304, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32104923

RESUMO

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.


Assuntos
Ácidos Cetoglutáricos/sangue , Atrofia Muscular/genética , Receptores Purinérgicos P2/genética , Treinamento de Força/métodos , Adulto , Idoso , Animais , Linhagem Celular , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Atrofia Muscular/metabolismo , Receptores Purinérgicos P2/metabolismo
16.
Sci Adv ; 6(2): eaax9605, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31934629

RESUMO

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in CTNNB1/ß-catenin associated with increased obesity risk. Specific ablation of ß-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα+ preadipocytes and less mature adipocytes. Mechanistically, ß-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ß-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that ß-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ß-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/ß-catenin pathway to combat obesity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Adiposidade , Diferenciação Celular , beta Catenina/genética , Células 3T3-L1 , Tecido Adiposo Branco/metabolismo , Animais , Sítios de Ligação , Proliferação de Células , Dieta Hiperlipídica , Mutação com Ganho de Função/genética , Homeostase , Humanos , Ativação de Macrófagos , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Tamanho do Órgão , Células RAW 264.7 , Proteína Amiloide A Sérica/metabolismo , Fatores de Transcrição TCF/metabolismo , Transcrição Genética , Via de Sinalização Wnt
17.
Acta Diabetol ; 57(1): 53-61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31240398

RESUMO

AIM: To explore the glycemic characteristics of non-diabetic shift workers and associations with metabolic indices. METHODS: In this cross-sectional study, 450 non-diabetic males, including 238 shift workers, aged 23-58 years, were recruited after a screening oral glucose tolerance test. Blood samples and anthropometric data were collected. Hundred and fifty of them finished a continuous glucose monitoring for 3-7 days. RESULTS: Compared to daytime workers, shift workers presented with larger WHR (p < 0.001), higher HOMA-IR (p < 0.001), higher hs-CRP level (p < 0.001) and worse lipid profiles. In glycemic characteristics, shift workers with normal glucose regulation had a similar mean blood glucose (MBG), daytime MBG, percentage of time of hyperglycemia, hypoglycemia, euglycemia, and fluctuation parameters, including standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursions (MAGE) and mean of daily differences (p > 0.05, respectively), while they had a higher nighttime MBG (p = 0.026) and blood glucose (BG) at 3 a.m. (p = 0.015). For subjects with impaired glucose regulation, both groups had no difference in any clinical characteristics or glycemic parameters (p > 0.05, respectively). Further regression analysis revealed the association between MBG/SDBG/MAGE/nighttime MBG/BG at 3 a.m. and age/WHR/hs-CRP/TC. CONCLUSION: For non-diabetic shift workers, the glycemic characteristic was the elevated nighttime glycemia, presented as higher nighttime MBG and BG at 3 a.m. And both metrics were closely associated with central obesity. Elevated nighttime glycemia was an early signal of glucose metabolism disorder in shift workers.


Assuntos
Glicemia/análise , Hiperglicemia/metabolismo , Jornada de Trabalho em Turnos/efeitos adversos , Adulto , Glicemia/metabolismo , Automonitorização da Glicemia , Estudos Transversais , Teste de Tolerância a Glucose , Índice Glicêmico , Humanos , Hiperglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Diabetes ; 12(5): 365-371, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31846221

RESUMO

Geographically, the Qinling Mountain-Huai River line divides China into two parts, Northern and Southern. Surprisingly, the line also divides the high prevalence of obesity and metabolic syndrome in Northern China from the low prevalence of Southern China. In past decades, the diet-center hypothesis has gained much support from the apparent cardiometabolic disease-protection effect of the Mediterranean diet. Questions include the following: Does the diet pattern explain the disease prevalence difference between two parts with similar genetic background? What kind of diet pattern is suitable for future national diet recommendation for Chinese, as the Mediterranean diet does for the Western countries? Here, we review the main healthy diet components, which the native inhabitants in the Yangtze River Delta region have eaten for several hundreds of years, and refer to this healthy diet as "Southern River ()-style dietary pattern" or "Jiangnan Diet."


Assuntos
Dieta Saudável/métodos , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , China/epidemiologia , Dieta/etnologia , Dieta Saudável/etnologia , Dieta Saudável/estatística & dados numéricos , Comportamento Alimentar/etnologia , Comportamento Alimentar/fisiologia , Geografia , Humanos , Síndrome Metabólica/etiologia , Obesidade/etiologia , Prevalência , Fatores de Risco
19.
Nat Commun ; 10(1): 5070, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699980

RESUMO

ß-Adrenergic receptor (ß-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the ß3-adrenergic receptor (ß3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses ß3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Adipogenia/genética , Metabolismo Energético/genética , Fatores de Transcrição Forkhead/genética , Receptores Adrenérgicos beta 3/genética , Proteínas Repressoras/genética , Termogênese/genética , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Camundongos , Obesidade/genética , Obesidade/metabolismo , Omento/metabolismo , Feocromocitoma/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Repressoras/metabolismo
20.
Mol Cell ; 75(4): 823-834.e5, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31302001

RESUMO

Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.


Assuntos
Cisteína Endopeptidases/metabolismo , Mitocôndrias/metabolismo , Mutação , Obesidade/metabolismo , Transdução de Sinais , Sirtuína 3/metabolismo , Sumoilação , Acetilação , Animais , Cisteína Endopeptidases/genética , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Mutantes , Mitocôndrias/genética , Mitocôndrias/patologia , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Sirtuína 3/genética
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