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1.
Mol Cell ; 75(4): 823-834.e5, 2019 Aug 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.

2.
Acta Diabetol ; 2019 Jun 24.
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.

3.
Diabetes ; 68(9): 1730-1746, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31167878

RESUMO

Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

4.
Mol Metab ; 22: 1-11, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30737105

RESUMO

OBJECTIVE: Obesity is a complex chronic disease of high prevalence worldwide. Multiple factors play integral roles in obesity development, with rising interest focusing on the contribution of environmental pollutants frequent in modern society. Silver nanoparticles (AgNPs) are widely used for bactericidal purpose in various applications in daily life. However, their potential toxicity and contribution to the obesity epidemic are not clear. METHODS: Beige adipocytes are newly discovered adipocytes characterized by high thermogenic and energy dissipating capacity upon activation and the "browning" process. In the present study, we assess the impact of AgNPs exposure on beige adipocytes differentiation and functionality both in vitro and in vivo. We also systematically investigate the influence of AgNPs on adiposity and metabolic performance in mice, as well as the possible underlying molecular mechanism. RESULTS: The results showed that, independent of particle size, AgNPs inhibit the adipogenic, mitochondrial, and thermogenic gene programs of beige adipocytes, thus suppressing their differentiation ability, mitochondrial activity, and thermogenic response. Importantly, exposure to AgNPs in mice suppresses browning gene programs in subcutaneous fat, leading to decreased energy expenditure and increased adiposity in mice. Mechanistically, we found that AgNPs increase reactive oxidative species (ROS) levels and specifically activate MAPK-ERK signaling in beige adipocytes. The negative impacts of AgNPs on beige adipocytes can be ameliorated by antioxidant or ERK inhibitor FR180204 treatment. CONCLUSIONS: Taken together, these results revealed an unexpected role of AgNPs in promoting adiposity through the inhibition of beige adipocyte differentiation and functionality, possibly by disrupting ROS homeostasis and ERK phosphorylation. Future assessments on the health risk of AgNPs applications and their safe dosages are warranted.

5.
EBioMedicine ; 40: 56-66, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528454

RESUMO

BACKGROUND: Parathyroid hormone related protein (PTHrP) triggers white adipose tissue (WAT) browning and cachexia in lung cancer mouse models. It remains unknown whether excessive PTH secretion affects WAT browning and to what extent it contributes to body weight change in primary hyperparathyroidism (PHPT). METHODS: Using the adeno-associated virus injection, Pth gene over-expressed mice mimicking PHPT were firstly established to observe their WAT browning and body weight alteration. The association between PTH and body weight was investigated in 496 PHPT patients. The adipose browning activities of 20 PHPT and 60 control subjects were measured with PET/CT scanning. FINDINGS: Elevated plasma PTH triggered adipose tissue browning, leading to increased energy expenditure, reduced fat content, and finally decreased body weight in PHPT mice. Higher circulating PTH levels were associated with lower body weight (ß = -0.048, P = .0003) independent of renal function, serum calcium, phosphorus,and albumin levels in PHPT patients. PHPT patients exhibited both higher prevalence of detectable brown/beige adipose tissue (20% vs 3.3%, P = .03) and increased browning activities (SUV in cervical adipose was 0.77 vs 0.49,P = .02) compared with control subjects. INTERPRETATION: Elevated serum PTH drove WAT browning program, which contributed in part to body weight loss in both PHPT mice and patients. These results give insights into the novel pathological effect of PTH and are of importance in understanding the metabolic changes of PHPT. FUND: This research is supported by the National Key Research and Development Program of China and National Natural Science Foundation of China.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Hiperparatireoidismo Primário/metabolismo , Perda de Peso , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Dependovirus/genética , Feminino , Expressão Gênica , Vetores Genéticos/genética , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/fisiopatologia , Masculino , Camundongos , Pessoa de Meia-Idade , Consumo de Oxigênio , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ratos
6.
J Mol Endocrinol ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30400041

RESUMO

Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor co-activator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common co-activator of several steroid receptors, such as estrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies.

7.
J Mol Endocrinol ; 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496126

RESUMO

Browning of white adipose tissue has been proven to be a potential target to fight against obesity and its metabolic commodities, making the exploration of molecules involved in browning process important. Among those browning agents reported recently, FGF21 play as a quite promising candidate for treating obesity for its obvious enhancement of thermogenic capacity in adipocyte and significant improvement of metabolic disorders in both mice and human. However, whether other members of FGF family play roles in adipose thermogenesis and obese development is still an open question. Here we examined the mRNA expression of all FGF family members in three adipose tissues of male C57BL/6 mice, and found that FGF9 is highly expressed in adipose tissue and decreased under cold stress. Furthermore, FGF9 treatment inhibited thermogenic genes in the process of beige adipocytes differentiation from stromal vascular fraction (SVF) in a dose- dependent manner. Similar results were obtained with FGF9-overexpression. Consistently, knockdown of FGF9 in SVF cells by using lentiviral shRNA increased thermogenic genes in differentiated beige adipocytes. RNA sequencing analysis revealed a significant increment of hypoxia-inducible factor (HIF) pathway in the early stage of beige adipocytes differentiation under FGF9 treatment, which was validated by real-time PCR. FGF9 expression was increased in subcutaneous WAT of obese human and mice. This study shows that adipose-derived FGF9 play as an inhibitory role in the browning of white adipocytes. Activation of hypoxia signaling at early stage of adipose browning process may contribute to this anti- thermogenic effect of FGF9.

8.
Front Physiol ; 9: 792, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30065654

RESUMO

Obesity has become epidemic worldwide, which triggers several obesity-associated complications. Obesity is characterized by excess fat storage mainly in the visceral white adipose tissue (vWAT), subcutaneous WAT (sWAT), and other tissues. Myriad studies have demonstrated the crucial role of canonical Wnt/ß-catenin cascade in the development of organs and physiological homeostasis, whereas recent studies show that genetic variations/mutations in the Wnt/ß-catenin pathway are associated with human metabolic diseases. In this review, we highlight the regulation of updated Wnt/ß-catenin signaling in obesity, especially the distinctly depot-specific roles between subcutaneous and visceral adipose tissue under high-fed diet stimulation and WAT browning process.

9.
Artigo em Inglês | MEDLINE | ID: mdl-29556215

RESUMO

The clinical application of dipeptidyl peptidase IV inhibitors (DPP4i) increasing active glucagon-like peptide-1 (AGLP-1) levels has been linked to pancreatitis, pancreatic tumors, and cardiovascular events. However, DPP4 mutations in humans or the long-term outcomes of high glucagon-like peptide-1 (GLP-1) level exposure have not been reported. A trio family with a proband showing an extremely high AGLP-1 level [defined here as hyperglipemia (hyper-glucagon-like peptide-1-emia)] were conducted whole-exome sequencing for potential pathogenic genetic defects. One novel DPP4 mutation, p.V486M (c.1456 G>A), was identified in the proband and showed damaged enzymatic activity of DPP4. Ex vivo functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight DPP4 variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. Of note, the levels of glucose, lipids, and tumor markers (especially for CA15-3 and CA125), increased gradually in the proband during a 4-year follow-up period, although no abnormal physical symptoms or imaging results were observed at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs.

10.
Front Physiol ; 9: 85, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515452

RESUMO

Obesity has spread worldwide and become a common health problem in modern society. One typical feature of obesity is the excessive accumulation of fat in adipocytes, which occurs through the following two physiological phenomena: hyperplasia (increase in quantity) and hypertrophy (increase in size) of adipocytes. In clinical and scientific research, the accurate quantification of the number and diameter of adipocytes is necessary for assessing obesity. In this study, we present a new automatic adipocyte counting system, AdipoCount, which is based on image processing algorithms. Comparing with other existing adipocyte counting tools, AdipoCount is more accurate and supports further manual correction. AdipoCount counts adipose cells by the following three-step process: (1) It detects the image edges, which are used to segment the membrane of adipose cells; (2) It uses a watershed-based algorithm to re-segment the missing dyed membrane; and (3) It applies a domain connectivity analysis to count the cells. The outputs of this system are the labels and the statistical data of all adipose cells in the image. The AdipoCount software is freely available for academic use at: http://www.csbio.sjtu.edu.cn/bioinf/AdipoCount/.

11.
J Mol Cell Biol ; 10(3): 258-266, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29272473

RESUMO

One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is associated with many pathological conditions including hyperlipidemia, insulin resistance, and type 2 diabetes. In this study, we observed the overexpression of SUMO-specific protease 2 (Senp2) in adipose tissues during obesity. Adipocyte Senp2 deficiency resulted in less adipose lipid storage accompanied by an ectopic fat accumulation and insulin resistance under high-fat diet feeding. We further found that SET domain bifurcated 1 (Setdb1) was a SUMOylated protein and that SUMOylation promoted Setdb1 occupancy on the promoter locus of Pparg and Cebpa genes to suppress their expressions by H3K9me3. Senp2 could suppress Setdb1 function by de-SUMOylation. In adipocyte Senp2-deficiency mice, accumulation of the SUMOylated Setdb1 suppressed the expression of Pparg and Cebpa genes as well as lipid metabolism-related target genes, which would decrease the ability of lipid storage in adipocytes. These results revealed the crucial role of Senp2-Setdb1 axis in controlling adipose lipid storage.

12.
EBioMedicine ; 24: 64-75, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28988979

RESUMO

BACKGROUND: IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity. METHODS: IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls. RESULTS: IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P=0.038, OR=2.27; 95% CI, 1.02-5.05). CONCLUSIONS: IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Adulto , Animais , Estudos de Casos e Controles , Linhagem Celular , Modelos Animais de Doenças , Feminino , Mutação da Fase de Leitura , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Mutação , Mutação de Sentido Incorreto , Obesidade/genética , Regiões Promotoras Genéticas , Termogênese , Proteína Desacopladora 1/metabolismo , Adulto Jovem
13.
Bone Res ; 5: 17020, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28698818

RESUMO

Bone is an endocrine organ involved in modulating glucose homeostasis. The role of the bone formation marker osteocalcin (OCN) in predicting diabetes was reported, but with conflicting results. No study has explored the association between baseline bone resorption activity and incident diabetes or prediabetes during follow-up. Our objective was to examine the relationship between the baseline bone resorption marker crosslinked C-telopeptide of type I collagen (CTX) and glycemic dysregulation after 4 years. This longitudinal study was conducted in a university teaching hospital. A total of 195 normal glucose tolerant (NGT) women at baseline were invited for follow-up. The incidence of diabetes and prediabetes (collectively defined as dysglycemia) was recorded. A total of 128 individuals completed the 4-year study. The overall conversion rate from NGT to dysglycemia was 31.3%. The incidence of dysglycemia was lowest in the middle tertile [16.3% (95% confidence interval (CI), 6.8%-30.7%)] compared with the lower [31.0% (95% CI, 17.2%-46.1%)] and upper [46.5% (95% CI, 31.2%-62.6%)] tertiles of CTX, with a significant difference seen between the middle and upper tertiles (P=0.002 5). After adjusting for multiple confounding variables, the upper tertile of baseline CTX was associated with an increased risk of incident dysglycemia, with an odds ratio of 7.09 (95% CI, 1.73-28.99) when the middle tertile was the reference. Osteoclasts actively regulate glucose homeostasis in a biphasic model that moderately enhanced bone resorption marker CTX at baseline provides protective effects against the deterioration of glucose metabolism, whereas an overactive osteoclastic function contributes to an increased risk of subsequent dysglycemia.

14.
Nat Med ; 23(7): 859-868, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28628112

RESUMO

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.


Assuntos
DNA Bacteriano/análise , Disbiose/microbiologia , Microbioma Gastrointestinal/genética , Metaboloma , Obesidade/microbiologia , Adiposidade , Adulto , Animais , Bacteroides/genética , Bacteroides thetaiotaomicron/genética , Cirurgia Bariátrica , Estudos de Casos e Controles , Disbiose/metabolismo , Feminino , Fusobacterium/genética , Gastrectomia , Ácido Glutâmico/sangue , Humanos , Masculino , Metagenoma , Camundongos , Obesidade/metabolismo , Obesidade/cirurgia , Ganho de Peso , Adulto Jovem
15.
Nucl Med Commun ; 38(8): 676-682, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28614134

RESUMO

PURPOSE: We aimed to assess the frequency of carcinoma in cases with suspected parathyroid adenoma and test the value of Tc-methoxyisobutylisonitrile (Tc-MIBI) single-photon emission computed tomography/computed tomography (SPECT/CT) parathyroid imaging and neck ultrasonography in detecting concomitant thyroid carcinoma. PATIENTS AND METHODS: We enrolled 741 patients with clinically suspected parathyroid adenoma who underwent Tc-MIBI planer scans and SPECT/CT of the skull base, neck, and thorax; patients also underwent ultrasonography within 1 month before SPECT/CT. Each case with suspected lesion was analyzed and correlated with pathology. We estimated the frequency of carcinoma detection on SPECT/CT performed for suspected parathyroid adenoma. The sensitivity, specificity, and accuracy of detecting thyroid carcinoma were estimated for both SPECT/CT and ultrasonography. RESULTS: In total, 222 patients with 250 pathology results were assessed. Of these, 54 patients showed carcinoma. With respect to the anatomical distribution of the incidental findings, 19 (35.19%) had parathyroid carcinoma, 20 (37.04%) had papillary thyroid carcinoma, three (5.56%) had follicular thyroid carcinoma, six (11.11%) had medullary thyroid carcinoma, and six (11.11%) had other carcinomas. For thyroid carcinoma detection, the sensitivity, specificity, and accuracy were 35.71, 88.16, and 80.49% for SPECT/CT and 73.81, 95.10, and 91.99% for ultrasonography, respectively. CONCLUSION: The frequency of carcinoma is high on Tc-MIBI SPECT/CT performed for suspected parathyroid adenoma. Although Tc-MIBI SPECT/CT plays an important role in the diagnosis and location of parathyroid adenoma, ultrasonography appears to be more suitable for identifying a concomitant thyroid carcinoma. This may vitally influence the choice of therapeutic regimen in patients with primary hyperparathyroidism.


Assuntos
Glândulas Paratireoides/diagnóstico por imagem , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Tecnécio Tc 99m Sestamibi , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pescoço/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
16.
Mol Nutr Food Res ; 61(9)2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28500724

RESUMO

SCOPE: Obesity and associated metabolic complications is a worldwide public health issue. Gut microbiota have been recently linked to obesity and its related inflammation. In this study, we have explored the anti-inflammatory effect of grape seed proanthocyanindin extract (GSPE) in the high-fat diet (HFD)-induced obesity and identified the contribution of the gut microbiota to GSPE effects on metabolism. METHODS AND RESULTS: Mice were fed a normal diet and a high-fat diet with or without GSPE (300 mg/kg body weight/day) by oral gavage for 7 weeks. Supplementation with GSPE significantly decreased plasma levels of inflammatory factors such as TNF-α, IL-6 and MCP-1, companied with ameliorated macrophage infiltration in epidydimal fat and liver tissues. Furthermore, GSPE also reduced epidydimal fat mass and improved insulin sensitivity. 16S rDNA analyses revealed that GSPE supplementation modulated the gut microbiota composition and certain bacteria including Clostridium XIVa, Roseburia and Prevotella. More importantly, depleting gut microbiota by antibiotics treatment abolished the beneficial effects of GSPE on inflammation and adiposity. CONCLUSION: Our study identifies the novel links between gut microbiota alterations and metabolic benefits by GSPE supplementation, providing possibilities for the prevention and treatment of metabolic disorders by targeting gut microbiota through a potential prebiotic agent GSPE.


Assuntos
Adiposidade/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Inflamação/tratamento farmacológico , Proantocianidinas/farmacologia , Animais , Dieta Hiperlipídica , Interleucina-6/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
17.
Endocrine ; 56(2): 366-378, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28243972

RESUMO

PURPOSE: DGAT2 is the critical catalyzing enzyme for triglyceride biosynthesis, and excess triglyceride accumulation in fat tissues is a fundamental process for obesity. Mutations in DGAT2 or other genes interacting with DGAT2 associated with adiposity have not been reported in human to date. METHODS: DGAT2 mutation was identified based on our in-home database-exome sequencing 227 young obese subjects (body-mass index (BMI), 35.1-61.7 kg/m2) and 219 lean controls (BMI, 17.5-23.0 kg/m2), further validated in 1190 lean subjects and the pedigree of the proband. The trios of the proband were further subjected to whole-exome sequencing to explore the candidate genes for obesity. The mutations in DGAT2 and FAAH were functionally evaluated in vitro. RESULTS: We detected two rare variants in DGAT2 with no significant difference between obese and lean individuals. One novel heterozygous nonsense variant c.382C > T (p.R128*) was identified in one obese subject but not in 219 lean subjects and another 1190 lean subjects. Notably, in vitro study showed that R128* mutation severely damaged the TG-biosynthesis ability of DGAT2, and all other R128* carriers in the pedigree were lean. Thus, we further identified a loss-of-function variant c. 944G > T (p.R315I) in FAAH in the proband inheriting from his obese father. Importantly, FAAH overexpression inhibited DGAT2 expression and TG synthesis, while R315I mutant largely eliminated this inhibitory effect. We first report loss-of-function mutations in DGAT2 and FAAH in one obese subject, which may interact with each other to affect the adiposity penetrance, providing a model of genetic interaction associated with human obesity.


Assuntos
Amidoidrolases/genética , Diacilglicerol O-Aciltransferase/genética , Epistasia Genética , Mutação , Obesidade/genética , Adiposidade , Alelos , Animais , Linhagem Celular , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Camundongos , Linhagem
18.
Cell Discov ; 3: 16054, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28224045

RESUMO

DJ-1 protein is involved in multiple physiological processes, including Parkinson's disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasisvia regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.

19.
Diabetes ; 66(4): 935-947, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28130309

RESUMO

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. We found that male NPC1+/- carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/- mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, P = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of NPC1 in the familial NP-C disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte/genética , Dieta Hiperlipídica , Glicoproteínas de Membrana/genética , Obesidade Mórbida/genética , Proteínas/genética , Adulto , Animais , Estudos de Casos e Controles , China , Feminino , Mutação da Fase de Leitura , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Fenótipo , Adulto Jovem
20.
Diabetologia ; 60(5): 900-910, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28074253

RESUMO

AIMS/HYPOTHESIS: High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance. METHODS: The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling. RESULTS: c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat. CONCLUSIONS/INTERPRETATION: Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.


Assuntos
Tecido Adiposo/metabolismo , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Gordura Subcutânea/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Teste de Tolerância a Glucose , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Obesidade/tratamento farmacológico , Obesidade/etiologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/deficiência , Proteínas Proto-Oncogênicas c-abl/genética , Pirimidinas/uso terapêutico , Gordura Subcutânea/efeitos dos fármacos
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