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1.
Commun Biol ; 7(1): 787, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38951550

RESUMO

Adipose tissue development begins in the fetal period, and continues to expand after birth. Dysregulation of adipose tissue during weaning may predispose individuals to lifelong metabolic disorders. However, the developmental remodeling of adipose tissue during weaning remains largely unexplored. Here we comprehensively compare the changes in mouse subcutaneous white adipose tissue from 7 days after birth to 7 days after weaning using single-cell RNA sequencing along with other molecular and histologic assays. We characterize the developmental trajectory of preadipocytes and indicate the commitment of preadipocytes with beige potential during weaning. Meanwhile, we find immune cells unique to weaning period, whose expression of extracellular matrix proteins implies potential regulation on preadipocyte. Finally, the strongest cell-cell interaction during weaning determined by the TGFß ligand-receptor pairs is between preadipocytes and endotheliocytes. Our results provide a detailed and unbiased cellular landscape and offer insights into the potential regulation of adipose tissue remodeling during weaning.


Assuntos
Tecido Adiposo Branco , Análise de Célula Única , Gordura Subcutânea , Desmame , Animais , Camundongos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Gordura Subcutânea/metabolismo , Gordura Subcutânea/citologia , Camundongos Endogâmicos C57BL , Adipócitos/metabolismo , Adipócitos/citologia , Masculino , Feminino
2.
Science ; 384(6701): eadk5382, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38870290

RESUMO

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.


Assuntos
Proteases Dependentes de ATP , Artemisininas , Enzima de Clivagem da Cadeia Lateral do Colesterol , Proteínas Mitocondriais , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Camundongos , Ratos , Androgênios/metabolismo , Artemisininas/uso terapêutico , Artemisininas/farmacologia , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Modelos Animais de Doenças , Hiperandrogenismo/tratamento farmacológico , Hiperandrogenismo/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Ovário/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Proteólise , Camundongos Endogâmicos C57BL , Adulto Jovem , Adulto , Ratos Sprague-Dawley , Proteases Dependentes de ATP/genética , Proteases Dependentes de ATP/metabolismo
3.
Mol Metab ; 81: 101891, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38307386

RESUMO

OBJECTIVE: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. METHODS: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. RESULTS: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. CONCLUSIONS: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.


Assuntos
Adipócitos Marrons , Tecido Adiposo Marrom , Animais , Masculino , Camundongos , Adipócitos Marrons/metabolismo , Adipogenia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Homeostase
4.
Proc Natl Acad Sci U S A ; 120(33): e2305717120, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37549287

RESUMO

Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.


Assuntos
Adipócitos Marrons , Biogênese de Organelas , Animais , Camundongos , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Homeostase , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Termogênese/fisiologia
5.
Adv Sci (Weinh) ; 10(19): e2207223, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37088731

RESUMO

There is a need for point-of-care bacterial sensing and identification technologies that are rapid and simple to operate. Technologies that do not rely on growth cultures, nucleic acid amplification, step-wise reagent addition, and complex sample processing are the key for meeting this need. Herein, multiple materials technologies are integrated for overcoming the obstacles in creating rapid and one-pot bacterial sensing platforms. Liquid-infused nanoelectrodes are developed for reducing nonspecific binding on the transducer surface; bacterium-specific RNA-cleaving DNAzymes are used for bacterial identification; and redox DNA barcodes embedded into DNAzymes are used for binding-induced electrochemical signal transduction. The resultant single-step and one-pot assay demonstrates a limit-of-detection of 102 CFU mL-1 , with high specificity in identifying Escherichia coli amongst other Gram positive and negative bacteria including Klebsiella pneumoniae, Staphylococcus aureus, and Bacillus subtilis. Additionally, this assay is evaluated for analyzing 31 clinically obtained urine samples, demonstrating a clinical sensitivity of 100% and specify of 100%. When challenging this assay with nine clinical blood cultures, E. coli-positive and E. coli-negative samples can be distinguished with a probability of p < 0.001.


Assuntos
DNA Catalítico , Escherichia coli , Escherichia coli/genética , Sensibilidade e Especificidade , Bactérias , DNA
6.
Chemistry ; 29(36): e202300240, 2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37086393

RESUMO

Clostridium difficile frequently causes an infectious disease known as Clostridium difficile infection (CDI), and there is an urgent need for the development of more effective rapid diagnostic tests for CDI. Previously we have developed an RNA-cleaving fluorogenic DNAzyme (RFD) probe, named RFD-CD1, that is capable of detecting a specific strain of C. difficile but is too specific to recognize other pathogenic C. difficile strains. To overcome this issue, herein we report RFD-CD2, another RFD that is not only highly specific to C. difficile but also capable of recognizing diverse pathogenic C. difficile strains. Extensive sequence and structure characterization establishes a pseudoknot structure and a significantly minimized sequence for RFD-CD2. As a fluorescent sensor, RFD-CD2 can detect C. difficile at a concentration as low as 100 CFU/mL, thus making this DNAzyme an attractive molecular probe for rapid diagnosis of CDI caused by diverse strains of C. difficile.


Assuntos
Clostridioides difficile , Infecções por Clostridium , DNA Catalítico , Humanos , Clostridioides difficile/genética , Infecções por Clostridium/diagnóstico , Testes de Diagnóstico Rápido
7.
Biomolecules ; 13(3)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36979389

RESUMO

Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4fl/fl and Tlr4LoxTB) that allow ablation of TLR4 only in hepatocytes (Tlr4LKO) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4LoxTB × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4LKO) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3ß (GSK3ß) was observed in the liver of Tlr4LKO mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4LoxTB × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4LoxTB). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4LoxTB × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4LoxTB × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.


Assuntos
Intolerância à Glucose , Resistência à Insulina , Animais , Camundongos , Etanol/toxicidade , Etanol/metabolismo , Intolerância à Glucose/metabolismo , Hepatócitos/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
8.
Cell Rep ; 42(1): 111948, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640325

RESUMO

Obesity, particularly increased visceral fat, positively correlates with various metabolic challenges, including atherosclerosis, but the mechanism is not fully understood. The aim of this study is to determine the role of visceral-fat-derived exosomes (Exo) in endothelial cells and atherosclerosis. We show that obesity changes the miRNA profile of visceral adipose exosomes in mice. Importantly, exosomal miR-27b-3p efficiently enters into the vascular endothelial cells and activates the NF-κB pathway by downregulating PPARα. Mechanistically, miR-27b-3p binds directly to the CDS region of PPARα mRNA, thereby promoting mRNA degradation and suppressing translation. In ApoE-deficient mice, administration of miR-27b-3p mimic increases inflammation and atherogenesis, while overexpression of PPARα protects against atherosclerosis. Thus, obesity-induced exosomal miR-27b-3p promotes endothelial inflammation and facilitates atherogenesis by PPARα suppression. We reveal an exosomal pathway by which obesity aggravates atherosclerosis and proposed therapeutic strategies for atherosclerosis in people with obesity.


Assuntos
Aterosclerose , Exossomos , MicroRNAs , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Células Endoteliais/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Adipócitos/metabolismo , Inflamação/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Obesidade/metabolismo , Exossomos/metabolismo
9.
Front Cardiovasc Med ; 9: 1038176, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457800

RESUMO

Background: Perivascular adipose tissue (PVAT), an active endocrine organ, exerts direct effect on vascular tone through paracrine. Activation of PVAT metabolism plays an inhibitory role in atherosclerosis via secreting relaxing factors. The present studies were designed to investigate the role of PVAT metabolism in regulation of hypertension. Materials and methods: Apolipoprotein E (ApoE) knockout mice with BMP4 knockout in adipose tissue or brown adipose tissue (aP2-DKO or UCP1-DKO, respectively) were used for exploring the role of impaired PVAT metabolism in hypertension. Vascular function was assessed using wire myography. The potential regulatory factor of vascular function was explored using qPCR and ELISA and further confirmed in perivascular fat cell line. Results: Knockout of BMP4 either in adipose tissue or specifically in BAT aggravates high-fat diet (HFD, 40% fat)-induced hypertension and endothelial dysfunction in ApoE-/- mice. In the meanwhile, deficiency of BMP4 also aggravates Ang II (angiotensin II) -induced hypertension and vascular remodeling in ApoE-/- mice. Moreover, deficiency of BMP4 inhibits NO release and induces ROS production. In vitro system, aortic rings pretreated with PVAT extracts from BMP4-DKO mice showed increased vasoconstriction and reduced endothelial-dependent relaxation compared with the controls. We further demonstrated that PVAT of BMP4-DKO mice expressed higher level of angiotensinogen (AGT) and Ang II compared with the controls. Conclusion: Impaired PVAT metabolism aggravates hypertension, and this effect is dependent on the activation of local renin-angiotensin-aldosterone system (RAAS). The results of this study first demonstrate the regulatory role of PVAT metabolism in hypertension.

10.
Diabetes ; 71(9): 1862-1879, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35709007

RESUMO

Brown and beige adipocytes dissipate energy in a nonshivering thermogenesis manner, exerting beneficial effects on metabolic homeostasis. CHCHD10 is a nuclear-encoded mitochondrial protein involved in cristae organization; however, its role in thermogenic adipocytes remains unknown. We identify CHCHD10 as a novel regulator for adipocyte thermogenesis. CHCHD10 is dramatically upregulated during thermogenic adipocyte activation by PPARγ-PGC1α and positively correlated with UCP1 expression in adipose tissues from humans and mice. We generated adipocyte-specific Chchd10 knockout mice (Chchd10-AKO) and found that depleting CHCHD10 leads to impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state, with no effect in the fed state. Lipolysis in adipocytes is disrupted by CHCHD10 deficiency, while augmented lipolysis through ATGL overexpression recovers adipocyte thermogenesis in Chchd10-AKO mice. Consistently, overexpression of Chchd10 activates thermogenic adipocytes. Mechanistically, CHCHD10 deficiency results in the disorganization of mitochondrial cristae, leading to impairment of oxidative phosphorylation complex assembly in mitochondria, which in turn inhibits ATP generation. Decreased ATP results in downregulation of lipolysis by reducing nascent protein synthesis of ATGL, thereby suppressing adipocyte thermogenesis. As a result, Chchd10-AKO mice are prone to develop high-fat diet-induced metabolic disorders. Together, our findings reveal an essential role of CHCHD10 in regulating lipolysis and the thermogenic program in adipocytes.


Assuntos
Adipócitos Bege , Adipócitos Marrons , Lipólise , Proteínas Mitocondriais , Termogênese , Trifosfato de Adenosina/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Animais , Humanos , Lipólise/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
11.
ACS Sens ; 7(4): 985-994, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35384648

RESUMO

Rapid, ultrasensitive, and specific detection and identification of bacteria in unprocessed clinical specimens is critically needed to enable point-of-care diagnosis of infectious diseases. However, existing systems require sample processing and/or analyte enrichment for direct bacterial analysis in clinical samples, which significantly adds to the assay time and complexity. Herein, we integrate RNA-cleaving DNAzymes specific to Escherichia coli (E. coli) and programmed for electrochemical signal transduction, multifunctional microgel magnetic beads for immobilizing the DNAzyme into a hydrated and three-dimensional scaffold, and hierarchical electrodes for ultrasensitive electrochemical readout to achieve rapid bacterial analysis in undiluted and unprocessed urine collected from symptomatic patients suspected of having urinary tract infections (UTIs). The microgel magnetic bead assay enables highly efficient conjugation and hydration of the immobilized DNAzymes, resulting in low limits-of-detection of 6 CFU/mL in buffer and 138 CFU/mL in unprocessed urine with high specificity against multiple urinary pathogens within a 1 hour assay time. The assay successfully identifies which patients are infected with E. coli as the causative organism for their UTI symptoms, indicating the clinical relevance of this assay.


Assuntos
DNA Catalítico , Microgéis , Bactérias , DNA Catalítico/química , Escherichia coli/química , Humanos , Fenômenos Magnéticos
12.
EBioMedicine ; 78: 103969, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35349825

RESUMO

BACKGROUND: Some circulating proteins are linked to central adiposity. Gremlin 2 (GREM2) functions as a secreted factor involved in osteogenesis and adipogenesis. Here, we investigated the association of blood GREM2 levels and central adiposity, and the biological roles of GREM2 in the browning program of visceral preadipocytes. METHODS: Three independent cohorts were applied to detect circulating GREM2 levels. Recombinant Grem2 protein, Grem2 overexpression and knockout mouse models, and preadipocyte-specific Bmpr2 knockout mice were used to assess the roles of Grem2 in the browning program. FINDINGS: We detected the presence of GREM2 protein in human serum using an ELISA approach. We revealed elevated GREM2 levels in severely obese subjects and validated this finding in a large-scale community population involving 10,327 subjects. Notably, serum GREM2 was positively associated with visceral fat volume, as quantified by 3D reconstruction methods. In mice, Grem2 was highly expressed in visceral fat and liver tissues, while surgical removal of visceral fat lowered circulating Grem2 levels. Visceral fat secreted more Grem2 in obese mice. Grem2-overexpressed mice exhibited a reduced browning ability of visceral fat, whereas Grem2 ablation enhanced the browning capacity and reduced visceral fat content. Mechanistically, Grem2 attenuated the browning program of visceral preadipocytes partially by antagonizing BMP4/7-SMAD1/5/8 signaling pathway. Further, genetic deletion of Bmpr2 in Pdgfrα+ preadipocytes abolished the antagonistic effect of Grem2. INTERPRETATION: These findings indicate that GREM2 might function as a circulating protein factor associated with human visceral adiposity, and Grem2 inhibits the browning capacity of visceral preadipocytes partially by BMP4/7-BMPR2 signaling pathway. FUNDING: The complete list of funders can be found in the Acknowledgement section.


Assuntos
Citocinas , Obesidade Abdominal , Adipogenia/genética , Tecido Adiposo Marrom , Animais , Citocinas/genética , Humanos , Gordura Intra-Abdominal/metabolismo , Camundongos , Camundongos Obesos , Obesidade Abdominal/genética
13.
Anal Chim Acta ; 1196: 339511, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35151405

RESUMO

Aptamers are molecular recognition elements made of nucleic acids. Diverse synthetic aptamers have been discovered in a large number of SELEX experiments since 1990. This review begins with the analysis of these SELEX experiments by examining the range of targets as well as the affinity and specificity for these targets by DNA, RNA or modified nucleic acid aptamers generated from these experiments. This is followed by comparisons of synthetic aptamers with natural RNA aptamers from riboswitches and with some of the best naturally occurring protein based recognition elements for proteins and small molecules. These comparisons reveal the gaps between man-made aptamers and natural recognition elements. We then put forward a series of ideas for consideration by the aptamer community towards developing better aptamers to solve real world problems. These include performing aptamer selections with libraries containing larger random sequence domains to derive larger aptamers with more intricate structures, conducting more reselection experiments using mutagenized DNA libraries based on initially selected aptamer sequences to search for better members of an aptamer family, selecting aptamers that are programmed to recognize two or more different epitopes of the same target in order to build multivalent aptamers for increased affinity, expanding the effort of selecting aptamers using modified nucleic acids with enhanced chemical functionalities, innovating SELEX methods to drive for the selection of aptamers with truly outstanding affinity and specificity, and having terminal applications in mind when creating new aptamers so that they are highly functional in the environment where the applications are planned.


Assuntos
Aptâmeros de Nucleotídeos , Técnica de Seleção de Aptâmeros , Biblioteca Gênica , Humanos
14.
J Biol Chem ; 298(2): 101544, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34971706

RESUMO

Uncontrolled gluconeogenesis results in elevated hepatic glucose production in type 2 diabetes (T2D). The small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is known to catalyze deSUMOylation of target proteins, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic gluconeogenesis and the occurrence of T2D remain unknown. Herein, we established SENP2 hepatic knockout mice and found that SENP2 deficiency could protect against high-fat diet-induced hyperglycemia. Pyruvate- or glucagon-induced elevation in blood glucose was attenuated by disruption of SENP2 expression, whereas overexpression of SENP2 in the liver facilitated high-fat diet-induced hyperglycemia. Using an in vitro assay, we showed that SENP2 regulated hepatic glucose production. Mechanistically, the effects of SENP2 on gluconeogenesis were found to be mediated by the cellular fuel sensor kinase, 5'-AMP-activated protein kinase alpha (AMPKα), which is a negative regulator of gluconeogenesis. SENP2 interacted with and deSUMOylated AMPKα, thereby promoting its ubiquitination and reducing its protein stability. Inhibition of AMPKα kinase activity dramatically reversed impaired hepatic gluconeogenesis and reduced blood glucose levels in SENP2-deficient mice. Our study highlights the novel role of hepatic SENP2 in regulating gluconeogenesis and furthers our understanding of the pathogenesis of T2D.


Assuntos
Proteínas Quinases Ativadas por AMP , Cisteína Endopeptidases , Diabetes Mellitus Tipo 2 , Hiperglicemia , Sumoilação , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese , Glucose/metabolismo , Hiperglicemia/metabolismo , Fígado/metabolismo , Camundongos , Peptídeo Hidrolases/metabolismo
15.
Nat Metab ; 3(11): 1536-1551, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34782792

RESUMO

Beiging of white adipose tissue (WAT) is associated with an increase of anti-inflammatory M2-like macrophages in WAT. However, mechanisms through which M2-like macrophages affect beiging are incompletely understood. Here, we show that the macrophage cytokine Slit3 is secreted by adipose tissue macrophages and promotes cold adaptation by stimulating sympathetic innervation and thermogenesis in mice. Analysing the transcriptome of M2-like macrophages in murine inguinal WAT (iWAT) after cold exposure, we identify Slit3 as a secreted cytokine. Slit3 binds to the ROBO1 receptor on sympathetic neurons to stimulate Ca2+/calmodulin-dependent protein kinase II signalling and norepinephrine release, which enhances adipocyte thermogenesis. Adoptive transfer of Slit3-overexpressing M2 macrophages to iWAT promotes beiging and thermogenesis, whereas mice that lack Slit3 in myeloid cells are cold-intolerant and gain more weight. Our findings shed new light on the integral role of M2-like macrophages for adipose tissue homeostasis and uncover the macrophage-Slit3-sympathetic neuron-adipocyte signalling axis as a regulator of long-term cold adaptation.


Assuntos
Tecido Adiposo/inervação , Tecido Adiposo/fisiologia , Fibras Adrenérgicas/fisiologia , Macrófagos/metabolismo , Proteínas de Membrana/biossíntese , Termogênese , Tecido Adiposo Branco/inervação , Tecido Adiposo Branco/metabolismo , Animais , Plasticidade Celular , Metabolismo Energético , Regulação da Expressão Gênica , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Especificidade de Órgãos/genética , Fosforilação , Ligação Proteica , Receptores Imunológicos/metabolismo , Temperatura , Termogênese/genética , Proteínas Roundabout
16.
Hepatology ; 74(4): 1864-1883, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33934381

RESUMO

BACKGROUND AND AIMS: NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is responsible for de-SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear. APPROACH AND RESULTS: We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver-specific SENP2 knockout (Senp2-LKO) mice. Senp2-LKO mice exhibited resistance to high-fat diet-induced hepatic steatosis and obesity. RNA-sequencing analysis showed that Senp2 deficiency up-regulated genes involved in fatty acid oxidation and down-regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2-LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator-activated receptor alpha (PPARα) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPARα and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPARα, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders. CONCLUSIONS: Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver-adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.


Assuntos
Tecido Adiposo/metabolismo , Cisteína Endopeptidases/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , PPAR alfa/metabolismo , Animais , Cisteína Endopeptidases/metabolismo , Dieta Hiperlipídica , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Lipogênese/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo , Sumoilação , Termogênese/genética , Ubiquitinação
17.
J Biol Chem ; 296: 100678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33872596

RESUMO

Adipose tissues, including white, beige, and brown adipose tissue, have evolved to be highly dynamic organs. Adipose tissues undergo profound changes during development and regeneration and readily undergo remodeling to meet the demands of an everchanging metabolic landscape. The dynamics are determined by the high plasticity of adipose tissues, which contain various cell types: adipocytes, immune cells, endothelial cells, nerves, and fibroblasts. There are numerous proteins that participate in regulating the plasticity of adipose tissues. Among these, bone morphogenetic proteins (BMPs) were initially found to regulate the differentiation of adipocytes, and they are being reported to have pleiotropic functions by emerging studies. Here, in the first half of the article, we summarize the plasticity of adipocytes and macrophages, which are two groups of cells targeted by BMP signaling in adipose tissues. We then review how BMPs regulate the differentiation, death, and lipid metabolism of adipocytes. In addition, the potential role of BMPs in regulating adipose tissue macrophages is considered. Finally, the expression of BMPs in adipose tissues and their metabolic relevance are discussed.


Assuntos
Tecido Adiposo/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Transdução de Sinais , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Morte Celular , Diferenciação Celular , Senescência Celular , Humanos , Macrófagos/citologia , Transcrição Gênica
18.
Redox Biol ; 43: 101979, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895484

RESUMO

Loss of perivascular adipose tissue (PVAT) impairs endothelial function and enhances atherosclerosis. However, the roles of PVAT thermoregulation in vascular inflammation and the development of atherosclerosis remains unclear. Bone morphogenetic protein 4 (BMP4) transforms white adipocyte to beige adipocyte, while promotes a brown-to-white shift in inter-scapular brown adipose tissue (BAT). Here, we found that knockdown of BMP4 in PVAT reduced expression of brown adipocyte-characteristic genes and increased endothelial inflammation in vitro co-culture system. Ablating BMP4 expression either in adipose tissues or specifically in BAT in ApoE-/- mice demonstrated a marked exacerbation of atherosclerotic plaque formation in vivo. We further demonstrated that proinflammatory factors (especially IL-1ß) increased in the supernatant of BMP4 knockdown adipocytes. Overexpression of BMP4 in adipose tissues promotes browning of PVAT and protects against atherosclerosis in ApoE-/- mice. These findings uncover an organ crosstalk between PVAT and blood endothelial cells that is engaged in atherosclerosis.


Assuntos
Aterosclerose , Células Endoteliais , Tecido Adiposo , Tecido Adiposo Marrom , Tecido Adiposo Branco , Animais , Anti-Inflamatórios , Proteína Morfogenética Óssea 4 , Camundongos
19.
J Lipid Res ; 61(12): 1589-1604, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32978274

RESUMO

Beiging of white adipose tissue (WAT) has beneficial effects on metabolism. Although it is known that beige adipocytes are active in lipid catabolism and thermogenesis, how they are regulated deserves more explorations. In this study, we demonstrate that stearoyl-CoA desaturase 1 (SCD1) in subcutaneous WAT (scWAT) responded to cold stimulation and was able to promote mobilization of triacylglycerol [TAG (triglyceride)]. In vitro studies showed that SCD1 promoted lipolysis in C3H10T1/2 white adipocytes. The lipolytic effect was contributed by one of SCD1's products, oleic acid (OA). OA upregulated adipose TAG lipase and hormone-sensitive lipase expression. When SCD1 was overexpressed in the scWAT of mice, lipolysis was enhanced, and oxygen consumption and heat generation were increased. These effects were also demonstrated by the SCD1 knockdown experiments in mice. In conclusion, our study suggests that SCD1, known as an enzyme for lipid synthesis, plays a role in upregulating lipid mobilization through its desaturation product, OA.


Assuntos
Tecido Adiposo Branco/metabolismo , Metabolismo dos Lipídeos , Estearoil-CoA Dessaturase/metabolismo , Gordura Subcutânea/metabolismo , Animais , Camundongos
20.
Commun Biol ; 3(1): 200, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350411

RESUMO

Adipocyte cell death is pathologically involved in both obesity and lipodystrophy. Inflammation and pro-inflammatory cytokines are generally regarded as inducers for adipocyte apoptosis, but whether some innate defects affect their susceptibility to cell death has not been extensively studied. Here, we found bone morphogenetic protein receptor type 2 (BMPR2) knockout adipocytes were prone to cell death, which involved both apoptosis and pyroptosis. BMPR2 deficiency in adipocytes inhibited phosphorylation of perilipin, a lipid-droplet-coating protein, and impaired lipolysis when stimulated by tumor necrosis factor (TNFα), which lead to failure of fatty acid oxidation and oxidative phosphorylation. In addition, impaired lipolysis was associated with mitochondria-mediated apoptosis and pyroptosis as well as elevated inflammation. These results suggest that BMPR2 is important for maintaining the functional integrity of adipocytes and their ability to survive when interacting with inflammatory factors, which may explain why adipocytes among individuals show discrepancy for death responses in inflammatory settings.


Assuntos
Adipócitos Brancos/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Morte Celular , Ácidos Graxos/metabolismo , Adulto , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/deficiência , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Oxirredução
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