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1.
Cells ; 10(9)2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34572017

RESUMO

The present study sought to identify gene networks that are hallmarks of the developing inguinal subcutaneous adipose tissue (iWAT) and the interscapular brown adipose tissue (BAT) in the mouse. RNA profiling revealed that the iWAT of postnatal (P) day 6 mice expressed thermogenic and lipid catabolism transcripts, along with the abundance of transcripts associated with the beige adipogenesis program. This was an unexpected finding, as thermogenic BAT was believed to be the only site of nonshivering thermogenesis in the young mouse. However, the transcriptional landscape of BAT in P6 mice suggests that it is still undergoing differentiation and maturation, and that the iWAT temporally adopts thermogenic and lipolytic potential. Moreover, P6 iWAT and adult (P56) BAT were similar in their expression of immune gene networks, but P6 iWAT was unique in the abundant expression of antimicrobial proteins and virus entry factors, including a possible receptor for SARS-CoV-2. In summary, postnatal iWAT development is associated with a metabolic shift from thermogenesis and lipolysis towards fat storage. However, transcripts of beige-inducing signal pathways including ß-adrenergic receptors and interleukin-4 signaling were underrepresented in young iWAT, suggesting that the signals for thermogenic fat differentiation may be different in early postnatal life and in adulthood.


Assuntos
Adipócitos Bege/metabolismo , Transcrição Genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Ciclo Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Redes Reguladoras de Genes , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Desenvolvimento Muscular/genética , Neuropeptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
2.
J Agric Food Chem ; 69(40): 11900-11911, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34581185

RESUMO

This study explored whether the antiobesity effect of theabrownin (TB) extracted from Fu brick tea (FBT) was associated with the activation of brown adipose tissue (BAT) or browning of the white adipose tissue (WAT) in mice fed a high-fat diet (HFD). Mice were divided into five groups, which received a normal diet, HFD, or HFD plus TB (200, 400, and 800 mg/kg), respectively. A 12-week administration of TB in a dose-dependent manner reduced the body weight and WAT weight and improved lipid and glucose disorders in the HFD-fed mice (p < 0.05). TB also promoted the expression of thermogenic and mitochondrial genes, whereas inflammation genes were reduced in interscapular BAT (iBAT), inguinal WAT (iWAT), and epididymis white adipose tissue (eWAT), accompanied by improvement in the intestinal homeostasis by improving SCFAs, especially butyric acid levels (p < 0.05), which was related to thermogenic and inflammatory factors of iBAT and iWAT. Mechanistically, TB was shown to efficiently promote thermogenesis by stimulating the AMPK-PGC1α pathway with an increase in uncoupling protein 1 (UCP1). Conclusively, these findings suggest that long-term consumption of TB can enhance BAT activity and WAT browning by activating the AMPK-PGC1α pathway and modulating SCFAs; meanwhile, SCFAs regulating TB improved inflammatory disorder in HFD-fed mice.


Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Adipócitos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Catequina/análogos & derivados , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Chá/metabolismo , Termogênese/genética
3.
Nat Commun ; 12(1): 4725, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354051

RESUMO

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


Assuntos
Tecido Adiposo Marrom/metabolismo , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antibacterianos/administração & dosagem , Ceco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Termogênese/fisiologia , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445209

RESUMO

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Genômica , Glucocorticoides , Lipogênese , Lipólise , Animais , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos
5.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371916

RESUMO

White adipose tissue (WAT) is a dynamic endocrine organ that can play a significant role in thermoregulation. WAT has the capacity to adopt structural and functional characteristics of the more metabolically active brown adipose tissue (BAT) and contribute to non-shivering thermogenesis under specific stimuli. Non-shivering thermogenesis was previously thought to be uncoupling protein 1 (UCP1)-dependent however, recent evidence suggests that UCP1-independent mechanisms of thermogenesis exist. Namely, futile creatine cycling has been identified as a contributor to WAT thermogenesis. The purpose of this study was to examine the efficacy of creatine supplementation to alter mitochondrial markers as well as adipocyte size and multilocularity in inguinal (iWAT), gonadal (gWAT), and BAT. Thirty-two male and female Sprague-Dawley rats were treated with varying doses (0 g/L, 2.5 g/L, 5 g/L, and 10 g/L) of creatine monohydrate for 8 weeks. We demonstrate that mitochondrial markers respond in a sex and depot specific manner. In iWAT, female rats displayed significant increases in COXIV, PDH-E1alpha, and cytochrome C protein content. Male rats exhibited gWAT specific increases in COXIV and PDH-E1alpha protein content. This study supports creatine supplementation as a potential method of UCP1-independant thermogenesis and highlights the importance of taking a sex-specific approach when examining the efficacy of browning therapeutics in future research.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Creatina/farmacologia , Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Masculino , Mitocôndrias/metabolismo , Piruvato Desidrogenase (Lipoamida) , Ratos Sprague-Dawley , Fatores Sexuais , Proteína Desacopladora 1/metabolismo
6.
Am J Physiol Endocrinol Metab ; 321(3): E433-E442, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370596

RESUMO

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype. However, this browning process was not observed in obese mice during sepsis. White adipose tissue browning is detrimental in patients with burn injury and cancer. We hypothesize that norepinephrine (NE) induces WAT browning in nonobese mice but not in obese mice similarly to sepsis-induced WAT browning. Six-week-old C57BL/6 male mice were randomized to a high-fat diet or normal diet. After 6-7 wk of feeding, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Norepinephrine was administered intraperitoneally via osmotic minipumps for 18 h or 72 h (no CLP) at which time tissue and plasma were harvested. Controls were mice that underwent CLP (no NE) with 18-h harvest. A separate group of mice underwent pretreatment with NE or vehicle infusion for 72 h, CLP was performed, and at 18 h had tissue and plasma harvested. Sepsis resulted in significant weight loss in both nonobese and obese mice. NE treatment alone caused weight loss in obese mice. Septic nonobese mice had higher uncoupling protein-1 (UCP1) expression compared with control and obese septic mice. NE treatment increased UCP1 expression in nonobese, but not obese mice. NE-treated obese septic mice had lower lung myeloperoxidase (MPO) activity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNFα, and IL-6 levels compared with NE-treated nonobese septic mice. Obesity protects mice from septic-induced and NE-induced WAT browning.NEW & NOTEWORTHY White adipose tissue browning is detrimental in patients with burn injury and cancer. WAT browning occurs in nonobese mice and can be induced by ß receptor norepinephrine infusion, but obese mice are resistant to sepsis-induced and norepinephrine-induced WAT browning. We propose that the lack of WAT browning and unchanged inflammatory cytokine response may contribute to the protection of obese mice from sepsis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Norepinefrina/administração & dosagem , Obesidade/metabolismo , Sepse/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/diagnóstico por imagem , Animais , Dieta Hiperlipídica , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Sepse/complicações
7.
FASEB J ; 35(9): e21868, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34449920

RESUMO

Brown adipose tissue (BAT) plays an important role on no shivering thermogenesis during cold exposure to maintain animal body temperature and energy homeostasis. However, knowledge of the cellular transition from white adipose tissue (WAT) to BAT is still limited. In this study, we provided a comprehensive metabolomics and transcriptional signatures of goat BAT and WAT. A total of 157 metabolites were significantly changed, including 81 upregulated and 76 downregulated metabolites. In addition, we identified the citric acid cycle, fatty acid elongation, and degradation pathways as coordinately activated in BAT. Interestingly, five unsaturated fatty acids (Eicosadienoic Acid, C20:2; γ-Linolenic acid, C20:3; Arachidonic Acid, C20:4; Adrenic acid, C22:4; Docosahexaenoic acid, C22:6), Succinate, L-carnitine, and L-palmitoyl-carnitine were found to be abundant in BAT. Furthermore, L-carnitine, an intermediate of fatty acid degradation, is required for goat brown adipocyte differentiation and thermogenesis through activating AMPK pathway. However, L-carnitine decreased lipid accumulation through inducing lipolysis and thermogenesis in white adipocytes. These results revealed that there are the significant alterations in transcriptomic and metabolomic profiles between goat WAT and BAT, which may contribute to better understanding the roles of metabolites in BAT thermogenesis process.


Assuntos
Tecido Adiposo Marrom/metabolismo , Cabras/metabolismo , Termogênese/fisiologia , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/fisiologia , Regulação para Baixo/fisiologia , Metabolismo Energético/fisiologia , Ácidos Graxos Insaturados/metabolismo , Homeostase/fisiologia , Lipólise/fisiologia , Metabolômica/métodos , RNA-Seq/métodos , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
8.
Nutrients ; 13(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34444719

RESUMO

Low birthweight (LBW) is associated with metabolic complications, such as glucose and lipid metabolism disturbances in early life. The objective of this study was to assess: (1) the effect of dietary tryptophan (Trp) on glucose and fat metabolism in an LBW piglet model, and (2) the role peripheral 5-hydroxytryptamine type 3 (5HT3) receptors in regulating the feeding behavior in LBW piglets fed with Trp-supplemented diets. Seven-day-old piglets were assigned to 4 treatments: normal birthweight-0%Trp (NBW-T0), LBW-0%Trp (LBW-T0), LBW-0.4%Trp (LBW-T0.4), and LBW-0.8%Trp (LBW-T0.8) for 3 weeks. Compared to LBW-T0, the blood glucose was decreased in LBW-T0.8 at 60 min following the meal test, and the triglycerides were lower in LBW-T0.4 and LBW-T0.8. Relative to LBW-T0, LBW-T0.8 had a lower transcript and protein abundance of hepatic glucose transporter-2, a higher mRNA abundance of glucokinase, and a lower transcript of phosphoenolpyruvate carboxykinase. LBW-T0.4 tended to have a lower protein abundance of sodium-glucose co-transporter 1 in the jejunum. In comparison with LBW-T0, LBW-T0.4 and LBW-T0.8 had a lower transcript of hepatic acetyl-CoA carboxylase, and LBW-T0.4 had a higher transcript of 3-hydroxyacyl-CoA dehydrogenase. Blocking 5-HT3 receptors with ondansetron reduced the feed intake in all groups, with a transient effect on LBW-T0, but more persistent effect on LBW-T0.8 and NBW-T0. In conclusion, Trp supplementation reduced the hepatic lipogenesis and gluconeogenesis, but increased the glycolysis in LBW piglets. Peripheral serotonin is likely involved in the regulation of feeding behavior, particularly in LBW piglets fed diets supplemented with a higher dose of Trp.


Assuntos
Suplementos Nutricionais , Glucose/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Triptofano/administração & dosagem , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Peso ao Nascer , Glicemia/análise , Peso Corporal , Colesterol/sangue , Dieta , Hipotálamo/metabolismo , Insulina/sangue , Mucosa Intestinal/anatomia & histologia , Mucosa Intestinal/crescimento & desenvolvimento , Intestino Delgado/anatomia & histologia , Intestino Delgado/crescimento & desenvolvimento , Modelos Animais , Ondansetron/farmacologia , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Suínos/crescimento & desenvolvimento , Triglicerídeos/sangue
9.
Nutrients ; 13(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34444660

RESUMO

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Anticolesterolemiantes/farmacologia , Colesterol/sangue , Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Protaminas/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Perda de Peso/efeitos dos fármacos
10.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299261

RESUMO

Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.


Assuntos
Tecido Adiposo/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Adipocinas/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
11.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199596

RESUMO

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


Assuntos
Tecido Adiposo Branco/metabolismo , Mitocôndrias/genética , Obesidade/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adipócitos/metabolismo , Tecido Adiposo Branco/fisiologia , Restrição Calórica , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Obesidade/patologia , Biogênese de Organelas
12.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202651

RESUMO

Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of increasing leptin levels in the hypothalamus using gene therapy with conventional caloric restriction on weight gain, food consumption, serum leptin and adiponectin levels, white adipose tissue, marrow adipose tissue, and bone in nine-month-old female Sprague-Dawley rats. Rats (n = 16) were implanted with a cannula in the 3rd ventricle of the hypothalamus and injected with a recombinant adeno-associated virus, encoding the rat gene for leptin (rAAV-Lep), and maintained on standard rat chow for 18 weeks. A second group (n = 15) was calorically-restricted to match the weight of the rAAV-Lep group. Both approaches prevented weight gain, and no differences in bone were detected. However, calorically-restricted rats consumed 15% less food and had lower brown adipose tissue Ucp-1 mRNA expression than rAAV-Lep rats. Additionally, calorically-restricted rats had higher abdominal white adipose tissue mass, higher serum leptin and adiponectin levels, and higher marrow adiposity. Caloric restriction and hypothalamic leptin gene therapy, while equally effective in preventing weight gain, differ in their effects on energy intake, energy expenditure, adipokine levels, and body composition.


Assuntos
Restrição Calórica , Metabolismo Energético , Terapia Genética , Hipotálamo/metabolismo , Leptina/genética , Adipocinas/sangue , Adipocinas/genética , Adipocinas/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Biomarcadores , Peso Corporal , Medula Óssea/metabolismo , Dependovirus/genética , Ingestão de Energia , Metabolismo Energético/genética , Feminino , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos , Leptina/metabolismo , Ratos , Transgenes
13.
FASEB J ; 35(8): e21760, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34309918

RESUMO

White adipose tissue (WAT) has the capacity to undergo a white-to-beige phenotypic switch, known as browning, in response to stimuli such as cold. However, the mechanism underlying beige adipocyte formation is largely unknown. Apolipoprotein E (ApoE) is highly induced in WAT and has been implicated in lipid metabolism. Here, we show that ApoE deficiency in mice increased oxygen consumption and thermogenesis and enhanced adipose browning pattern in inguinal WAT (iWAT), with associated characteristics such as increased Ucp1 and Pparγ expression. At the cellular level, ApoE deficient beige adipocytes had increased glucose uptake and higher mitochondrial respiration than wild-type cells. Mechanistically, we showed that ApoE deficient iWAT and primary adipose precursor cells activated the thermogenic genes program by stimulating the production of ketone body ß-hydroxybutyrate (ßHB), a novel adipose browning promoting factor. This was accompanied by increased expression of genes involved in ketogenesis and could be compromised by the treatment for ketogenesis inhibitors. Consistently, ApoE deficient mice show higher serum ßHB level than wild-type mice in the fed state and during cold exposure. Our results further demonstrate that the increased ßHB production in ApoE deficient adipose precursor cells could be attributed, at least in part, to enhanced Cd36 expression and CD36-mediated fatty acid utilization. Our findings uncover a previously uncharacterized role for ApoE in energy homeostasis via its cell-autonomous action in WAT.


Assuntos
Ácido 3-Hidroxibutírico/biossíntese , Tecido Adiposo Branco , Apolipoproteínas E/deficiência , Metabolismo Energético , Termogênese , Adipócitos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Células Cultivadas , Fibroblastos , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
14.
J Chromatogr A ; 1652: 462350, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34198103

RESUMO

This study aimed to (i) develop a sensitive method for simultaneous detection and quantification of imidacloprid (IMI) and seven of its metabolites in tissue specimens, and to (ii) determine the biodistribution of the IMI compounds in tissues of C57BL/6J male mice; after exposure to 0.6 mg/kg bw/day of IMI (10% of no observable adverse effect level of IMI) through a powdered diet for 24 weeks. We successfully developed a method which was accurate (recoveries were ≥ 70% for most compounds), sensitive (LODs ≤ 0.47 ng/mL and LOQs ≤ 1.43 ng/mL were recorded for all detected compounds, R2 ≥ 0.99) and precise (RSDs ≤ 20%) for routine analysis of IMI and seven of its metabolites in blood and various tissue matrices. After bio-distributional analysis, IMI and five of its metabolites were detected in mice. Brain, testis, lung, kidney, inguinal white adipose tissue and gonadal white adipose tissue mainly accumulated IMI, blood and mesenteric white adipose tissue mainly accumulated IMI-olefin; liver mainly accumulated desnitro-IMI; pancreas predominately accumulated 4-hydroxy-IMI. The desnitro-dehydro-IMI and the desnitro-IMI metabolites recorded tissue-blood concentration ratios ≥ 1.0 for testis, brain, lung and kidney. The cumulative levels of the six detected IMI compounds (Σ6 IMI compounds) were found in the decreasing order: blood > testis > brain > kidney > lung > iWAT > gWAT > mWAT > liver > pancreas. Altogether, this study provided essential data needed for effective mechanistic elucidation of compound-specific adverse outcomes associated with chronic exposures to IMI in mammalian species.


Assuntos
Cromatografia Líquida , Inseticidas/farmacocinética , Neonicotinoides/farmacocinética , Nitrocompostos/farmacocinética , Espectrometria de Massas em Tandem , Tecido Adiposo Branco/metabolismo , Animais , Encéfalo/metabolismo , Inseticidas/administração & dosagem , Inseticidas/análise , Inseticidas/sangue , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neonicotinoides/administração & dosagem , Neonicotinoides/análise , Neonicotinoides/sangue , Nitrocompostos/administração & dosagem , Nitrocompostos/análise , Nitrocompostos/sangue , Testículo/metabolismo , Distribuição Tecidual
15.
Cell Death Dis ; 12(7): 666, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215724

RESUMO

High-mobility group box 2 (HMGB2) is an abundant, chromatin-associated protein that plays an essential role in the regulation of transcription, cell proliferation, differentiation, and tumorigenesis. However, the underlying mechanism of HMGB2 in adipogenesis remains poorly known. Here, we provide evidence that HMGB2 deficiency in preadipocytes impedes adipogenesis, while overexpression of HMGB2 increases the potential for adipogenic differentiation. Besides, depletion of HMGB2 in vivo caused the decrease in body weight, white adipose tissue (WAT) mass, and adipocyte size. Consistently, the stromal vascular fraction (SVF) of adipose tissue derived from hmgb2-/- mice presented impaired adipogenesis. When hmgb2-/- mice were fed with high-fat diet (HFD), the body size, and WAT mass were increased, but at a lower rate. Mechanistically, HMGB2 mediates adipogenesis via enhancing expression of C/EBPß by binding to its promoter at "GGGTCTCAC" specifically during mitotic clonal expansion (MCE) stage, and exogenous expression of C/EBPß can rescue adipogenic abilities of preadipocytes in response to HMGB2 inhibition. In general, our findings provide a novel mechanism of HMGB2-C/EBPß axis in adipogenesis and a potential therapeutic target for obesity.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína HMGB2/metabolismo , Mitose , Obesidade/metabolismo , Regiões Promotoras Genéticas , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Animais , Sítios de Ligação , Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Proteína HMGB2/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Transdução de Sinais , Ganho de Peso
16.
Biomed Pharmacother ; 139: 111687, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243611

RESUMO

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.


Assuntos
Benzofuranos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/fisiologia , Obesidade/metabolismo , Substâncias Protetoras/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Termogênese/efeitos dos fármacos
17.
Front Immunol ; 12: 670566, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220817

RESUMO

White adipose tissue (AT) contributes significantly to inflammation - especially in the context of obesity. Several of AT's intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.


Assuntos
Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Animais , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/imunologia , Obesidade/metabolismo
18.
Front Immunol ; 12: 629391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122403

RESUMO

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.


Assuntos
Metabolismo Energético , Células Epiteliais/metabolismo , Intestino Delgado/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Epiteliais/imunologia , Regulação da Expressão Gênica , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Masculino , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/imunologia , Fenótipo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Serpinas/genética , Serpinas/metabolismo , Transdução de Sinais , Fatores de Tempo , Ganho de Peso
19.
Life Sci ; 279: 119677, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081990

RESUMO

AIMS: Pancreastatin (PST) is a crucial bioactive peptide derived from chromogranin A (CHGA) proprotein that exhibits an anti-insulin effect on adipocytes. Herein, we investigated the effects of PST on brown adipose tissues (BAT) and white adipose tissue (WAT) in connection with uncoupling protein-1 (UCP-1) regulated energy expenditure in high fructose diet (HFrD) fed and vinylcyclohexenediepoxide (VCD) induced perimenopausal rats. MATERIAL AND METHODS: We administered VCD in rats for 17 consecutive days and fed HFrd for 12 weeks. After 12 weeks estradiol and progesterone levels were detected. Furthermore, detection of glucose tolerance, insulin sensitivity, and body composition revealed impaired glucose homeostasis and enhanced PST levels. Effects of enhanced PST on UCP-1 level in BAT and WAT of perimenopausal rats were further investigated. KEY FINDINGS: Reduced serum estradiol, progesterone, and attenuated insulin response confirmed perimenopausal model development. Furthermore, enhanced PST serum level and its increased expression in BAT and WAT downregulated the UCP-1 expression. Subsequently, impaired ATP level, NADP/NADPH ratio, citrate synthase activity, enhanced mitochondrial reactive oxygen species (ROS) generation and perturbed mitochondrial membrane potential, further exacerbated mitochondrial dysfunction, cellular ROS production, and promoted apoptosis. Interestingly, PST inhibition by PST inhibitor peptide-8 (PSTi8) displayed a favorable impact on UCP-1 and energy expenditure. SIGNIFICANCE: The aforementioned outcomes indicated the substantial role of PST in altering the UCP-1 expression and associated energy homeostasis. Hence our results corroborate novel avenues to unravel the quest deciphering PST's role in energy homeostasis and its association with perimenopause.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Cromogranina A/farmacologia , Metabolismo Energético , Frutose/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Feminino , Resistência à Insulina , Menopausa , Ratos , Ratos Sprague-Dawley , Edulcorantes/administração & dosagem , Proteína Desacopladora 1/genética
20.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072024

RESUMO

Overweight, obesity, and psychiatric disorders are serious health problems. To evidence the anxiolytic-like effects and lipid reduction in mice receiving a high-calorie diet and Bertholletia excelsa seeds in a nonpolar extract (SBHX, 30 and 300 mg/kg), animals were assessed in open-field, hole-board, and elevated plus-maze tests. SBHX (3 and 10 mg/kg) potentiated the pentobarbital-induced hypnosis. Chronic administration of SBHX for 40 days was given to mice fed with a hypercaloric diet to determine the relationship between water and food intake vs. changes in body weight. Testes, epididymal white adipose tissue (eWAT), and liver were dissected to analyze fat content, triglycerides, cholesterol, and histological effects after administering the hypercaloric diet and SBHX. Fatty acids, such as palmitoleic acid (0.14%), palmitic acid (21.42%), linoleic acid (11.02%), oleic acid (59.97%), and stearic acid (7.44%), were identified as constituents of SBHX, producing significant anxiolytic-like effects and preventing body-weight gain in mice receiving the hypercaloric diet without altering their water or food consumption. There was also a lipid-lowering effect on the testicular tissue and eWAT and a reduction of adipocyte area in eWAT. Our data evidence beneficial properties of B. excelsa seeds influencing global health concerns such as obesity and anxiety.


Assuntos
Ansiedade/metabolismo , Bertholletia/metabolismo , Lipídeos/química , Sobrepeso/metabolismo , Sementes , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal , Sistema Nervoso Central , Ingestão de Alimentos , Epididimo/metabolismo , Ácidos Graxos/metabolismo , Hipnose , Masculino , Aprendizagem em Labirinto , Camundongos , Pentobarbital , Testículo/metabolismo
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