RESUMO
The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.
Assuntos
Proteínas Quinases Ativadas por AMP , Azoximetano , Carcinogênese , Neoplasias Colorretais , Metilação de DNA , Dioxigenases , Animais , Humanos , Camundongos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Azoximetano/toxicidade , Azoximetano/efeitos adversos , Células CACO-2 , Carcinogênese/genética , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/etiologia , Sulfato de Dextrana/toxicidade , Dioxigenases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Ácidos Cetoglutáricos/metabolismo , Camundongos Knockout , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismoRESUMO
Pluripotent stem cells (PSCs), comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), offer immense potential for regenerative medicine due to their ability to differentiate into all cell types of the adult body. A critical aspect of harnessing this potential is understanding their metabolic requirements during derivation, maintenance, and differentiation in vitro. Traditional culture methods using fetal bovine serum often lead to issues such as heterogeneous cell populations and diminished pluripotency. Although the chemically-defined 2i/LIF medium has provided solutions to some of these challenges, prolonged culturing of these cells, especially female ESCs, raises concerns related to genome integrity. This review discusses the pivotal role of lipids in genome stability and pluripotency of stem cells. Notably, the introduction of lipid-rich albumin, AlbuMAX, into the 2i/LIF culture medium offers a promising avenue for enhancing the genomic stability and pluripotency of cultured ESCs. We further explore the unique characteristics of lipid-induced pluripotent stem cells (LIP-ESCs), emphasizing their potential in regenerative medicine and pluripotency research.
Assuntos
Instabilidade Genômica , Lipídeos , Humanos , Animais , Lipídeos/química , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Metabolismo dos LipídeosRESUMO
SCOPE: Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut, accompanied by impaired epithelial integrity, increased macrophage infiltration, and enhanced colon cancer risk. METHODS AND RESULTS: Cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, is supplemented into mice diet, and its beneficial effects against dextran sulfate sodium (DSS)-induced experimental colitis is evaluated. Eight-week-old mice were fed a standard diet supplemented with or without CBD (200 mg kg-1 ) for 5 weeks. In the 4th week of dietary treatment, mice were subjected to 2.5% DSS induction for 7 days, followed by 7 days of recovery, to induce colitis. CBD supplementation reduced body weight loss, gross bleeding, fecal consistency, and disease activity index. In addition, CBD supplementation protected the colonic structure, promoted tissue recovery, and ameliorated macrophage infiltration in the colonic tissue, which was associated with the activation of cyclic AMP-protein kinase A, extracellular signal-regulated kinase ½, and AMP-activated protein kinase signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and related pro-inflammatory marker secretion. Consistently, CBD feeding reduced tight junction protein claudin2 and myosin light chain kinase in DSS-treated mice. CONCLUSION: Dietary CBD protects against inflammation and colitis symptoms induced by DSS, providing an alternative approach to IBD management.
Assuntos
Canabidiol , Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Canabidiol/efeitos adversos , Canabidiol/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dieta , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colo/metabolismoRESUMO
RATIONALE AND OBJECTIVES: The study was designed to evaluate microvascular invasion (MVI) using three-dimensional (3D) morphological indicators prior to surgery. MATERIALS AND METHODS: This retrospective study included 156 patients with hepatocellular carcinoma (HCC) at our hospital from 2017 to 2018. Through thin-layer CT scanning and 3D reconstruction, the tumor surface inclination angles can be quantitatively analyzed to determine the surface irregularity rate (SIR), which serves as a comprehensive assessment method for tumor irregularity based on preoperative 3D morphological evaluation. Univariate and multivariate logistic regression analyses were employed to investigate the correlation with MVI. RESULTS: The SIR was related to MVI (OR: 10.667, P < 0.001). Multivariate logistic regression analysis showed that the SIR was an independent risk factor for MVI. The area under the receiver operating characteristic curve (ROC) of prediction model composed of the morphological indicator SIR was 0.831 (95% confidence interval: 0.759-0.895). CONCLUSION: The preoperative 3D morphological indicator SIR of a tumor is an accurate predictor of MVI, providing a valuable tool in clinical decision-making.
RESUMO
Colorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Grape pomace (GP) is a rich source of bioactive compounds with anti-inflammatory, and anticancer effects. We recently found that dietary GP had protective effects against CRC development in the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC mouse model through suppression of cell proliferation and modulation of DNA methylation. However, the underlying molecular mechanisms associated with changes in metabolites remain unexamined. This study profiled fecal metabolomic changes in a mouse CRC model in response to GP supplementation using gas chromatography-mass spectrometry (GC-MS) based metabolomic analysis. A total of 29 compounds showed significant changes due to GP supplementation, including bile acids, amino acids, fatty acids, phenols/flavonoids, glycerolipids, carbohydrates, organic acids, and others. The major changes in metabolites of feces include increased deoxycholic acid (DCA) and decreased amino acid content. Dietary GP upregulated the expression of farnesoid X receptor (FXR) downstream genes while decreasing fecal urease activity. DNA repair enzyme MutS Homolog 2 (MSH2) was upregulated by GP supplementation. Consistently, γ-H2AX, as a DNA damage marker, decreased in GP supplemented mice. Moreover, MDM2, a protein in the ataxia telangiectasia mutated (ATM) signaling, was decreased by GP supplementation. These data provided valuable metabolic clues for unraveling the protective effects of GP supplementation against CRC development.
Assuntos
Neoplasias Colorretais , Vitis , Camundongos , Animais , Vitis/química , Dieta , Suplementos Nutricionais , Metabolômica , Azoximetano/toxicidade , Modelos Animais de Doenças , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais/metabolismoRESUMO
BACKGROUND: Following muscle injury, fibro-adipogenic progenitors (FAPs) are rapidly activated and undergo apoptosis at the resolution stage, which is required for proper muscle regeneration. When excessive FAPs remain, it contributes to fibrotic and fatty infiltration, impairing muscle recovery. Mechanisms controlling FAP apoptosis remain poorly defined. We hypothesized that AMP-activated protein kinase (AMPK) in FAPs mediates their apoptosis during the muscle regeneration. METHODS: To test, AMPKα1fl/fl PDGFRαCre mice were used to knock out AMPKα1 in FAPs. Following AMPKα1 knockout, the mice were injected with phosphate-buffered saline or glycerol to induce muscle injury. Tibialis anterior muscle and FAPs were collected at 3, 7 and 14 days post-injury (dpi) for further analysis. RESULTS: We found that AMPKα1 deletion in FAPs enhanced p65 translocation to the nuclei by 110% (n = 3; P < 0.01). AMPKα1 knockout group had a higher gene expression of MMP-9 (matrix metalloproteinase-9) by 470% (n = 3; P < 0.05) and protein level by 39% (n = 3; P < 0.05). Loss of AMPKα1 up-regulated the active TGF-ß1 (transforming growth factor-ß1) levels by 21% (n = 3; P < 0.05). TGF-ß promoted apoptotic resistance, because AMPKα1-deficient group had 36% lower cleaved Caspase 3 (cCAS3) content (n = 3; P < 0.05). Fibrotic differentiation of FAPs was promoted, with increased collagen protein level by 54% (n = 3; P < 0.05). Moreover, obesity decreased phosphorylation of AMPK by 54% (n = 3; P < 0.05), which decreased cCAS3 in FAPs by 44% (n = 3; P < 0.05) and elevated collagen accumulation (52%; n = 3; P < 0.05) during muscle regeneration. CONCLUSIONS: These data suggest that AMPK is a key mediator of FAPs apoptosis, and its inhibition due to obesity results in fibrosis of regenerated muscle.
Assuntos
Proteínas Quinases Ativadas por AMP , Doenças Musculares , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Fibrose , Colágeno/metabolismo , RegeneraçãoRESUMO
As the prevalence of inflammatory bowel diseases (IBD) rises, the etiology of IBD draws increasing attention. Glucoraphanin (GRP), enriched in cruciferous vegetables, is a precursor of sulforaphane, known to have anti-inflammatory and antioxidative effects. We hypothesized that dietary GRP supplementation can prevent mitochondrial dysfunction and oxidative stress in an acute colitis mouse model induced by dextran sulfate sodium (DSS). Eight-week-old mice were fed a regular rodent diet either supplemented with or without GRP. After 4 weeks of dietary treatments, half of the mice within each dietary group were subjected to 2.5% DSS treatment to induce colitis. Dietary GRP decreased DSS-induced body weight loss, disease activity index, and colon shortening. Glucoraphanin supplementation protected the colonic histological structure, suppressed inflammatory cytokines, interleukin (IL)-1ß, IL-18, and tumor necrosis factor-α (TNF-α), and reduced macrophage infiltration in colonic tissues. Consistently, dietary GRP activated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, and nuclear factor erythroid 2-related factor 2 (NRF2) pathways in the colonic tissues of DSS-treated mice, which was associated with increased mitochondrial DNA and decreased content of the oxidative product 8-hydroxydeoxyguanosine (8-OHDG), a nucleotide oxidative product of DNA. In conclusion, dietary GRP attenuated mitochondrial dysfunction, inflammatory response, and oxidative stress induced by DSS, suggesting that dietary GRP provides a dietary strategy to alleviate IBD symptoms.
RESUMO
Collagen is the main component of connective tissue surrounding adipocytes. Collagen cross-linking affects adipose remodeling, which is crucial for maintaining function and metabolic homeostasis of adipose tissue. However, the effects of obesity on collagen cross-linking and adipose fibrosis remain to be examined. Therefore, the objective of this study was to investigate obesity-induced collagen cross-linking in adipose tissue and explore the underlying mechanisms. We found that obesity increased mature nonreducible collagen cross-linking in white adipose tissue (WAT) of mice, which was associated with inhibition of AMPK, up-regulation of transforming growth factor-ß (TGF-ß) signaling and the expression of lysyl oxidase (LOX), a key enzyme catalyzing the synthesis of mature cross-linking products. In SVCs and 3T3-L1 adipocytes, AMPK activation by metformin or AICAR inhibited TGF-ß1-induced fibrogenesis and expression of LOX, which was further confirmed by ectopic expression of AMPK WT and K45R mutant. Consistently, in vivo, knocking out AMPK increased fibrosis and collagen cross-linking. Our study showed that AMPK downregulation due to obesity increases TGF-ß signaling and LOX expression, which enhances adipose fibrosis and collagen cross-linking. Thus, AMPK is a therapeutic target for ameliorating the obesity-induced fibrosis, improving metabolic health of adipose tissue.
Assuntos
Proteínas Quinases Ativadas por AMP , Proteína-Lisina 6-Oxidase , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Animais , Colágeno/metabolismo , Fibrose , Camundongos , Obesidade/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
The metabolite, alpha-ketoglutarate (aKG), shows promise as an approach for ameliorating colitis, but much remains unknown about the full extent of its effects on the metabolome and mucosal barrier. To further elucidate this matter, C57BL/6 male mice received drinking water with or without 1% aKG for three weeks, then were subjected to 2.5% dextran sulfate sodium (DSS) induction for 7 days followed by 7 days of recovery. Cecal content and intestinal tissue samples were analyzed for changes in metabolite profile and signaling pathways. Gas chromatography-mass spectrometry (GC-MS) metabolomics revealed a separation between the metabolome of mice treated with or without aKG; putrescine and glycine were significantly increased; and ornithine and amide products, oleamide and urea were significantly decreased. Based on a pathway analysis, aKG treatment induced metabolite changes and enriched glutathione metabolism and the urea cycle. Additionally, signaling pathways committing epithelial cells to the secretory lineage were elevated in aKG-treated mice. Consistently, aKG supplementation increased goblet cells staining, mRNA expression of mucin 2, and, trefoil factor 3 and Krüppel-like factor 4, markers of goblet cell differentiation. These data suggest the ameliorating the effects of aKG against chemically induced colitis involves a reduction in harmful metabolites and the promotion of goblet cell differentiation, resulting in a more-fortified mucus layer.
Assuntos
Colite , Células Caliciformes , Animais , Diferenciação Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Células Caliciformes/metabolismo , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ureia/metabolismoRESUMO
Succinic acid widely exists in foods and is used as a food additive. Succinate not only serves as an energy substrate, but also induces protein succinylation. Histone succinylation activates gene transcription. The brown adipose tissue (BAT) is critical for prevention of obesity and metabolic dysfunction, and the fetal stage is pivotal for BAT development. Up to now, the role of maternal succinate supplementation on fetal BAT development and offspring BAT function remains unexamined. To test, female C57BL/6J mice (2-month-old) were separated into 2 groups, received with or without 0.5% succinic acid in drinking water during gestation and lactation. After weaning, female offspring were challenged with high fat diet (HFD) for 12 weeks. Newborn, female weanling, and HFD female offspring mice were analyzed. For neonatal and weaning mice, the BAT weight relative to the whole body weight was significantly increased in the succinate group. The expression of PGC-1α, a key transcription co-activator promoting mitochondrial biogenesis, was elevated in BAT of female neonatal and offspring born to succinate-fed dams. Consistently, maternal succinate supplementation enhanced thermogenesis and the expression of thermogenic genes in offspring BAT. Additionally, maternal succinate supplementation protected female offspring against HFD-induced obesity. Furthermore, in C3H10T1/2 cells, succinate supplementation promoted PGC-1α expression and brown adipogenesis. Mechanistically, succinate supplementation increased permissive histone succinylation and H3K4me3 modification in the Ppargc1a promoter, which correlated with the higher expression of Ppargc1a. In conclusion, maternal succinate supplementation during pregnancy and lactation enhanced fetal BAT development and offspring BAT thermogenesis, which prevented HFD-induced obesity and metabolism dysfunction in offspring.
Assuntos
Adipogenia , Tecido Adiposo Marrom/embriologia , Suplementos Nutricionais , Ácido Succínico/administração & dosagem , Termogênese , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Animais , Animais Recém-Nascidos , Linhagem Celular , Dieta Hiperlipídica , Feminino , Código das Histonas , Histonas/metabolismo , Lactação , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Gravidez , Regiões Promotoras GenéticasRESUMO
SCOPE: As a natural compound in foods, alpha-ketoglutarate (aKG) is one of the key metabolites maintaining energy homeostasis. This study examines the beneficial effects of dietary aKG against the development of experimental colitis and further explores the underlying molecular mechanisms. METHODS AND RESULTS: Eight-week-old male C57BL/6 mice receive drinking water with or without 1% aKG for 4 weeks. At week 3, colitis is induced by 2.5% dextran sulfate sodium (DSS) for 7 days followed by 7 days recovery. Dietary aKG supplementation decreases DSS-induced body weight loss, gross bleeding, fecal consistency score, and disease activity index. In agreement, aKG supplementation restores DSS-associated colon shortening, ameliorated mucosal damage, and macrophage infiltration into colonic tissue, which are associated with suppressed gut inflammation and Wnt signaling, and improved epithelial structure. Consistently, aKG supplementation enhances M1 to M2 macrophage polarization and strengthens intestinal barrier function. Additionally, aKG supplementation elevates colonic aKG levels while decreasing 2-hydroxyglutarate levels, which increases oxidative instead of glycolytic metabolism. CONCLUSION: aKG supplementation protects against epithelial damage and ameliorates DSS-induced colitis, which are associated with suppressed inflammation, Wnt signaling pathway, and glycolysis. Intake of foods enriched with aKG or aKG supplementation can be an alternative approach for the prevention or treatment of colitis that are common in Western societies.
Assuntos
Colite/prevenção & controle , Colo/metabolismo , Ácidos Cetoglutáricos/farmacologia , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/fisiopatologia , Sulfato de Dextrana/toxicidade , Suplementos Nutricionais , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Ácidos Cetoglutáricos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
BACKGROUND: During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. METHODS: Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro. Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model. FINDINGS: Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice. INTERPRETATION: These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues. FUNDING: This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D.
Assuntos
Células-Tronco Mesenquimais/metabolismo , Músculo Esquelético/fisiologia , Regeneração , Transdução de Sinais , Tretinoína/metabolismo , Adipogenia , Animais , Diferenciação Celular , Fibrose , Imuno-Histoquímica , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologiaAssuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Envelhecimento/efeitos dos fármacos , Ácidos Cetoglutáricos/farmacologia , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Marrom/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Cetoglutáricos/sangue , Camundongos , RejuvenescimentoRESUMO
Grape pomace (GP), a by-product of the wine and juice industry, is rich in bioflavonoids and dietary fibers. We hypothesized that GP has protective effects against colitis-associated colorectal cancer (CRC). Nine-week-old female mice were fed a control diet (CON) or CON with 5% grape pomace (GP) for 2 weeks, when mice were subjected to azoxymethane (AOM)/dextran sulfate sodium (DSS) induced-CRC induction. GP supplementation ameliorated the disease activity index (DAI) score, reduced tumor number, tumor size and pathological scores in AOM/DSS treated mice. Furthermore, dietary GP suppressed colonic expression of inflammatory cytokines, IL-1ß and TNF-α, and inhibited NF-κB inflammatory signaling, while increased anti-inflammatory cytokine TGF-ß mRNA expression. Colorectal inflammation is known to enhance Wnt signaling and cell proliferation. In agreement, the content of ß-catenin, a key downstream mediator of Wnt signaling, was reduced as was the expression of Cyclin D1, phosphorylation and content of p53 and PCNA level in GP-fed mice. In addition, GP reduced the expression of ALDH1, a marker of cell stemness, and increased the expression of Cdx2, a key transcription factor initiating epithelial cell differentiation, DNA methylation of the promoter region of Cdx2 gene and hypermethylation of CpG island methylator phenotype (CIMP), which commonly occurs during CRC carcinogenesis, was alleviated in the GP group. In conclusion, GP supplementation suppressed colitis-associated CRC carcinogenesis, which was associated with the suppression of inflammation and cell proliferation and the enhancement of DNA demethylation in Cdx2 and CIMP genes in the colon. These data suggest that dietary GP supplementation has preventive effects against colorectal carcinogenesis.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Flavonoides/uso terapêutico , Vitis , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Colo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Flavonoides/química , Camundongos , Vitis/químicaRESUMO
Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process. Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle-aged mice (10-month-old) compared with young mice (2-month-old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high-fat diet (HFD). These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold-induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle-aged mice. Besides, AKG administration up-regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD-induced obesity in middle-aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene.
Assuntos
Adipogenia/efeitos dos fármacos , Ácidos Cetoglutáricos/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Feminino , Ácidos Cetoglutáricos/farmacologia , Camundongos , Obesidade/prevenção & controleRESUMO
KEY POINTS: Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet. Exercise intervention of obese mothers prevents fetal overgrowth. Exercise intervention reverses impaired placental vascularization in obese mice. Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity. ABSTRACT: More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO-induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP-activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was associated with improved maternal metabolism and placental vascularization in obese mothers with exercise.
Assuntos
Desenvolvimento Fetal/fisiologia , Feto/fisiologia , Obesidade/fisiopatologia , Condicionamento Físico Animal/fisiologia , Placenta/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Feto/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Doenças Metabólicas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos/metabolismo , Camundongos Obesos/fisiologia , Mães , Obesidade/metabolismo , Obesidade Materna/metabolismo , Obesidade Materna/fisiopatologia , Placenta/metabolismo , GravidezRESUMO
Two experiments were conducted to evaluate the digestible (DE) and metabolisable energy (ME), apparent (AID) and standardised ileal digestibility (SID) of amino acids (AA) in yeast extract (YE) and spray-dried porcine plasma (SDPP). In Experiment 1, 18 barrows (25.1 ± 1.2 kg body weight [BW]) were randomly allotted to three treatments with six replicates per treatment. The DE and ME of YE was 20.64 and 19.31 MJ/kg, respectively, which were not significantly different with the DE and ME of SDPP (18.74 and 18.05 MJ/kg, respectively). In Experiment 2, six barrows (20.6 ± 2.6 kg BW) fitted with ileal T-cannulas were fed three diets in a repeated 3-period Latin square design. For Met and Glu, the AID tended to be, while the SID was significantly higher (p < 0.05), in YE than in SDPP. The AID of Cys tended to be lower in YE (p = 0.07), while the SID of Phe tended to be higher in YE than in SDPP (p = 0.06). Accordingly, YE could be a potential substitute for SDPP as a superior protein ingredient in diets for pigs in terms of the available energy and AA digestibility.
Assuntos
Aminoácidos/metabolismo , Digestão , Metabolismo Energético , Íleo/fisiologia , Sus scrofa/fisiologia , Aminoácidos/administração & dosagem , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Digestão/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Íleo/efeitos dos fármacos , Masculino , Plasma , Distribuição Aleatória , Saccharomyces cerevisiae/químicaRESUMO
Formation of beige adipocytes within white adipose tissue enhances energy expenditure, which is a promising strategy to reduce obesity and prevent metabolic symptoms. Vitamin A and its bioactive metabolite, retinoic acid (RA), have regulatory roles in lipid metabolism. Here we report that RA induces white adipose tissue browning via activating vascular endothelial growth factor (VEGF) signaling. RA triggered angiogenesis and elicited de novo generation of platelet-derived growth factor receptor α positive (PDGFRα+) adipose precursor cells via VEGFA/VEGFR2 signaling. In addition, RA promoted beige/brown adipocyte formation from capillary networks in vitro. Using PDGFRα tracking mice, we found that the vascular system acted as an adipogenic repository by containing PDGFRα+ progenitors which differentiated into beige adipocytes under RA or VEGF164 treatments. Conditional knockout of VEGF receptors blocked RA-stimulated white adipose tissue browning. Moreover, the VEGFA and RA activated p38MAPK to enhance the binding of RA receptor to RA response elements of the Prdm16 promoter and upregulated Prdm16 transcription. In conclusion, RA induces white adipose tissue browning by increasing adipose vascularity and promoting beige adipogenesis of PDGFRα+ adipose progenitors.
RESUMO
Clinically, low and moderate alcohol intake improves human health with protection against metabolic syndromes, including type 2 diabetes; however, mechanisms that are associated with these effects remain to be elucidated. The aims of this study were to investigate the effects of moderate alcohol intake on thermogenic brown/beige adipocyte formation and glucose and lipid homeostasis, as well as the involvement of retinoic acid (RA) signaling in the entire process. C57BL6 male mice were supplemented with 8% (w/v) alcohol in water for 1 or 4 mo. Alcohol intake prevented body weight gain, induced the formation of uncoupling protein 1-positive beige adipocytes in white adipose tissue, and increased thermogenesis in mice, which is associated with decreased serum glucose and triacylglycerol levels. Mechanistically, alcohol intake increased RA levels in serum and adipose tissue, which was associated with increased expression of aldehyde dehydrogenase family 1 subfamily A1 (Aldh1a1). When RA receptor-α signaling was conditionally blocked in platelet-derived growth factor receptor-α-positive adipose progenitors, the effects of alcohol on beige adipogenesis were largely abolished. Finally, moderate alcohol prevented high-fat diet-induced obesity and metabolic dysfunction. In conclusion, moderate alcohol intake induces thermogenic brown/beige adipocyte formation and promotes glucose and lipid oxidation via elevation of RA signaling.-Wang, B., Wang, Z., de Avila, J. M., Zhu, M.-J., Zhang, F., Gomez, N. A., Zhao, L., Tian, Q., Zhao, J., Maricelli, J., Zhang, H., Rodgers, B. D., Du, M. Moderate alcohol intake induces thermogenic brown/beige adipocyte formation via elevating retinoic acid signaling.
Assuntos
Adipócitos Bege/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Álcoois/farmacologia , Termogênese/efeitos dos fármacos , Adipócitos Bege/metabolismo , Adipogenia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/metabolismoRESUMO
To determine the effects of standardized ileal digestible (SID) valine : lysine ratio on the performance, milk composition and plasma indices of lactating sows, 32 Large White × Landrace sows (219.78 ± 7.15 kg body weight; parity 1.82 ± 0.62) were allotted to one of four dietary treatments with eight sows per treatment based on parity, back fat thickness and body weight. The sows were fed corn-soybean meal-based diets containing 63, 83, 103 or 123% SID valine : lysine from day 107 of gestation until day 28 of lactation. The average daily feed intake of sows and daily weight gain of piglets increased linearly (P < 0.05) while back fat loss decreased linearly (P < 0.05) as the SID valine : lysine ratio increased. All of the analyzed amino acids in sow colostrum and valine concentrations of sow and piglet plasma increased linearly (P < 0.05) with the increasing SID valine : lysine ratio. In conclusion, 88 and 113% dietary SID valine : lysine ratios were optimal to achieve minimum back fat loss and maximum piglet growth rate using a linear-break point model which exceeds the requirement of 85% that is estimated by the National Research Council (2012).