RESUMO
Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.
Assuntos
Adipócitos , Adipogenia , Adiposidade , PPAR gama , Receptores CXCR4 , Células-Tronco , Animais , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Feminino , Masculino , Camundongos , Adipócitos/metabolismo , Adipócitos/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , PPAR gama/metabolismo , PPAR gama/genética , Camundongos Knockout , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Dieta Hiperlipídica/efeitos adversos , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Camundongos Endogâmicos C57BL , Estradiol/farmacologia , Estradiol/metabolismo , Proliferação de Células , Fatores Sexuais , Caracteres SexuaisRESUMO
Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.
Assuntos
Adaptação Fisiológica , Tecido Adiposo Branco , Temperatura Baixa , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Animais , Tecido Adiposo Branco/metabolismo , Camundongos , Masculino , Proteoma/metabolismo , Termogênese/fisiologia , Glucose/metabolismoRESUMO
To investigate the effects of rapeseed diacylglycerol oil (RDG) intake on lipid accumulation and metabolism in C57BL/6J mice, obese mice were fed a high-fat diet in which 45% of the total energy content came from RDG (RDGM group) or rapeseed triacylglycerol oil (RTGM group). This diet intervention was conducted for 12 weeks following the establishment of the obese mouse model. By the end of the experiment, the serum glucose levels of the mice in the RTGM and RDGM groups were 13.0 ± 1.3 mmol/L and 9.7 ± 1.5 mmol/L, respectively. Meanwhile, the serum triglyceride level in the RDGM group was 26.3% lower than that in the RTGM group. The weight-loss effect in the RDGM group was accompanied by a significant decrease in the white adipose tissue (WAT) index. The RDG intervention did not significantly change the antioxidant and anti-inflammatory properties of the rapeseed oil in vivo. The RDG diet improved the liver lipid metabolism abnormalities induced by a high-fat diet, leading to decreased liver damage index values (AST and ALT). Additionally, compared to that in the RTGM group, the expression of the adipogenic genes PPAR-γ and DGAT decreased in both the liver and intestine by 21.7% and 16.7% and by 38.7% and 47.2%, respectively, in the RDGM group. Further, most lipolytic genes in BAT showed no significant change after the RDG intervention. This implies that RDG regulates lipid metabolism by altering the expression of adipogenic genes in the liver, intestine, and adipose tissue, thereby reducing the accumulation of WAT. Furthermore, the RDG diet enhanced gut flora diversity, increasing the relative levels of unclassified Muribaculaceae and decreasing the levels of Dubosiella and Faecalibaculum in the mouse gut, potentially accelerating lipid metabolism. Thus, a three-month RDG diet intervention in obese mice exhibited benefits in regulating the somatotype, serum obesity-related indices, gut flora structure, and lipid metabolism in the adipose tissue, liver, and intestine.
Assuntos
Fármacos Antiobesidade , Dieta Hiperlipídica , Diglicerídeos , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Obesidade , Óleo de Brassica napus , Animais , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Diglicerídeos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Óleo de Brassica napus/farmacologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Fármacos Antiobesidade/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Triglicerídeos/sangue , Diacilglicerol O-Aciltransferase/metabolismo , Diacilglicerol O-Aciltransferase/genética , Microbioma Gastrointestinal/efeitos dos fármacos , PPAR gama/metabolismo , Camundongos ObesosRESUMO
INTRODUCTION: Obesity, characterized by excess adipose tissue, is a major public health problem worldwide. Brown adipose tissue (BAT) and beige adipose tissue participate in thermogenesis through uncoupling protein 1 (UCP1). Polyphenols including those from Calafate (a native polyphenol-rich Patagonian berry), are considered as potential anti-obesity compounds due to their pro-thermogenic characteristics. However, polyphenols are mainly metabolized by the gut microbiota (GM) that may influence their bioactivity and bioavailability. The aim of this study was to determine the impact of dietary administration with a Calafate polyphenol-rich extract on thermogenic activity of BAT and beige adipose tissue and GM composition. METHODS: Eight-week-old C57BL6 mice (n = 30) were divided into 4 groups to receive for 24 weeks a control diet (C), a high-fat diet alone (HF), or high-fat diet supplemented with Calafate extract (HFC) or the same high-fat diet supplemented with Calafate extract but treated with antibiotics (HFCAB) from week 19-20. Administration with Calafate extract (50 mg/kg per day) was carried out for 3 weeks from week 21-23 in the HFC and HFCAB groups. After euthanasia, gene expression of thermogenic markers was analyzed in BAT and inguinal white adipose tissue (iWAT). Transmission electron microscopy was performed to assess mitochondrial morphology and cristae density in BAT. GM diversity and composition were characterized by deep sequencing with the MiSeq Illumina platform. RESULTS: Calafate extract administration had no effect on weight gain in mice fed a high-fat diet. However, it prevented alterations in mitochondrial cristae induced by HFD and increased Dio2 expression in BAT and iWAT. The intervention also influenced the GM composition, preventing changes in specific bacterial taxa induced by the high-fat diet. However, the antibiotic treatment prevented in part these effects, suggesting the implications of GM. CONCLUSION: These results suggest that the acute administration of a Calafate extract modulates the expression of thermogenic markers, prevents alterations in mitochondrial cristae and intestinal microbiota in preclinical models. The study highlights the complex interaction between polyphenols, thermogenesis, and the GM, providing valuable insights into their potential roles in the treatment of obesity-related metabolic diseases.
Assuntos
Tecido Adiposo Marrom , Dieta Hiperlipídica , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Extratos Vegetais , Termogênese , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Camundongos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Extratos Vegetais/farmacologia , Masculino , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , BiomarcadoresRESUMO
Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of 10 human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells. The screen identified an adipogenic modulator, zinc-alpha-2-glycoprotein (ZAG/AZGP1) that is secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG is linked to poor prognosis in patients with TNBC but not in patients with other clinical subtypes of breast cancer. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of adipocyte stem and progenitor cells into cancer-associated fibroblasts to support tumorigenesis. SIGNIFICANCE: Functional screening of breast cancer secretomes revealed that triple-negative breast cancer promotes fibrosis in the adipose tissue microenvironment by secreting zinc-alpha-2-glycoprotein and promoting the transdifferentiation of adipocyte stem cells into myofibroblasts.
Assuntos
Fibrose , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Feminino , Camundongos , Fibrose/metabolismo , Fibrose/patologia , Animais , Linhagem Celular Tumoral , Adipogenia , Adipócitos/metabolismo , Adipócitos/patologia , Glicoproteína Zn-alfa-2 , Microambiente Tumoral , Proteínas de Plasma Seminal/metabolismo , Proteínas de Plasma Seminal/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologiaRESUMO
There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.
Assuntos
Tecido Adiposo Branco , Quimiocina CCL22 , Metabolismo Energético , Linfonodos , Macrófagos , Termogênese , Animais , Feminino , Humanos , Masculino , Camundongos , Adipócitos Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Quimiocina CCL22/metabolismo , Eosinófilos/metabolismo , Linfonodos/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Receptores CCR4/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: Adipogenesis, the process of white adipose tissue expansion, plays a critical role in the development of obesity. Osteoprotegerin (OPG), known for its role in bone metabolism regulation, emerges as a potential regulator in mediating adipogenesis during obesity onset. OBJECTIVES: This study aims to elucidate the involvement of OPG in adipogenesis during the early phases of diet-induced obesity and explore its therapeutic potential in obesity management. METHODS: Using a diet-induced obesity model, we investigated OPG expression patterns in adipocytes and explored the mechanisms underlying its involvement in adipogenesis. We also assessed the effects of targeted silencing of OPG and recombinant OPG administration on obesity progression and insulin resistance. Additionally, the impact of electroacupuncture treatment on OPG levels and obesity management was evaluated in both animal models and human participants. RESULTS: OPG expression was prominently activated in adipocytes of white adipose tissues during the early phase of diet-induced obesity. Hyperlipidemia induced Cbfa1-dependent OPG transcription, initiating and promoting adipogenesis, leading to cell-size expansion and lipid storage. Intracellular OPG physically bound to RAR and released the PPARɤ/RXR complex, activating adipogenesis-associated gene expression. Targeted silencing of OPG suppressed obesity development, while recombinant OPG administration promoted disease progression and insulin resistance in obese mice. Electroacupuncture treatment suppressed obesity development in an OPG-dependent manner and improved obesity parameters in obese human participants. CONCLUSION: OPG emerges as a key regulator in mediating adipogenesis during obesity development. Targeting OPG holds promise for the prevention and treatment of obesity, as evidenced by the efficacy of electroacupuncture treatment in modulating OPG levels and managing obesity-related outcomes.
Assuntos
Adipócitos , Adipogenia , Obesidade , Osteoprotegerina , Obesidade/metabolismo , Animais , Humanos , Osteoprotegerina/metabolismo , Camundongos , Masculino , Adipócitos/metabolismo , Resistência à Insulina , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , AdultoRESUMO
Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.
Assuntos
Tecido Adiposo Branco , Pele , Cicatrização , Animais , Tecido Adiposo Branco/metabolismo , Camundongos , Pele/metabolismo , Pele/patologia , Camundongos Endogâmicos C57BL , Gordura Subcutânea/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neurregulinas/metabolismo , Neurregulinas/genética , Masculino , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Tecido Adiposo Marrom/metabolismo , Adipócitos Bege/metabolismo , Macrófagos/metabolismo , Humanos , Miofibroblastos/metabolismoRESUMO
AIM: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting. METHODS: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. RESULTS: Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. CONCLUSION: Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.
Assuntos
Adiponectina , Caquexia , Neoplasias Pulmonares , Rosiglitazona , Animais , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Caquexia/metabolismo , Caquexia/tratamento farmacológico , Adiponectina/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , PPAR gama/metabolismo , PPAR gama/agonistas , Masculino , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêuticoRESUMO
Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.
Assuntos
Adipogenia , Lipase , Animais , Masculino , Camundongos , Aciltransferases , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Lipase/metabolismo , Lipase/genética , Lipogênese , Lipólise , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteína Desacopladora 1/metabolismoRESUMO
Obesity is a global public health problem and is related with fatal diseases such as cancer and cardiovascular and metabolic diseases. Medical and lifestyle-related strategies to combat obesity have their limitations. White adipose tissue (WAT) browning is a promising strategy for increasing energy expenditure in individuals with obesity. Uncoupling protein 1 (UCP1) drives WAT browning. We previously screened natural products that enable induction of Ucp1 and demonstrated that these natural products induced WAT browning and increased energy expenditure in mice with diet-induced obesity. In this study, we aimed to extensively optimise the structure of compound 1, previously shown to promote WAT browning. Compound 3 s exhibited a significantly higher ability to induce Ucp1 in white and brown adipocytes than did compound 1. A daily injection of compound 3 s at 5 mg/kg prevented weight gain by 13.6 % in high-fat diet-fed mice without any toxicological observation. In addition, compound 3 s significantly improved glucose homeostasis, decreased serum triacylglycerol levels, and reduced total cholesterol and LDL cholesterol levels, without altering dietary intake or physical activity. Pharmaceutical properties such as solubility, lipophilicity, and membrane permeability as well as metabolic stability, half-life (T1/2), and blood exposure ratio of i.p to i.v were significantly improved in compound 3 s when compared with those in compound 1. Regarding the mode of action of WAT browning, the induction of Ucp1 and Prdm4 by compounds 1 and 3 s was dependent on Akt1 in mouse embryonic fibroblasts. Therefore, this study suggests the potential of compound 3 s as a therapeutic agent for individuals with obesity and related metabolic diseases, which acts through the induction of WAT browning as well as brown adipose tissue activation.
Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Resistência à Insulina , Camundongos Endogâmicos C57BL , Obesidade , Proteína Desacopladora 1 , Animais , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Chalconas/farmacologia , Camundongos Obesos , Fármacos Antiobesidade/farmacologia , Células 3T3-L1RESUMO
Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRß) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.
Assuntos
Cádmio , Diabetes Mellitus Tipo 2 , Fígado , Animais , Feminino , Diabetes Mellitus Tipo 2/induzido quimicamente , Ratos , Cádmio/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Diabetes Mellitus Tipo 1/induzido quimicamente , Ratos Wistar , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Disruptores Endócrinos/toxicidadeRESUMO
Perigonadal adipose tissue is a homogeneous white adipose tissue (WAT) in adult male mice without any brown adipose tissue (BAT). However, there are congenital differences in the gonads between male and female mice. Whether heterogeneity existed in perigonadal adipose tissues (ATs) in female mice remains unknown. This study reported a perigonadal brown-like AT located between abdominal lymph nodes and the uterine cervix in female mice, termed lymph node-cervical adipose tissue (LNCAT). Its counterpart, lymph node-prostatic adipose tissue (LNPAT), exhibited white phenotype in adult virgin male mice. When exposed to cold, LNCAT/LNPAT increased uncoupling protein 1 (UCP1) expression via activation of tyrosine hydroxylase (TH), in which abdominal lymph nodes were involved. Interestingly, the UCP1 expression in LNCAT/LNPAT varied under different reproductive stages. The UCP1 expression in LNCAT was upregulated at early pregnancy, declined at midlate pregnancy, and reverted in weaning dams. Mating behavior stimulated LNPAT browning in male mice. We found that androgen but not estrogen or progesterone inhibited UCP1 expression in LNCAT. Androgen administration reversed the castration-induced LNPAT browning. Our results identified a perigonadal brown-like AT in female mice and characterized its UCP1 expression patterns under various conditions.NEW & NOTEWORTHY A novel perigonadal brown-like AT (LNCAT) of female mice was identified. Abdominal lymph nodes were involved in cold-induced browning in this newly discovered adipose tissue. The UCP1 expression in LNCAT/LNPAT was also related to ages, sexes, and reproductive stages, in which androgen acted as an inhibitor role.
Assuntos
Tecido Adiposo Marrom , Colo do Útero , Linfonodos , Próstata , Proteína Desacopladora 1 , Animais , Masculino , Feminino , Camundongos , Linfonodos/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Tecido Adiposo Marrom/metabolismo , Colo do Útero/metabolismo , Próstata/metabolismo , Gravidez , Tecido Adiposo Branco/metabolismo , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Androgênios/farmacologia , Androgênios/metabolismo , Comportamento Sexual Animal/fisiologiaRESUMO
Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.
Assuntos
Caquexia , Ácido Láctico , Neoplasias , Receptores Acoplados a Proteínas G , Humanos , Ácido Láctico/metabolismo , Neoplasias/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Caquexia/metabolismo , Animais , Tecido Adiposo Branco/metabolismoRESUMO
Background and Objectives: The hormonal state of hypoestrogenism is associated with the accumulation of white adipose tissue, which can induce an increase in pro-inflammatory markers, leading to progressive health complications. Melatonin can act on adipose tissue mass, promoting its reduction and influencing inflammation, reducing IL-6 and releasing IL-10, pro- and anti-inflammatory markers, respectively. However, the role of melatonin regarding such parameters under the context of hypoestrogenism remains unknown. The aim of this study was to determine the effect of 12 weeks of hypoestrogenism and melatonin on white adipose tissue mass and circulating levels of IL-6, IL-10, TGF-ß-1, and leukotriene C4 (LTC4). Materials and Methods: The animals (Wistar rats with sixteen weeks of age at the beginning of the experiment) under hypoestrogenism were submitted to the surgical technique of bilateral ovariectomy. The animals received melatonin (10 mg·kg-1) or vehicles by orogastric gavage every day for 12 weeks and administration occurred systematically 1 h after the beginning of the dark period. White adipose tissue (perigonadal, peritoneal, and subcutaneous) was collected for mass recording, while blood was collected for the serum determination of IL-6, IL-10, TGF-ß-1, and LTC4. Results: Hypoestrogenism increased the perigonadal and subcutaneous mass and IL-6 levels. Melatonin kept hypoestrogenic animals in physiological conditions similar to the control group and increased thymus tissue mass. Conclusions: Hypoestrogenism appears to have a negative impact on white adipose tissue mass and IL-6 and although melatonin commonly exerts a significant effect in preventing these changes, this study did not have a sufficiently negative impact caused by hypoestrogenism for melatonin to promote certain benefits.
Assuntos
Interleucina-6 , Melatonina , Ratos Wistar , Animais , Melatonina/análise , Melatonina/sangue , Ratos , Feminino , Interleucina-6/sangue , Interleucina-6/análise , Biomarcadores/sangue , Biomarcadores/análise , Tecido Adiposo/metabolismo , Tecido Adiposo/efeitos dos fármacos , Interleucina-10/sangue , Ovariectomia , Inflamação , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/análise , Estrogênios/sangue , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismoRESUMO
BACKGROUND: Cancer-associated cachexia (CAC) arises from malignant tumors and leads to a debilitating wasting syndrome. In the pathophysiology of CAC, the depletion of fat plays an important role. The mechanisms of CAC-induced fat loss include the enhancement of lipolysis, inhibition of lipogenesis, and browning of white adipose tissue (WAT). However, few lipid-metabolic enzymes have been reported to be involved in CAC. This study hypothesized that ELOVL6, a critical enzyme for the elongation of fatty acids, may be involved in fat loss in CAC. METHODS: Transcriptome sequencing technology was used to identify CAC-related genes in the WAT of a CAC rodent model. Then, the expression level of ELOVL6 and the fatty acid composition were analyzed in a large clinical sample. Elovl6 was knocked down by siRNA in 3T3-L1 mouse preadipocytes to compare with wild-type 3T3-L1 cells treated with tumor cell conditioned medium. RESULTS: In the WAT of patients with CAC, a significant decrease in the expression of ELOVL6 was found, which was linearly correlated with the extent of body mass reduction. Gas chromatographic analysis revealed an increase in palmitic acid (C16:0) and a decrease in linoleic acid (C18:2n-6) in these tissue samples. After treatment with tumor cell-conditioned medium, 3T3-L1 mouse preadipocytes showed a decrease in Elovl6 expression, and Elovl6-knockdown cells exhibited a reduction in preadipocyte differentiation and lipogenesis. Similarly, the knockdown of Elovl6 in 3T3-L1 cells resulted in a significant increase in palmitic acid (C16:0) and a marked decrease in oleic acid (C18:1n-9) content. CONCLUSION: Overall, the expression of ELOVL6 was decreased in the WAT of CAC patients. Decreased expression of ELOVL6 might induce fat loss in CAC patients by potentially altering the fatty acid composition of adipocytes. These findings suggest that ELOVL6 may be used as a valuable biomarker for the early diagnosis of CAC and may hold promise as a target for future therapies.
Assuntos
Células 3T3-L1 , Tecido Adiposo Branco , Caquexia , Elongases de Ácidos Graxos , Neoplasias , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Animais , Caquexia/genética , Caquexia/metabolismo , Caquexia/patologia , Camundongos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/complicações , Neoplasias/patologia , Masculino , Feminino , Ácido Palmítico/metabolismo , Lipogênese/genética , Pessoa de Meia-Idade , Ácidos Graxos/metabolismoRESUMO
Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17ß-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.
Assuntos
Tecido Adiposo Marrom , Estrogênios , Hipotálamo , Fígado , Camundongos Knockout , Olanzapina , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Desacopladora 1 , Animais , Feminino , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Estrogênios/metabolismo , Estrogênios/farmacologia , Olanzapina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Masculino , Metabolismo Energético/efeitos dos fármacos , Injeções Intraperitoneais , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estradiol/farmacologia , OvariectomiaRESUMO
Growing obesity is linked to shifts in dietary patterns, particularly the increased intake of ultra-processed high-fat foods. This study aimed to evaluate the effects of interesterified palm oil consumption on glucose homeostasis, adipose tissue remodeling, and hepatic lipogenesis in C57BL/6 mice fed a high-fat diet. Sixty C57BL/6 mice were divided into four groups (n = 15): the control group (C) fed a standard diet (4% soybean oil), the high-fat group (HF) (23.8% lard), the high palm oil fat group (HFP) (23.8% palm oil), and the high interesterified palm fat group (HFI) (23.8% interesterified palm oil) for 8 weeks (all groups received 50% energy from lipids). The HFI group exhibited higher body mass than the HF group (+ 11%, P < 0.05), which was attributed to an increased percentage of fat mass. Plasma concentrations of IL-6, insulin, and HOMA-IR were also elevated in the HFI group. Both the HFP and HFI groups showed hypertrophied adipocytes and pancreatic islets, increased alpha and beta cell masses, hepatic steatosis, low expression of genes related to beta-oxidation, and upregulated lipogenesis. In conclusion, the consumption of interesterified palm oil alters inflammatory and glucose profiles.
Assuntos
Tecido Adiposo Branco , Dieta Hiperlipídica , Inflamação , Camundongos Endogâmicos C57BL , Óleo de Palmeira , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Masculino , Lipogênese/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/etiologia , Obesidade/induzido quimicamente , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Insulina/sangue , Insulina/metabolismo , Resistência à InsulinaRESUMO
The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.
Assuntos
Tecido Adiposo , Proto-Oncogene Mas , Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Animais , Humanos , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Obesidade/metabolismo , Obesidade/patologia , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/fisiologia , Transdução de SinaisRESUMO
BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit ß5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit ß1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.