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1.
Mol Syst Biol ; 20(4): 374-402, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38459198

RESUMO

Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.


Assuntos
Fígado Gorduroso , Hepatopatia Gordurosa não Alcoólica , Animais , Feminino , Humanos , Masculino , Camundongos , Dieta Hiperlipídica/efeitos adversos , Estrogênios , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Expressão Gênica , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/uso terapêutico , Fatores de Transcrição de Domínio TEA
2.
Commun Biol ; 5(1): 1057, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195702

RESUMO

Male and female offspring of obese mothers are known to differ extensively in their metabolic adaptation and later development of complications. We investigate the sex-dependent responses in obese offspring mice with maternal obesity, focusing on changes in liver glucose and lipid metabolism. Here we show that maternal obesity prior to and during gestation leads to hepatic steatosis and inflammation in male offspring, while female offspring are protected. Females from obese mothers display important changes in hepatic transcriptional activity and triglycerides profile which may prevent the damaging effects of maternal obesity compared to males. These differences are sustained later in life, resulting in a better metabolic balance in female offspring. In conclusion, sex and maternal obesity drive differently transcriptional and posttranscriptional regulation of major metabolic processes in offspring liver, explaining the sexual dimorphism in obesity-associated metabolic risk.


Assuntos
Obesidade Materna , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Mães , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Triglicerídeos/metabolismo
3.
Int J Obes (Lond) ; 46(4): 831-842, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34997206

RESUMO

OBJECTIVE: The prevalence of overweight and obesity among children has drastically increased during the last decades and maternal obesity has been demonstrated as one of the ultimate factors. Nutrition-stimulated transgenerational regulation of key metabolic genes is fundamental to the developmental origins of the metabolic syndrome. Fetal nutrition may differently influence female and male offspring. METHODS: Mice dam were fed either a control diet or a high-fat diet (HFD) for 6-week prior mating and continued their respective diet during gestation and lactation. At weaning, female and male offspring were fed the HFD until sacrifice. White (WAT) and brown (BAT) adipose tissues were investigated in vivo by nuclear magnetic resonance at two different timepoints in life (midterm and endterm) and tissues were collected at endterm for lipidomic analysis and RNA sequencing. We explored the sex-dependent metabolic adaptation and gene programming changes by maternal HFD in visceral AT (VAT), subcutaneous AT (SAT) and BAT of offspring. RESULTS: We show that the triglyceride profile varies between adipose depots, sexes and maternal diet. In female offspring, maternal HFD remodels the triglycerides profile in SAT and BAT, and increases thermogenesis and cell differentiation in BAT, which may prevent metabolic complication later in life. Male offspring exhibit whitening of BAT and hyperplasia in VAT when born from high-fat mothers, with impaired metabolic profile. Maternal HFD differentially programs gene expression in WAT and BAT of female and male offspring. CONCLUSION: Maternal HFD modulates metabolic profile in offspring in a sex-dependent manner. A sex- and maternal diet-dependent gene programming exists in VAT, SAT, and BAT which may be key player in the sexual dimorphism in the metabolic adaptation later in life.


Assuntos
Tecido Adiposo Marrom , Lipidômica , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Humanos , Masculino , Camundongos , Gravidez , Termogênese , Transcriptoma/genética
4.
Commun Biol ; 4(1): 14, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398027

RESUMO

With the increasing prevalence of obesity in women of reproductive age, there is an urgent need to understand the metabolic impact on the fetus. Sex-related susceptibility to liver diseases has been demonstrated but the underlying mechanism remains unclear. Here we report that maternal obesity impacts lipid metabolism differently in female and male offspring. Males, but not females, gained more weight and had impaired insulin sensitivity when born from obese mothers compared to control. Although lipid mass was similar in the livers of female and male offspring, sex-specific modifications in the composition of fatty acids, triglycerides and phospholipids was observed. These overall changes could be linked to sex-specific regulation of genes controlling metabolic pathways. Our findings revised the current assumption that sex-dependent susceptibility to metabolic disorders is caused by sex-specific postnatal regulation and instead we provide molecular evidence supporting in utero metabolic adaptations in the offspring of obese mothers.


Assuntos
Metabolismo dos Lipídeos , Fígado/metabolismo , Obesidade , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Adaptação Fisiológica , Animais , Feminino , Lipidômica , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Gravidez , Caracteres Sexuais
5.
Metabolites ; 10(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32244965

RESUMO

In this communication, we aim to summarize the role of estrogen receptor beta (ERß) in lipid metabolism in the main metabolic organs with a special focus on sex differences. The action of ERß is tissue-specific and acts in a sex-dependent manner, emphasizing the necessity of developing sex- and tissue-selective targeting drugs in the future.

6.
J Lipid Res ; 61(4): 480-491, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086245

RESUMO

Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles ("Lp-X") in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Animais , Ácidos Cólicos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Fenótipo , Especificidade da Espécie
7.
Mol Cell Endocrinol ; 502: 110672, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811898

RESUMO

Estrogen exerts its action through the binding to two major receptors, estrogen receptor (ER)α and ß. Recently, the beneficial role of selective ERß activation in the regulation of metabolic homeostasis in obesity has been demonstrated, but its importance is still controversial. However, no data are available regarding possible gender differences in response to pharmaceutical activation of ERß. Male mice were fed a control diet (CD) or a high fat diet (HFD) before being treated with the ERß selective ligand, 4-(2-(3-5-dimethylisoxazol-4-yl)-1H-indol-3yl)phenol (DIP) in the same conditions as in our recently published paper in female mice. Magnetic resonance imaging and spectroscopy were performed repeatedly in vivo after 6 weeks of diet and after 2 weeks of DIP. Adipose tissue distribution and hepatic triglycerides composition were quantified. HFD-treated males showed a feminization of their fat distribution towards more subcutaneous fat depots and increase total fat content and visceral adipose tissue showed clear browning sites after DIP. Hepatic lipid composition was modified by DIP, with less saturated and more unsaturated lipids and an improved insulin sensitivity. Finally, brown adipose tissue size expended after DIP, due to an increase of the size of the lipid droplets. Our data demonstrate that selective activation of ERß exerts a tissue-specific and sex-dependent response to metabolic adaptation to overfeeding. Most importantly, together with our previously published results in females, the current findings support the concept that sex should be considered in the future development of obesity-moderating drugs.


Assuntos
Receptor beta de Estrogênio/metabolismo , Obesidade/metabolismo , Fenóis/farmacologia , Triglicerídeos/metabolismo , Gordura Abdominal/metabolismo , Animais , Estudos de Casos e Controles , Dieta Hiperlipídica , Feminino , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Obesos , Obesidade/induzido quimicamente , Caracteres Sexuais , Gordura Subcutânea/metabolismo , Distribuição Tecidual
8.
Biol Sex Differ ; 10(1): 11, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808418

RESUMO

The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob/ob mice. These data could settle the basis for future pharmacological treatment in obesity.


Assuntos
Tecido Adiposo/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Caracteres Sexuais , Animais , Feminino , Metabolismo dos Lipídeos , Lipidômica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos
9.
Mol Cell Endocrinol ; 479: 147-158, 2019 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-30342056

RESUMO

OBJECTIVE: Estrogens play a key role in the distribution of adipose tissue and have their action by binding to both estrogen receptors (ER), α and ß. Although ERß has a role in the energy metabolism, limited data of the physiological mechanism and metabolic response involved in the pharmacological activation of ERß is available. METHODS: For clinical relevance, non-ovariectomized female mice were subjected to high fat diet together with pharmacological (DIP - 4-(2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl)phenol) interventions to ERß selective activation. The physiological mechanism was assessed in vivo by magnetic resonance imaging and spectroscopy, and oral glucose and intraperitoneal insulin tolerance test before and after DIP treatment. Liver and adipose tissue metabolic response was measured in HFD + vehicle and HFD + DIP by stable isotope, RNA sequencing and protein content. RESULTS: HFD-fed females treated with DIP had a tissue-specific response towards ERß selective activation. The metabolic profile showed an improved fasting glucose level, insulin sensitivity and reduced liver steatosis. CONCLUSIONS: Our data demonstrate that selective activation of ERß exerts a tissue-specific activity which promotes a beneficial effect on whole body metabolic response to obesity.


Assuntos
Tecido Adiposo/metabolismo , Metabolismo Energético , Receptor beta de Estrogênio/metabolismo , Mitocôndrias/metabolismo , Obesidade/metabolismo , Biogênese de Organelas , Animais , Feminino , Perfilação da Expressão Gênica , Isoxazóis , Ligantes , Lipogênese , Lipólise , Fígado/metabolismo , Camundongos Endogâmicos C57BL
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