RESUMO
The circadian clock system coordinates metabolic, physiological, and behavioral functions across a 24-h cycle, crucial for adapting to environmental changes. Disruptions in circadian rhythms contribute to major metabolic pathologies like obesity and Type 2 diabetes. Understanding the regulatory mechanisms governing circadian control is vital for identifying therapeutic targets. It is well characterized that chromatin remodeling and 3D structure at genome regulatory elements contributes to circadian transcriptional cycles; yet the impact of rhythmic chromatin topology in metabolic disease is largely unexplored. In this study, we explore how the spatial configuration of the genome adapts to diet, rewiring circadian transcription and contributing to dysfunctional metabolism. We describe daily fluctuations in chromatin contacts between distal regulatory elements of metabolic control genes in livers from lean and obese mice and identify specific lipid-responsive regions recruiting the clock molecular machinery. Interestingly, under high-fat feeding, a distinct interactome for the clock-controlled gene Dbp strategically promotes the expression of distal metabolic genes including Fgf21. Alongside, new chromatin loops between regulatory elements from genes involved in lipid metabolism control contribute to their transcriptional activation. These enhancers are responsive to lipids through CEBPß, counteracting the circadian repressor REVERBa. Our findings highlight the intricate coupling of circadian gene expression to a dynamic nuclear environment under high-fat feeding, supporting a temporally regulated program of gene expression and transcriptional adaptation to diet.
Assuntos
Cromatina , Relógios Circadianos , Ácidos Graxos , Fígado , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade , Animais , Cromatina/metabolismo , Cromatina/genética , Fígado/metabolismo , Camundongos , Relógios Circadianos/genética , Obesidade/metabolismo , Obesidade/genética , Ácidos Graxos/metabolismo , Masculino , Dieta Hiperlipídica/efeitos adversos , Montagem e Desmontagem da Cromatina , Ritmo Circadiano/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Metabolismo dos Lipídeos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Obesity is a global health concern implicated in numerous chronic degenerative diseases, including type 2 diabetes, dyslipidemia, and neurodegenerative disorders. It is characterized by chronic low-grade inflammation, gut microbiota dysbiosis, insulin resistance, glucose intolerance, and lipid metabolism disturbances. Here, we investigated the therapeutic potential of environmental enrichment (EE) to prevent the progression of gut dysbiosis in mice with high-fat diet (HFD)-induced metabolic syndrome. C57BL/6 male mice with obesity and metabolic syndrome, continuously fed with an HFD, were exposed to EE. We analyzed the gut microbiota of the mice by sequencing the 16s rRNA gene at different intervals, including on day 0 and 12 and 24 weeks after EE exposure. Fasting glucose levels, glucose tolerance, insulin resistance, food intake, weight gain, lipid profile, hepatic steatosis, and inflammatory mediators were evaluated in serum, adipose tissue, and the colon. We demonstrate that EE intervention prevents the progression of HFD-induced dysbiosis, reducing taxa associated with metabolic syndrome (Tepidimicrobium, Acidaminobacteraceae, and Fusibacter) while promoting those linked to healthy physiology (Syntrophococcus sucrumutans, Dehalobacterium, Prevotella, and Butyricimonas). Furthermore, EE enhances intestinal barrier integrity, increases mucin-producing goblet cell population, and upregulates Muc2 expression in the colon. These alterations correlate with reduced systemic lipopolysaccharide levels and attenuated colon inflammation, resulting in normalized glucose metabolism, diminished adipose tissue inflammation, reduced liver steatosis, improved lipid profiles, and a significant reduction in body weight gain despite mice's continued HFD consumption. Our findings highlight EE as a promising anti-inflammatory strategy for managing obesity-related metabolic dysregulation and suggest its potential in developing probiotics targeting EE-modulated microbial taxa.
Assuntos
Dieta Hiperlipídica , Disbiose , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Obesidade , Animais , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia , Masculino , Glucose/metabolismo , Camundongos Obesos , Resistência à Insulina , Síndrome Metabólica/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/microbiologiaRESUMO
Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.
Assuntos
Proteínas de Transporte , Dieta Hiperlipídica , Glucose , Resistência à Insulina , Músculo Esquelético , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Tiorredoxinas , Animais , Masculino , Camundongos , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Dieta Hiperlipídica/efeitos adversos , Furanos/farmacologia , Glucose/metabolismo , Indenos/farmacologia , Inflamassomos/metabolismo , Insulina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/metabolismo , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas , Tiorredoxinas/metabolismo , Tiorredoxinas/genéticaRESUMO
Obesity and overweight are multifactorial diseases affecting more than one-third of the world's population. Physical inactivity contributes to a positive energy balance and the onset of obesity. Exercise combined with a balanced diet is an effective non-pharmacological strategy to improve obesity-related disorders. Gallic acid (GA), is a natural endogenous polyphenol found in a variety of fruits, vegetables, and wines, with beneficial effects on energetic homeostasis. The present study aims to investigate the effects of exercise training on obese mice supplemented with GA. Animal experimentation was performed with male Swiss mice divided into five groups: ST (standard control), HFD (obese control), HFD + GA (GA supplement), HFD + Trained (training), and HFD + GA + Trained (GA and training). The groups are treated for eight weeks with 200 mg/kg/body weight of the feed compound and, if applicable, physical training. The main findings of the present study show that GA supplementation improves liver fat, body weight, adiposity, and plasma insulin levels. In addition, animals treated with the GA and a physical training program demonstrate reduced levels of anxiety. Gene expression analyses show that Sesn2 is activated via PGC-1α independent of the GATOR2 protein, which is activated by GA in the context of physical activity. These data are corroborated by molecular docking analysis, demonstrating the interaction of GA with GATOR2. The present study contributes to understanding the metabolic effects of GA and physical training and demonstrates a new hepatic mechanism of action via Sestrin 2 and PGC-1α.
Assuntos
Ácido Gálico , Fígado , Camundongos Obesos , Obesidade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Animais , Camundongos , Ácido Gálico/farmacologia , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/genética , Obesidade/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ansiedade/tratamento farmacológico , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , SestrinasRESUMO
INTRODUCTION: The excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AIM: Assess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. METHODS: Male C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. RESULTS: The dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. CONCLUSION: The HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.
Assuntos
Adiposidade , Anedonia , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Serotonina , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Anedonia/fisiologia , Serotonina/metabolismo , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Adiposidade/fisiologia , Camundongos , Peso Corporal/fisiologia , Camundongos Obesos , Hipocampo/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo , Comportamento Animal/fisiologia , Hipotálamo/metabolismo , Padrões DietéticosRESUMO
The aim was to understand the direct impact of aerobic short-term exercise on lipid metabolism, specifically in regulating the mitochondrial carrier homolog 2 (MTCH2) and how it interferes with lipid metabolism in mesenteric adipose tissue. Swiss mice were divided into three groups: control, sedentary obese, and exercised obese. The obese groups were induced into obesity for fourteen weeks of a high-fat diet, and the trained submitted to seven aerobic exercise sessions. The exercise proved the significant increase of the pPerilipin-1, a hormone-sensitive lipase gene, and modulates lipid metabolism by increasing the expression of Mtch2 and acetyl Co-A carboxylase, perhaps occurring as feedback to regulate lipid metabolism in adipose tissue. In conclusion, we demonstrate, for the first time, how aerobic physical exercise increases Mtch2 transcription in mesenteric adipose tissue. This increase was due to changes in energy demand caused by exercise, confirmed by observing the significant reduction in mesenteric adipose tissue mass in the exercised group. Also, we showed that physical exercise increased the phosphorylative capacity of PLIN1, a protein responsible for the degradation of fatty acids in the lipid droplet, providing acyl and glycerol for cellular metabolism. Although our findings demonstrate evidence of MTCH2 as a protein that regulates lipid homeostasis, scant knowledge exists concerning the signaling of the MTCH2 pathway in regulatingfatty acid metabolism. Therefore, unveiling the means of molecular signaling of MTCH2 demonstrates excellent potential for treating obesity.
Assuntos
Tecido Adiposo , Metabolismo dos Lipídeos , Proteínas de Transporte da Membrana Mitocondrial , Obesidade , Condicionamento Físico Animal , Animais , Camundongos , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lipídeos , Camundongos Obesos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologiaRESUMO
Benign prostatic hyperplasia (BPH) is characterised by increases in prostate volume and contraction. Downregulation of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway contributes to prostate dysfunctions. Previous studies in cancer cells or vessels have shown that the epigenetic mechanisms control the gene and protein expression of the enzymes involved in the production of NO and cGMP. This study is aimed to evaluate the effect of a 2-week treatment of 5-azacytidine (5-AZA), a DNA-methyltransferase inhibitor, in the prostate function of mice fed with a high-fat diet. Functional, histological, biochemical and molecular assays were carried out. Obese mice presented greater prostate weight, α-actin expression and contractile response induced by the α-1adrenoceptors agonist. The relaxation induced by the NO-donor and the protein expression of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) were significantly decreased in the prostate of obese mice. The treatment with 5-AZA reverted the higher expression of α-actin, reduced the hypercontractility state of the prostate and increased the expression of eNOS and sGC and intraprostatic levels of cGMP. When prostates from obese mice treated with 5-AZA were incubated in vitro with inhibitors of the NOS or sGC, the inhibitory effect of 5-AZA was reverted, therefore, showing the involvement of NO and cGMP. In conclusion, our study paves the way to develop or repurpose therapies that recover the expression of eNOS and sGC and, hence, to improve prostate function in BPH.
Assuntos
Óxido Nítrico , Hiperplasia Prostática , Masculino , Humanos , Camundongos , Animais , Óxido Nítrico/metabolismo , Guanilato Ciclase/metabolismo , Próstata/metabolismo , Camundongos Obesos , Guanosina Monofosfato/metabolismo , Azacitidina/metabolismo , Hiperplasia Prostática/metabolismo , Actinas/metabolismo , GMP Cíclico/metabolismoRESUMO
SCOPE: Obesity and insulin resistance constitute risk factors for the development of tauopathies and other neurodegenerative diseases. (Poly)phenol compounds are under study for its role in protecting effects against neural injuries and degeneration. Here, we investigated the effect of Amazonian açai pulp (AP) intake in the prevention of memory and cognitive impairment resulting from a high-fat diet intake in mice. METHODS AND RESULTS: Obesity and insulin resistance was induced with a high-fat diet and supplemented with 2% AP to investigate peripheral insulin resistance, recognition memory and tau protein stability via AKT/GSK3-ß signaling pathway. The consumption of AP for 70 days improved peripheral insulin sensitivity and phosphorylation of AKT/GSK3-ß in mice hippocampi. The animals fed high-fat diets supplemented with AP showed better performance in the novel object recognition test (NOR) in comparison to the H group. Catalase activity and reduced glutathione (GSH) values were improved in the treated mice. CONCLUSIONS: These results suggest that the supplementation of AP can attenuate the effects of high-fat diet consumption in peripheral insulin resistance and improve cognitive behavior.
Assuntos
Resistência à Insulina , Camundongos , Animais , Camundongos Obesos , Proteínas Proto-Oncogênicas c-akt , Quinase 3 da Glicogênio Sintase/farmacologia , Cognição , Obesidade/metabolismo , Insulina/metabolismo , Dieta Hiperlipídica , Camundongos Endogâmicos C57BLRESUMO
The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.