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1.
Reprod Biol Endocrinol ; 20(1): 161, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411474

RESUMO

BACKGROUND: Mammalian sperm maturation in the epididymis is mainly modulated by exosomes that are secreted into the epididymal lumen from epididymal epithelial cells (EECs). Exposure to oxidative stress (OS) resulting from being fed a high fat diet (HFD) reduces sperm fertility, which is one of the cause inducing male infertility. Thus, we hypothesize that stress-induced changes in exosome content play a critical role in mediating this detrimental process.  METHODS: An obese mouse model was established by feeding a HFD. Then oxidative stress status was measured in the mouse caput epididymis, epididymal fluid and spermatozoa. Meanwhile, epididymis-derived purified exosomes were isolated and validated. Subsequently, liquid chromatography tandem mass spectrometry (LC-MS) was used to perform proteomic analysis of purified exosomes. Gene Ontology (GO) analysis was performed along with pathway enrichment to identify differentially expressed proteins (DEPs). RESULTS: Two hundred and two DEPs mostly related to endoplasmic reticulum (ER) function were identified in the exosomes separated from the epididymis of control mice and obese mice. The ER stress and CD63 (an exosome marker), both increased in the caput epididymis of obese mice. Furthermore, an in vitro study showed that palmitic acid (PA), an-oxidative stress inducer, increased exosome biogenesis and secretion in the EECs. CONCLUSION: Oxidative stress in the epididymal microenvironment induces ER stress in the EECs. This effect alters the epididymis-derived exosome content, profile and amounts of their differentially expressed ER proteins. Such changes may affect exosome biogenesis and cargo packaging, finally leading to abnormalities in sperm maturation and fertility.


Assuntos
Exossomos , Maturação do Esperma , Masculino , Animais , Camundongos , Estresse do Retículo Endoplasmático , Camundongos Obesos , Proteômica , Sêmen , Estresse Oxidativo , Mamíferos
2.
Biomed Pharmacother ; 156: 113961, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411667

RESUMO

This study investigated the impacts of enteral cholecalciferol and/or intravenous calcitriol administration on the balance of cluster of differentiation 4-positive T cell subsets, the renin-angiotensin system (RAS), and the severity of acute lung injury (ALI) in obese mice with sepsis. Mice were fed a high-fat diet and then cecal ligation and puncture (CLP) was performed. Obese mice were divided into four sepsis groups: without vitamin D (VD) (S), with oral cholecalciferol 1 d before CLP (G), with intravenous calcitriol 1 h after CLP (V), and with both cholecalciferol before and intravenous calcitriol after CLP (GV). Mice were euthanized after CLP. The V and GV groups showed higher blood T helper (Th)1/Th2 and lower Th17/T regulatory (Treg) ratios than did the S and G groups. In the lungs, The V group had the lowest nuclear factor-κB and interleukin-1ß gene expressions among all groups 24 h post-CLP. In parallel, gene expressions of angiotensin type 2 receptor (AT2R), angiotensin-converting enzyme 2 (ACE2), and Mas receptor (MasR) were highest in the V group compared to other groups. The protein levels of MasR in the GV group and the AT2R/AT1R ratio in the V group were higher than those in the G and/or S groups. All of the VD-treated groups had lower injury scores than the S group. These findings suggest that calcitriol administration had more-pronounced impacts on regulating the homeostasis of Th/Treg cells and is prone to RAS-associated anti-inflammatory pathway in the lungs. However, both forms of VD attenuated sepsis-induced ALI in obese animals.


Assuntos
Lesão Pulmonar Aguda , Sepse , Camundongos , Animais , Vitamina D/farmacologia , Sistema Renina-Angiotensina , Camundongos Obesos , Calcitriol/farmacologia , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Vitaminas , Homeostase , Lesão Pulmonar Aguda/complicações , Receptor Tipo 2 de Angiotensina/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
3.
Front Endocrinol (Lausanne) ; 13: 1023264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339431

RESUMO

Background: Restoration of immune tolerance to disease-relevant antigens is an appealing approach to prevent or arrest an organ-specific autoimmune disease like type 1 diabetes (T1D). Numerous studies have identified insulin as a key antigen of interest to use in such strategies, but to date, the success of these interventions in humans has been inconsistent. The efficacy of antigen-specific immunotherapy may be enhanced by optimising the dose, timing, and route of administration, and perhaps by the inclusion of adjuvants like alum. The aim of our study was to evaluate the effect of an insulin peptide vaccine formulated with alum to prevent T1D development in female non-obese diabetic (NOD) mice when administered during late-stage pre-diabetes. Methods: Starting at 10 weeks of age, female NOD mice received four weekly subcutaneous injections of an insulin B:8-24 (InsB:8-24) peptide with (Ins+alum) or without Imject® alum (Ins) as adjuvant. Diabetes incidence was assessed for up to 30 weeks of age. Insulin autoantibodies and C-peptide concentrations were measured in plasma and flow cytometric analysis was performed on pancreatic-draining lymph nodes (PLN) and pancreas using an InsB:12-20-reactive tetramer. Results: InsB:8-24 peptide formulated in alum reduced diabetes incidence (39%), compared to mice receiving the InsB:8-24 peptide without alum (71%, P < 0.05), mice receiving alum alone (76%, P < 0.01), or mice left untreated (70%, P < 0.01). This was accompanied by reduced insulitis severity, and preservation of C-peptide. Ins+alum was associated with reduced frequencies of pathogenic effector memory CD4+ and CD8+ T cells in the pancreas and increased frequencies of insulin-reactive FoxP3+ Tregs in the PLN. Of interest, insulin-reactive Tregs were enriched amongst populations of Tregs expressing markers indicative of stable FoxP3 expression and enhanced suppressive function. Conclusion: An InsB:8-24 peptide vaccine prevented the onset of T1D in late-stage pre-diabetic NOD mice, but only when formulated in alum. These findings support the use of alum as adjuvant to optimise the efficacy of antigen-specific immunotherapy in future trials.


Assuntos
Diabetes Mellitus Tipo 1 , Estado Pré-Diabético , Humanos , Feminino , Camundongos , Animais , Recém-Nascido , Diabetes Mellitus Tipo 1/tratamento farmacológico , Insulina/metabolismo , Camundongos Endogâmicos NOD , Linfócitos T CD8-Positivos/patologia , Camundongos Obesos , Peptídeo C , Peptídeos , Fatores de Transcrição Forkhead
4.
Anal Chem ; 94(46): 16171-16179, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36350275

RESUMO

A fluorometric assay for single substrate-based glucose and lactate measurements was demonstrated by adopting an already established protocol for glucose and by optimizing pH, enzyme concentration, substrate concentration, and types of buffers for lactate. Linear calibration curves for glucose and lactate concentrations from 1 to 100 µM were obtained with correlation coefficients (R2) of 0.94 and 0.98, respectively. First, with the optimized protocol, single embryo quality was successfully evaluated. Three different initial stages of embryos (n = 58) were cultured for 24 h, and glycolytic activities were calculated by measuring amounts of glucose consumption and lactate production. Results showed that embryos cultured at a later stage had lower glycolytic activities, implying more developmental activities. Second, glucose and lactate concentrations in blood plasma of diet-induced obese (DIO) mice were measured. Levels of both glucose and lactate in DIO mice were higher than those in normal mice by 2.15 and 3.8 mmol/L, respectively (both p < 0.001). Finally, clinical serum samples were analyzed and categorized into three groups based on their measured glucose concentrations: normal (4.73 ± 0.29 mmol/L), prediabetic (6.49 ± 0.13 mmol/L), and diabetic (11.34 ± 1.36 mmol/L) (p < 0.05). Collectively, this developed technique can be used to select a high-quality embryo for transfer as well as to measure glucose and lactate levels in other biological samples.


Assuntos
Blastocisto , Glucose , Humanos , Camundongos , Animais , Glucose/farmacologia , Camundongos Obesos , Embrião de Mamíferos , Ácido Láctico
5.
Eur Rev Med Pharmacol Sci ; 26(21): 7797-7812, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36394728

RESUMO

OBJECTIVE: Obesity is characterized by excess fat accumulation and closely associated with insulin resistance and type 2 diabetes. We aimed at exploring the potential effect and mechanism of escin for the treatment of obesity using network pharmacology, and to verify the effect of escin on obese mice. MATERIALS AND METHODS: Escin targets were predicted by DrugBank and SwissTarget database. Potential targets for the treatment of obesity were identified based on the DisGeNET database. Comparative analysis was used to investigate the overlapping genes between escin targets and obesity treatment-related targets. Using STRING database and Cytoscape to analyze interactions among overlapping genes, hub genes were identified. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted in DAVID. High-fat diet (HFD) -induced obese mice were used to observe the anti-obesity effects of escin. The body weight, relevant biochemical markers and HE staining of fat and liver tissues were determined after escin was administered for 18 weeks. RESULTS: We screened 53 overlapping genes for escin and obesity. The mechanism of intervention of escin in treating obesity may involve 10 hub targets (STAT3, MTOR, NR3C1, IKBKB, PTGS2, MMP9, PRKCA, PRKCD, AR, CYP3A4). The screening and enrichment analysis revealed that the treatment of obesity using escin primarily involved 10 GO enriched terms and 13 related pathways. In vivo, escin can reduce the body weight of obese mice induced by HFD and improve lipid metabolism through lowering triglycerides (TG), total cholesterol (TC), and density lipoprotein (LDL) levels and increasing high density lipoprotein (HDL) levels and decreasing leptin level and increasing adiponectin (ADPN) level. Escin can regulate glucose metabolism caused by obesity through decreasing fasting glucose, postprandial blood glucose and regulating the level of insulin. These obese mice induced by HFD displayed the increased insulin resistance that was associated with the increased inflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). Escin may antagonize the increase of MCP-1 and partially antagonize the low-grade inflammation caused by obesity. From the morphological changes of fat and liver tissues stained by HE stain, escin could decrease the size of adipocytes and improve liver necrosis and fatty degeneration in obese mice fed by HFD. CONCLUSIONS: The network pharmacology of escin in treating obesity may involve 10 hub targets (STAT3, MTOR, NR3C1, IKBKB, PTGS2, MMP9, PRKCA, PRKCD, AR, CYP3A4), 10 GO enriched terms and 13 related pathways. In vivo, escin can be potentially used to prevent or treat obesity through reducing the weight, improving glucose and lipid metabolism, partially antagonizing the low-grade inflammation, and improved insulin resistance.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Camundongos , Ciclo-Oxigenase 2 , Citocromo P-450 CYP3A/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica , Escina/uso terapêutico , Glucose/metabolismo , Quinase I-kappa B , Inflamação/metabolismo , Metaloproteinase 9 da Matriz , Camundongos Obesos , Obesidade , Serina-Treonina Quinases TOR
6.
Cell Rep Med ; 3(11): 100810, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384093

RESUMO

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.


Assuntos
Glucagon , Redução de Peso , Camundongos , Animais , Glucagon/metabolismo , Metabolismo Energético/fisiologia , Receptores de Glucagon/metabolismo , Camundongos Obesos , Aminoácidos/farmacologia
7.
Drug Des Devel Ther ; 16: 3893-3913, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388084

RESUMO

Purpose: Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. Methods: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. Results: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. Conclusion: Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.


Assuntos
Resistência à Insulina , Nefropatias , Masculino , Camundongos , Animais , Camundongos Obesos , NAD , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Adenosina
8.
Elife ; 112022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36346018

RESUMO

While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adip ocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.


Assuntos
Adipocinas , Resistência à Insulina , Animais , Camundongos , Inflamação , Insulina , Obesidade , Camundongos Obesos , Glicoproteínas/genética
9.
Nat Metab ; 4(11): 1514-1531, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36376564

RESUMO

Food cues during fasting elicit Pavlovian conditioning to adapt for anticipated food intake. However, whether the olfactory system is involved in metabolic adaptations remains elusive. Here we show that food-odor perception promotes lipid metabolism in male mice. During fasting, food-odor stimulation is sufficient to increase serum free fatty acids via adipose tissue lipolysis in an olfactory-memory-dependent manner, which is mediated by the central melanocortin and sympathetic nervous systems. Additionally, stimulation with a food odor prior to refeeding leads to enhanced whole-body lipid utilization, which is associated with increased sensitivity of the central agouti-related peptide system, reduced sympathetic activity and peripheral tissue-specific metabolic alterations, such as an increase in gastrointestinal lipid absorption and hepatic cholesterol turnover. Finally, we show that intermittent fasting coupled with food-odor stimulation improves glycemic control and prevents insulin resistance in diet-induced obese mice. Thus, olfactory regulation is required for maintaining metabolic homeostasis in environments with either an energy deficit or energy surplus, which could be considered as part of dietary interventions against metabolic disorders.


Assuntos
Resistência à Insulina , Odorantes , Camundongos , Masculino , Animais , Tecido Adiposo/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Camundongos Obesos , Percepção
10.
Front Endocrinol (Lausanne) ; 13: 995007, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419767

RESUMO

Background: Obesity is a chronic metabolic disease caused by a combination of genetic and environmental factors. To determine whether semaglutide could improve aortic injury in obese C57BL/6J mice, and further explore its molecular mechanism of action using proteomics. Methods: 24 C57BL/6J male mice were randomly divided into normal diet group (NCD group), high-fat diet group (HFD group) and high-fat diet + semaglutide group (Sema group, semaglutide (30 nmol/kg/d) for 12 weeks). The serum samples were collected from mice to detect blood glucose, insulin and blood lipid concentrations. Aortic stiffness was detected by Doppler pulse wave velocity (PWV). Changes in vascular structure were detected by HE, masson, EVG staining and electron microscopy. The aorta-related protein expression profiles were detected by proteomic techniques, and proteins with potential molecular mechanisms were identified. Results: Semaglutide could reduce body weight, the concentrations of blood glucose, total cholesterol (TC), triglycerides (TG), lipoprotein cholesterol (LDL-C), and reduce the aortic PWV and ameliorate vascular damage in obese mice. The results of proteomic analysis showed there were 537 up-regulated differentially expressed proteins (DEPs) and 322 down-regulated DEPs in NCD/HFD group, 251 up-regulated DEPs and 237 down-regulated proteins in HFD/Sema group. There were a total of 25 meaningful overlapping DEPs in the NCD/HFD and HFD/Sema groups. GO enrichment analysis of overlapping DEPs found that these differential proteins were mainly located in the signaling pathways of the extracellular matrix. The most obvious changes of extracellular matrix associated proteins in the three experimental groups were Coll5a1, Lama4, Sparc. Conclusion: Semaglutide may protect vascular structure and improve endothelial permeability by reducing the levels of Coll5a1, Lama4, Sparc in extracellular matrix, so as to improve vascular function and achieve vascular protection.


Assuntos
Dieta Hiperlipídica , Doenças não Transmissíveis , Masculino , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos Obesos , Glicemia , Proteômica , Análise de Onda de Pulso , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo
11.
Nat Metab ; 4(11): 1495-1513, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36411386

RESUMO

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.


Assuntos
Leptina , Neurônios , Animais , Camundongos , Masculino , Humanos , Leptina/metabolismo , Neurônios/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Camundongos Obesos , Tronco Encefálico , Redução de Peso , Receptores de Orexina/metabolismo
12.
Lipids Health Dis ; 21(1): 115, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335399

RESUMO

BACKGROUND: Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. METHODS: C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. RESULTS: Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor-nitric oxide axis. CONCLUSIONS: Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT-kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.


Assuntos
Fibronectinas , Insuficiência Renal Crônica , Camundongos , Animais , Camundongos Obesos , Óxido Nítrico/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Rim/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/metabolismo , Albuminas/metabolismo
13.
Biochem Biophys Res Commun ; 635: 19-29, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36252333

RESUMO

Nobiletin can regulate lipid metabolism and protect the central nervous system. However, its role in the enteric nervous system (ENS) of obese subjects is still unclear. To investigate the ENS protective effects and mechanism of nobiletin in obese mice, male C57BL/6 mice were fed a chow diet and a high-fat diet (HFD) for 8 weeks. The identified obese and control mice were grouped and administered vehicle, nobiletin 40 mg/kg, 100 mg/kg or 200 mg/kg daily for 4 weeks. The major indexes of obesity, intestinal transit rate, PGP9.5, nNOS, TNF-α, IL-1ß, IL-6, IL-10, Bcl2 and Bax were measured. The full-length transcriptome was used to analyze differentially expressed genes (DEGs) in the colon. The results indicated that nobiletin effectively improved major indexes of obesity and bowel motility function, suppressed the expression of TNF-α, IL-1ß, IL-6 and Bax, and upregulated the expression of IL-10, Bcl2, PGP9.5 and nNOS. Based on full-length transcriptome sequencing, nobiletin regulated lipid metabolism and inflammation via the PPAR and NOD-like receptor signaling pathways. Trem2 expression was significantly reduced in obese mice. However, Trem2 expression was significantly increased after nobiletin treatment in obese mice. The enrichment analysis showed that Trem2 plays an important role in enteric neuroinflammation. In conclusion, nobiletin regulates lipid metabolism and inflammation in obese mice. Trem2 is a potential target of nobiletin for ENS protection in obese mice.


Assuntos
Interleucina-10 , Fator de Necrose Tumoral alfa , Animais , Masculino , Camundongos , Proteína X Associada a bcl-2 , Dieta Hiperlipídica/efeitos adversos , Inflamação/tratamento farmacológico , Interleucina-6 , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores Imunológicos , Motilidade Gastrointestinal
14.
Life Sci ; 310: 121078, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36252700

RESUMO

AIMS: Neurokinin-B (NKB)-Neurokinin-3-receptor (NK3R) pathway is remarkably sensitive to energy equilibrium; however, its role in metabolic regulation remains unexplored in polycystic ovary syndrome (PCOS). Therefore, this work aimed to investigate the role of NK3R antagonists (NK3Ra) on metabolic dysfunction and obesity in in vitro and in vivo PCOS models. MAIN METHODS: First, an observational study using serum samples collected from 19 PCOS patients was performed. Second, prospective case-control experimental studies where NK3Ra (SB222200) was used to treat PCOS-like mice (BALB/c mice), ovariectomized+estrogen implanted obese mice (C57BL/6J mice) and 3T3-L1 murine preadipocytes were carried out to investigate its effect on metabolism in vivo and in vitro. The fat volumes, serum biochemical indexes, adipokines and inflammatory cytokines, metabolism-related gene expression and the concentrations of ATP, NAD+, NADPH…etc. were studied. KEY FINDINGS: We found a positive correlation between serum NKB and lipid metabolism indicators in PCOS women. Using the mouse models, we demonstrated that administration of NK3Ra regulates serum adipokines, inhibits weight gain with a marked decrease in fat volume, adipocyte size, and inflammatory cytokines, and promotes oxidative metabolism and energy consumption. NK3Ra reduces lipid accumulation in mature murine adipocytes by inhibiting the expression of peroxisome proliferator- activated receptor gamma (PPAR-γ) and fatty acid binding protein 4 (FABP4) genes. NK3Ras also enhances oxidative metabolism and energy consumption by maintaining intracellular redox homeostasis. SIGNIFICANCE: This study backs the use of NK3Ras as a potential therapeutic for PCOS since it ameliorates both reproductive and metabolic aberrations.


Assuntos
Obesidade , Síndrome do Ovário Policístico , Receptores da Neurocinina-3 , Animais , Feminino , Humanos , Camundongos , Células 3T3-L1 , Adipócitos/metabolismo , Adipocinas/metabolismo , Citocinas/metabolismo , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , PPAR gama/metabolismo , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/metabolismo
15.
Diabet Med ; 39(12): e14978, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36245259

RESUMO

BACKGROUND: Adipose tissue mass expansion in obesity leads to alterations in expression and secretion of adipokines, some of which may alter islet function by binding to G-protein-coupled receptors (GPCRs) expressed by islets. We have therefore quantified expression of mRNAs encoding islet GPCR ligands in visceral adipose tissue retrieved from lean and diet-induced obese mice to determine alterations in islet GPCR ligand mRNAs in obesity. METHODS: Epididymal adipose tissue was retrieved from C57BL/6 mice that had been maintained on a control-fat diet (10% fat) or high-fat diet (60% fat) for 16 weeks and RT-qPCR was used to quantify mRNAs encoding ligands for islet GPCRs. RESULTS: Of the 155 genes that encode ligands for islet GPCRs, 45 and 40 were expressed in visceral adipose tissue retrieved from lean and obese mice respectively. The remaining mRNAs were either expressed at trace level (0.0001% to 0.001% relative to Actb expression) or absent (<0.0001%). Obesity was associated with significant alterations in GPCR ligand mRNA expression in visceral adipose tissue, some of which encode for peptides with established effects on islet function (e.g. neuropeptide Y), or for GPCR ligands that have not previously been investigated for their effects on islets (e.g. (C-C motif) ligand 4; Ccl4). CONCLUSION: Mouse visceral adipose tissue showed significant alterations in expression of mRNAs encoding islet GPCR ligands in obesity. Our data point to ligands of interest for future research on adipose-islet crosstalk via secreted ligands acting at islet GPCRs. Such research may identify islet GPCRs with therapeutic potential for T2D.


Assuntos
Gordura Intra-Abdominal , Receptores Acoplados a Proteínas G , Camundongos , Humanos , Animais , Ligantes , Camundongos Obesos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo/metabolismo , RNA Mensageiro/metabolismo
16.
Nat Metab ; 4(10): 1271-1286, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36253620

RESUMO

Obesity, dyslipidemia and gut dysbiosis are all linked to cardiovascular diseases. A Ganoderma meroterpene derivative (GMD) has been shown to alleviate obesity and hyperlipidemia through modulating the gut microbiota in obese mice. Here we show that GMD protects against obesity-associated atherosclerosis by increasing the abundance of Parabacteroides merdae in the gut and enhancing branched-chain amino acid (BCAA) catabolism. Administration of live P. merdae to high-fat-diet-fed ApoE-null male mice reduces atherosclerotic lesions and enhances intestinal BCAA degradation. The degradation of BCAAs is mediated by the porA gene expressed in P. merdae. Deletion of porA from P. merdae blunts its capacity to degrade BCAAs and leads to inefficacy in fighting against atherosclerosis. We further show that P. merdae inhibits the mTORC1 pathway in atherosclerotic plaques. In support of our preclinical findings, an in silico analysis of human gut metagenomic studies indicates that P. merdae and porA genes are depleted in the gut microbiomes of individuals with atherosclerosis. Our results provide mechanistic insights into the therapeutic potential of GMD through P. merdae in treating obesity-associated cardiovascular diseases.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Camundongos , Animais , Masculino , Aminoácidos de Cadeia Ramificada/metabolismo , Bacteroides/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Camundongos Obesos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Aterosclerose/prevenção & controle , Apolipoproteínas E
17.
J Appl Physiol (1985) ; 133(6): 1284-1294, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36201322

RESUMO

Obesity is associated with sleep-disordered breathing (SDB) and unrefreshing sleep. Residual daytime sleepiness and sleep impairments often persist after SDB treatment in patients with obesity, which suggests an independent effect of obesity on breathing and sleep. However, examining the relationship between sleep architecture and SDB in patients with obesity is complex and can be confounded by multiple factors. The main goal of this study was to examine the relationship between obesity-related changes in sleep architecture and SDB. Sleep recordings were performed in 15 lean C57BL/6J and 17 diet-induced obesity (DIO) mice of the same genetic background. Arousals from sleep and apneas were manually scored. Respiratory arousals were classified as events associated with ≥30% drops in minute ventilation (VE) from baseline. We applied Poincaré analysis of VE during sleep to estimate breathing variability. Obesity augmented the frequency of arousals by 45% and this increase was independent of apneas. Respiratory arousals comprised only 15% of the arousals in both groups of mice. Breathing variability during non-rapid-eye-movment (NREM) sleep was significantly higher in DIO mice, but it was not associated with arousal frequency. Our results suggest that obesity induces sleep fragmentation independently of SDB severity.NEW & NOTEWORTHY Our diet-induced obesity (DIO) model reproduces sleep features of human obesity, including sleep fragmentation, increased apnea frequency, and larger breathing variability. DIO induces sleep fragmentation independently of apnea severity. Sleep fragmentation in DIO mice is mainly attributed to non-respiratory arousals. Increased breathing variability during sleep did not account for the higher arousal frequency in DIO. Our results provide a rationale to examine sleep in patients with obesity even when they are adequately treated for sleep-disordered breathing.


Assuntos
Síndromes da Apneia do Sono , Privação do Sono , Humanos , Camundongos , Animais , Privação do Sono/complicações , Camundongos Endogâmicos C57BL , Sono , Obesidade/complicações , Dieta , Camundongos Obesos
18.
Drug Des Devel Ther ; 16: 3723-3735, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36304787

RESUMO

Purpose: This study aimed to investigate the effect of Semaglutide on skeletal muscle and its metabolomics. Methods: A total of 18 male C57BL/6 mice were randomly divided into normal control (NC) group, high-fat diet (HFD) group and HFD+Semaglutide group, and were given standard diet, HFD diet, HFD diet plus Semaglutide, respectively. The body weight, gastrocnemius weight, serum lipid, blood glucose and inflammatory index levels of mice in each group were observed and compared, and the morphological and structural changes of gastrocnemius were also analyzed. Meanwhile, gastrocnemius metabolite changes were analyzed by untargeted metabolomics. Results: After Semaglutide treatment, the food intake and body weight of mice were evidently decreased, while the relative gastrocnemius weight ratio were conversely increased. Meanwhile, the levels of TG, CHO, LDL, HDL, TNF-α, IL-6, IL-1ß and HOMA-IR were all observed to decrease remarkably after Semaglutide intervention. Histological analysis showed that Semaglutide significantly improved the pathological changes of gastrocnemius, manifested as increased type I/type II muscle fiber ratio, total muscle fiber area, muscle fiber density, sarcomere length, mitochondrial number and mitochondrial area. Furthermore, metabolic changes of gastrocnemius after Semaglutide intervention were analyzed, and 141 kinds of differential metabolites were screened out, mainly embodied in lipids and organic acids, and enriched in 9 metabolic pathways including a variety of amino acids. Conclusion: Semaglutide can significantly reduce the body weight and the accumulation of intramuscular fat, promote muscle protein synthesis, increase the relative proportion of skeletal muscle, and improve muscle function of obese mice, possibly by altering the metabolism of muscle lipids and organic acids.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Sarcopenia , Masculino , Camundongos , Animais , Camundongos Obesos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Sarcopenia/tratamento farmacológico , Sarcopenia/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Dieta Hiperlipídica , Músculo Esquelético , Lipídeos/farmacologia
19.
Cell Mol Life Sci ; 79(11): 570, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36306016

RESUMO

BACKGROUND: Obesity affects the cargo packaging of the adipocyte-derived exosomes. Furthermore, adipocytes in different adipose tissues have different genetic makeup, the cargo contents of the exosomes derived from different adipose tissues under obesity conditions should be different, and hence their impacts on the pathophysiological conditions. METHODS AND RESULTS: iTRAQ-based quantitative proteomics show that obesity has more prominent effects on the protein profiles of the exosomes derived from subcutaneous adipose tissue (SAT-Exos) in the high fat diet-induced obesity (DIO) mice than those derived from epididymal adipose tissue (EAT-Exos) and visceral adipose tissue (VAT-Exos). The differentially expressed proteins (DEPs) in SAT-Exos and VAT-Exos are mainly involved in metabolism. Subsequent untargeted metabolomic and lipidomics analyses reveal that injection of these SAT-Exos into the B6/J-Rab27a-Cas9-KO mice significantly affects the mouse metabolism such as fatty acid metabolism. Some of the DEPs in SAT-Exos are correlated with fatty acid metabolism including ADP-ribosylation factor and mitogen-activated protein kinase kinase kinase-3. Pathway analysis also shows that SAT-Exos affect adipocyte lipolysis and glycerophospholipid metabolism, which is in parallel with the enhanced plasma levels of fatty acids, diglycerides, monoglycerides and the changes in glycerophospholipid levels in DIO mice. CONCLUSION: Our data provide scientific evidence to suggest SAT-Exos contribute to the changes in plasma lipid profiles under obesity conditions.


Assuntos
Exossomos , Camundongos , Animais , Exossomos/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Camundongos Obesos , Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo
20.
J Agric Food Chem ; 70(43): 13893-13903, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36264038

RESUMO

The antiobesity efficacy and underlying mechanisms of polysaccharides extracted from Fu brick tea (FBTP) were investigated. An 8-week administration of FBTP dose-dependently inhibited increases in body weight and weights of the epididymal-, retroperitoneal- and inguinal-white adipose tissues and stimulated beige-fat development and brown adipose tissue-derived nonshivering thermogenesis in high-fat diet-induced obese mice. FBTP protected against obesity-associated abnormality in serum adiponectin and leptin, indicating its positive regulation of energy metabolism. FBTP reversed gut dysbiosis by enriching beneficial bacteria, for example, Lactobacillus, Parabacteroides, Akkermansia, Bifidobacterium, and Roseburia. Results from the fecal microbiota transplantation further confirmed that FBTP-induced microbial shifts contributed to adipose browning and thermogenesis, thereby alleviating host adiposity, glucose homeostasis, dyslipidemia, and its related hepatic steatosis. Our study demonstrates the great potential of FBTP with prebiotic-like activities in preventing diet-induced obesity and its related metabolic complications via gut microbiota-derived enhancement of fat burning and energy expenditures.


Assuntos
Microbioma Gastrointestinal , Camundongos , Animais , Chá/metabolismo , Termogênese , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica , Camundongos Obesos , Adipócitos/metabolismo , Polissacarídeos/metabolismo , Camundongos Endogâmicos C57BL
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