Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 10.308
Filter
1.
Cell Death Dis ; 15(6): 387, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824145

ABSTRACT

Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.


Subject(s)
Adipose Tissue , Cell Differentiation , Epigenesis, Genetic , Mesenchymal Stem Cells , Mitochondria , Obesity , Humans , Mesenchymal Stem Cells/metabolism , Obesity/metabolism , Obesity/genetics , Obesity/pathology , Mitochondria/metabolism , Adipose Tissue/metabolism , Cell Differentiation/genetics , Female , Male , 5-Methylcytosine/analogs & derivatives , 5-Methylcytosine/metabolism , Adult , Middle Aged , Cell Proliferation
2.
Nat Commun ; 15(1): 4827, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844451

ABSTRACT

Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9+CD55low APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9+CD55low APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.


Subject(s)
Diabetes Mellitus, Type 2 , Glucose , Homeostasis , Obesity , Single-Cell Analysis , Stem Cells , Humans , Animals , Single-Cell Analysis/methods , Diabetes Mellitus, Type 2/metabolism , Male , Mice , Stem Cells/metabolism , Glucose/metabolism , Obesity/metabolism , Obesity/pathology , Adipocytes/metabolism , Intra-Abdominal Fat/metabolism , Intra-Abdominal Fat/cytology , Adipose Tissue/metabolism , Adipose Tissue/cytology , Mice, Inbred C57BL , Lipolysis , Female , Middle Aged
3.
J Morphol ; 285(6): e21741, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38837268

ABSTRACT

It is largely unknown how the tongue base and soft palate deform to alter the configuration of the oropharyngeal airway during respiration. This study is to address this important gap. After live sleep monitoring of five Yucatan and two Panepinto minipigs to verify obstructive sleep apnea (OSA), eight and four ultrasonic crystals were implanted into the tongue base and soft palate to circumscribe a cubic and square region, respectively. The 3D and 2D deformational changes of the circumscribed regions were measured simultaneously with electromyographic activity of the oropharyngeal muscles during spontaneous respiration under sedated sleep. The results indicated that both obese Yucatan and Panepinto minipigs presented spontaneous OSA, but not in three nonobese Yucatan minipigs. During inspiration, the tongue base showed elongation in both dorsal and ventral regions but thinning and thickening in the anterior and posterior regions, respectively. The widths showed opposite directions, widening in the dorsal but narrowing in the ventral regions. The soft palate expanded in both length and width. Compared to normal controls, obese/OSA ones showed similar directions of deformational changes, but the magnitude of change was two times larger in the tongue base and soft palate, and obese/OSA Panepinto minipigs presented 10 times larger changes in all dimensions of both the tongue base and the soft palate. The distance changes between the dorsal surface of tongue base and soft palate during inspiration increased in normal but decreased in obese OSA minipigs.


Subject(s)
Obesity , Palate, Soft , Sleep Apnea, Obstructive , Swine, Miniature , Tongue , Animals , Swine , Sleep Apnea, Obstructive/physiopathology , Tongue/physiopathology , Palate, Soft/physiopathology , Obesity/physiopathology , Obesity/complications , Obesity/pathology , Biomechanical Phenomena , Electromyography , Respiration , Male
4.
Cancer Res ; 84(11): 1834-1855, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38831751

ABSTRACT

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.


Subject(s)
Diet, High-Fat , Lactic Acid , Obesity , Prostatic Neoplasms , Proto-Oncogene Proteins c-myc , Tumor Microenvironment , Male , Animals , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Diet, High-Fat/adverse effects , Mice , Humans , Lactic Acid/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/genetics , Obesity/metabolism , Obesity/pathology , Cell Line, Tumor , Mice, Inbred C57BL , Tumor-Associated Macrophages/metabolism
5.
Sci Rep ; 14(1): 13141, 2024 06 07.
Article in English | MEDLINE | ID: mdl-38849441

ABSTRACT

Obesity and food addiction are associated with distinct brain signatures related to reward processing, and early life adversity (ELA) also increases alterations in these same reward regions. However, the neural mechanisms underlying the effect of early life adversity on food addiction are unknown. Therefore, the aim of this study was to examine the interactions between ELA, food addiction, and brain morphometry in individuals with obesity. 114 participants with high body mass index (BMI) underwent structural MRIs, and completed several questionnaires (e.g., Yale Food Addiction Scale (YFAS), Brief Resilience Scale (BRS), Early Traumatic Inventory (ETI)). Freesurfer 6 was applied to generate the morphometry of brain regions. A multivariate pattern analysis was used to derive brain morphometry patterns associated with food addiction. General linear modeling and mediation analyses were conducted to examine the effects of ELA and resilience on food addiction in individuals with obesity. Statistical significance was determined at a level of p < 0.05. High levels of ELA showed a strong association between reward control brain signatures and food addiction (p = 0.03). Resilience positively mediated the effect of ELA on food addiction (B = 0.02, p = 0.038). Our findings suggest that food addiction is associated with brain signatures in motivation and reward processing regions indicative of dopaminergic dysregulation and inhibition of cognitive control regions. These mechanistic variabilities along with early life adversity suggest increased vulnerability to develop food addiction and obesity in adulthood, which can buffer by the neuroprotective effects of resilience, highlighting the value of incorporating cognitive appraisal into obesity therapeutic regimens.


Subject(s)
Body Mass Index , Brain , Food Addiction , Magnetic Resonance Imaging , Obesity , Humans , Female , Male , Food Addiction/psychology , Brain/diagnostic imaging , Brain/pathology , Brain/physiopathology , Adult , Obesity/psychology , Obesity/pathology , Adverse Childhood Experiences/psychology , Reward , Young Adult , Middle Aged , Surveys and Questionnaires , Resilience, Psychological
6.
Front Endocrinol (Lausanne) ; 15: 1366015, 2024.
Article in English | MEDLINE | ID: mdl-38774226

ABSTRACT

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods: This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results: Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion: These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.


Subject(s)
Carotid Intima-Media Thickness , Non-alcoholic Fatty Liver Disease , Severity of Illness Index , Vasa Vasorum , Humans , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/complications , Male , Female , Vasa Vasorum/pathology , Cross-Sectional Studies , Middle Aged , Adult , Adventitia/pathology , Atherosclerosis/pathology , Obesity/pathology , Obesity/complications
7.
Front Endocrinol (Lausanne) ; 15: 1388361, 2024.
Article in English | MEDLINE | ID: mdl-38745946

ABSTRACT

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.


Subject(s)
Disease Models, Animal , Metabolic Syndrome , Obesity , Rats, Sprague-Dawley , Tacrolimus , Animals , Tacrolimus/pharmacology , Metabolic Syndrome/metabolism , Metabolic Syndrome/pathology , Metabolic Syndrome/chemically induced , Obesity/metabolism , Obesity/pathology , Rats , Male , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacology , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Insulin-Secreting Cells/drug effects , Phenotype , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/metabolism , Insulin Resistance , Diet, High-Fat/adverse effects
8.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167258, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38788910

ABSTRACT

The increasing prevalence of obesity, type 2 diabetes mellitus (T2DM), and gestational diabetes (GDM) among pregnant women has risen dramatically worldwide. The antihyperglycemic drug metformin is the most common drug for T2DM treatment in non-pregnant individuals; nevertheless, it is increasingly being used for diabetes-complicated pregnancies. Studies on the long-term metabolic effects of this drug in offspring remain scarce. This work aimed to determine the effect of metformin exposure during pregnancy and lactation on the offspring of a model of diet-induced maternal hyperglycemia. Cohorts of pregnant mice were fed a 46% fat diet (HFD) or a control standard diet (SD). A group of dams were exposed to metformin during pregnancy and lactation. After weaning, the offspring were fed SD for 8 weeks and then challenged with a 46% HFD after puberty for 12 weeks. Irrespective of the maternal diet, offspring of metformin-exposed mothers had a lower body weight and reduced inguinal white adipose tissue (iWAT) mass after HFD challenge. This was associated with increased expression of Pparg, Fabp4, Glut4, Srebp1, and Fasn in the iWAT during adulthood in the metabolically impaired dams exposed to metformin, suggesting increased adipogenesis and de novo lipogenesis. Increased expression of Fasn associated with decreased methylation levels at its promoter and proximal coding region in the iWAT was found. These results suggest that metformin modulates gene expression levels by epigenetic mechanisms in maternal metabolic-impaired conditions.


Subject(s)
Body Weight , Diet, High-Fat , Lactation , Metformin , Prenatal Exposure Delayed Effects , Sterol Regulatory Element Binding Protein 1 , Animals , Metformin/pharmacology , Female , Pregnancy , Lactation/drug effects , Mice , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/chemically induced , Diet, High-Fat/adverse effects , Body Weight/drug effects , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 1/genetics , PPAR gamma/metabolism , PPAR gamma/genetics , Glucose Transporter Type 4/metabolism , Glucose Transporter Type 4/genetics , Hypoglycemic Agents/pharmacology , Adipose Tissue, White/metabolism , Adipose Tissue, White/drug effects , Obesity/metabolism , Obesity/pathology , Obesity/chemically induced , Fatty Acid Synthase, Type I/metabolism , Fatty Acid Synthase, Type I/genetics , Male , Mice, Inbred C57BL , Adipose Tissue/metabolism , Adipose Tissue/drug effects , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/chemically induced
9.
Curr Opin Hematol ; 31(4): 163-167, 2024 07 01.
Article in English | MEDLINE | ID: mdl-38723188

ABSTRACT

PURPOSE OF REVIEW: The repair of bone after injury requires the participation of many different immune cell populations, which are derived from the hematopoietic lineage. The field of osteoimmunology, or the study of the interactions between bone and the immune system, is a growing field with emerging impact on both the basic science and clinical aspects of fracture healing. RECENT FINDINGS: Despite previous focus on the innate immune system in fracture healing, recent studies have revealed an important role for the adaptive immune system in bone repair. The composition of adaptive and innate immune cell populations present at the fracture site is significantly altered during aging and diet-induced obesity, which may contribute to delayed healing. Recent data also suggest a complicated relationship between fracture repair and systemic inflammation, raising the possibility that immune populations from distant sites such as the gut can impact the bone repair process. SUMMARY: These findings have important implications for the treatment of fracture patients with antibiotics or anti-inflammatory drugs. Furthermore, the effects of systemic inflammation on fracture repair in the contexts of aging or obesity should be carefully interpreted, as they may not be uniformly detrimental.


Subject(s)
Fracture Healing , Hematopoiesis , Humans , Animals , Inflammation/metabolism , Inflammation/pathology , Bone and Bones/metabolism , Bone and Bones/pathology , Fractures, Bone/therapy , Fractures, Bone/metabolism , Fractures, Bone/pathology , Obesity/metabolism , Obesity/pathology
10.
Cell Signal ; 120: 111229, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38763181

ABSTRACT

Obesity is one of the major risk factors for diabetes. Excessive accumulation of fat leads to inflammation of adipose tissue, which can increase the risk of developing diabetes. Obesity-related chronic inflammation can result in anomalies in glucose-lipid metabolism and insulin resistance, and it is a major cause of ß-cell dysfunction in diabetes mellitus. Thus, a long-term tissue inflammatory response is crucial for metabolic diseases, particularly type 2 diabetes. Chronic inflammation associated with obesity increases oxidative stress, secretes inflammatory factors, modifies endocrine variables, and interferes with insulin signalling pathways, all of which contribute to insulin resistance and glucose tolerance. Insulin resistance and diabetes are ultimately caused by chronic inflammation in the stomach, pancreas, liver, muscle, and fat tissues. In this article, we systematically summarize the latest research progress on the mechanisms of adipose tissue inflammation and insulin resistance, as well as the mechanisms of cross-talk between adipose tissue inflammation and insulin resistance, with a view to providing some meaningful therapeutic strategies for the treatment of insulin resistance by controlling adipose tissue inflammation.


Subject(s)
Adipose Tissue , Inflammation , Insulin Resistance , Obesity , Humans , Adipose Tissue/metabolism , Inflammation/metabolism , Inflammation/pathology , Animals , Obesity/metabolism , Obesity/pathology , Obesity/complications , Diabetes Mellitus, Type 2/metabolism , Signal Transduction
11.
Cell Rep ; 43(5): 114240, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38753486

ABSTRACT

Adipose tissue remodeling and dysfunction, characterized by elevated inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2D) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here, we describe the functions of linc-ADAIN (adipose anti-inflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans. We demonstrate that linc-ADAIN knockdown (KD) increases KLF5 and interleukin-8 (IL-8) mRNA stability and translation by interacting with IGF2BP2. Upregulation of KLF5 and IL-8, via linc-ADAIN KD, leads to an enhanced adipogenic program and adipose tissue inflammation, mirroring the obese state, in vitro and in vivo. KD of linc-ADAIN in human adipose stromal cell (ASC) hTERT adipocytes implanted into mice increases adipocyte size and macrophage infiltration compared to implanted control adipocytes, mimicking hallmark features of obesity-induced adipose tissue remodeling. linc-ADAIN is an anti-inflammatory lincRNA that limits adipose tissue expansion and lipid storage.


Subject(s)
Adipogenesis , Interleukin-8 , Kruppel-Like Transcription Factors , RNA Stability , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Adipogenesis/genetics , Animals , RNA Stability/genetics , Interleukin-8/metabolism , Interleukin-8/genetics , Mice , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Adipocytes/metabolism , Adipose Tissue/metabolism , Obesity/metabolism , Obesity/genetics , Obesity/pathology , RNA, Messenger/metabolism , RNA, Messenger/genetics , Male , Inflammation/pathology , Inflammation/genetics , Inflammation/metabolism
12.
Nat Commun ; 15(1): 3769, 2024 May 04.
Article in English | MEDLINE | ID: mdl-38704393

ABSTRACT

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.


Subject(s)
Adipocytes , Bone Marrow , Leptin , Osteogenesis , Receptors, Estrogen , Animals , Osteogenesis/genetics , Adipocytes/metabolism , Adipocytes/cytology , Mice , Leptin/metabolism , Leptin/genetics , Bone Marrow/metabolism , Receptors, Estrogen/metabolism , Receptors, Estrogen/genetics , Mesenchymal Stem Cells/metabolism , Obesity/metabolism , Obesity/pathology , Obesity/genetics , ERRalpha Estrogen-Related Receptor , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/genetics , Female , Male , Mice, Inbred C57BL , Signal Transduction , Bone Marrow Cells/metabolism , Mice, Knockout
13.
Arch Biochem Biophys ; 757: 110029, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38729594

ABSTRACT

Endothelial cells play an important role in the metabolism of adipose tissue (AT). This study aimed to analyze the changes that adipose tissue in AT endothelial cells undergo during the development of obesity, using single-nucleus RNA sequence (snRNA-seq). Mouse paraepididymal AT cells were subjected to snRNA-seq with the 10X Genomics platform. The cell types were then clustered using t-distributed stochastic neighbor embedding and unbiased computational informatics analyses. Protein-protein interactions network was established using the STRING database and visualized using Cytoscape. The dataset was subjected to differential gene enrichment analysis. In total, 21,333 cells acquired from 24 mouse paraepididymal AT samples were analyzed using snRNA-seq. This study identified 18 distinct clusters and annotated macrophages, fibroblasts, epithelial cells, T cells, endothelial cells, stem cells, neutrophil cells, and neutrophil cell types based on representative markers. Cluster 12 was defined as endothelial cells. The proportion of endothelial cells decreased with the development of obesity. Inflammatory factors, such as Vegfa and Prdm16 were upregulated in the medium obesity group but downregulated in the obesity group. Genes, such as Prox1, Erg, Flt4, Kdr, Flt1, and Pecam1 promoted the proliferation of AT endothelial cells and maintained the internal environment of AT. This study established a reference model and general framework for studying the mechanisms, biomarkers, and therapeutic targets of endothelial cell dysfunction-related diseases at the single-cell level.


Subject(s)
Adipose Tissue , Cell Proliferation , Endothelial Cells , Gene Expression Profiling , Gene Regulatory Networks , Obesity , Animals , Mice , Endothelial Cells/metabolism , Obesity/genetics , Obesity/metabolism , Obesity/pathology , Adipose Tissue/metabolism , Adipose Tissue/cytology , Male , Mice, Inbred C57BL , Transcriptome , Single-Cell Analysis
14.
Biochem Pharmacol ; 225: 116324, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38815633

ABSTRACT

Obesity is characterized by adipose tissue expansion, extracellular matrix remodelling and unresolved inflammation that contribute to insulin resistance and fibrosis. Adipose tissue macrophages represent the most abundant class of immune cells in adipose tissue inflammation and could be key mediators of adipocyte dysfunction and fibrosis in obesity. Although macrophage activation states are classically defined by the M1/M2 polarization nomenclature, novel studies have revealed a more complex range of macrophage phenotypes in response to external condition or the surrounding microenvironment. Here, we discuss the plasticity of adipose tissue macrophages (ATMs) in response to their microenvironment in obesity, with special focus on macrophage infiltration and polarization, and their contribution to adipose tissue fibrosis. A better understanding of the role of ATMs as regulators of adipose tissue remodelling may provide novel therapeutic strategies against obesity and associated metabolic diseases.


Subject(s)
Adipose Tissue , Fibrosis , Macrophages , Obesity , Humans , Obesity/metabolism , Obesity/pathology , Obesity/immunology , Macrophages/metabolism , Macrophages/immunology , Macrophages/pathology , Macrophages/physiology , Adipose Tissue/metabolism , Adipose Tissue/pathology , Adipose Tissue/immunology , Animals
15.
Free Radic Biol Med ; 221: 155-168, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-38777204

ABSTRACT

Transient receptor potential vanilloid (TRPV) ion channels play a crucial role in various cellular functions by regulating intracellular Ca2+ levels and have been extensively studied in the context of several metabolic diseases. However, the regulatory effects of TRPV3 in obesity and lipolysis are not well understood. In this study, utilizing a TRPV3 gain-of-function mouse model (TRPV3G568V/G568V), we assessed the metabolic phenotype of both TRPV3G568V/G568V mice and their control littermates, which were randomly assigned to either a 12-week high-fat diet or a control diet. We investigated the potential mechanisms underlying the role of TRPV3 in restraining obesity and promoting lipolysis both in vivo and in vitro. Our findings indicate that a high-fat diet led to significant obesity, characterized by increased epididymal and inguinal white adipose tissue weight and higher fat mass. However, the gain-of-function mutation in TRPV3 appeared to counteract these adverse effects by enhancing lipolysis in visceral fat through the upregulation of the major lipolytic enzyme, adipocyte triglyceride lipase (ATGL). In vitro experiments using carvacrol, a TRPV3 agonist, demonstrated the promotion of lipolysis and antioxidation in 3T3-L1 adipocytes after TRPV3 activation. Notably, carvacrol failed to stimulate Ca2+ influx, lipolysis, and antioxidation in 3T3-L1 adipocytes treated with BAPTA-AM, a cell-permeable calcium chelator. Our results revealed that TRPV3 activation induced the action of transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of ferroptosis suppressor protein 1 (FSP1) and superoxide dismutase2 (SOD2). Moreover, the inhibition of NRF2 impeded carvacrol-induced lipolysis and antioxidation in 3T3-L1 adipocytes, with downregulation of ATGL, FSP1, and SOD2. In summary, our study suggests that TRPV3 promotes visceral fat lipolysis and inhibits diet-induced obesity through the activation of the NRF2/FSP1 signaling axis. We propose that TRPV3 may be a potential therapeutic target in the treatment of obesity.


Subject(s)
Diet, High-Fat , Lipolysis , NF-E2-Related Factor 2 , Obesity , Signal Transduction , TRPV Cation Channels , Animals , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , TRPV Cation Channels/metabolism , TRPV Cation Channels/genetics , Obesity/metabolism , Obesity/genetics , Obesity/pathology , Obesity/etiology , Mice , Diet, High-Fat/adverse effects , Male , Lipase/metabolism , Lipase/genetics , Adipocytes/metabolism , Adipocytes/pathology , Mice, Inbred C57BL , 3T3-L1 Cells , Gain of Function Mutation , Acyltransferases
16.
Sci Adv ; 10(20): eadn2867, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38758794

ABSTRACT

Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.


Subject(s)
Macrophages , Mitochondria , Organelle Biogenesis , Phosphoglycerate Dehydrogenase , Reactive Oxygen Species , Serine , Macrophages/metabolism , Animals , Mitochondria/metabolism , Phosphoglycerate Dehydrogenase/metabolism , Phosphoglycerate Dehydrogenase/genetics , Serine/metabolism , Mice , Reactive Oxygen Species/metabolism , Signal Transduction , Mice, Knockout , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Inflammation/metabolism , Inflammation/pathology , Obesity/metabolism , Obesity/pathology , Obesity/genetics , Mice, Inbred C57BL
17.
Invest Ophthalmol Vis Sci ; 65(5): 11, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38709524

ABSTRACT

Purpose: The corneal epithelium is the most highly innervated structure in the body. Previously, we reported a novel event whereby stromal axons fuse with basal epithelial cells, limiting nerve penetration into the epithelium. Although corneal-epithelial nerves undergo changes in sensitivity and distribution throughout life and in response to an obesogenic diet, it is unknown if neuronal-epithelial cell fusion is altered. Here, we sought to determine if neuronal-epithelial cell fusion frequency correlates with obesogenic diet consumption and age. Methods: Corneas were collected from C57BL/6 mice and evaluated for neuronal-epithelial cell fusion frequency using serial block-face scanning electron microscopy. To assess the correlation between diet-induced obesity and fusion frequency, 6-week-old mice were fed either a normal diet or an obesogenic diet for 10 weeks. To assess changes in fusion frequency between young and adult mice under normal dietary conditions, 9- and 24-week-old mice were used. Results: Mice fed a 10-week obesogenic diet showed 87% of central-cornea stromal nerves engaged in fusion compared with only 54% in age-matched controls (16 weeks old). In 9-week-old normal-diet animals, 48% of central-cornea stromal nerves contained fusing axons and increased to 81% at 24 weeks of age. Corneal sensitivity loss correlated with increased body weight and adiposity regardless of age and diet. Conclusions: Neuronal-epithelial cell fusion positively correlates with age and obesogenic diet consumption, and corneal nerve sensitivity loss correlates with increased body weight and adiposity, regardless of age and diet. As such, neuronal-epithelial cell fusion may play a role in corneal nerve density and sensitivity regulation.


Subject(s)
Corneal Stroma , Epithelium, Corneal , Mice, Inbred C57BL , Microscopy, Electron, Scanning , Obesity , Animals , Obesity/pathology , Mice , Epithelium, Corneal/pathology , Corneal Stroma/innervation , Corneal Stroma/pathology , Aging/physiology , Male , Disease Models, Animal , Cornea/innervation , Diet, High-Fat/adverse effects
18.
Cells ; 13(9)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38727299

ABSTRACT

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.


Subject(s)
Adipogenesis , Adipose Tissue, White , Aging , Obesity , Humans , Aging/pathology , Obesity/pathology , Obesity/metabolism , Adipose Tissue, White/metabolism , Adipose Tissue, White/pathology , Animals , Adipocytes/metabolism , Adipocytes/pathology
19.
Nat Commun ; 15(1): 3982, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38729945

ABSTRACT

The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.


Subject(s)
Endoplasmic Reticulum , Fasting , Hepatocytes , Liver , Obesity , Fasting/metabolism , Endoplasmic Reticulum/metabolism , Animals , Hepatocytes/metabolism , Obesity/metabolism , Obesity/pathology , Liver/metabolism , Mice , Male , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondria, Liver/metabolism , Mitochondria, Liver/ultrastructure , Fatty Acids/metabolism , Humans , Oxidation-Reduction , Ribosomal Proteins/metabolism
20.
Proc Natl Acad Sci U S A ; 121(20): e2306776121, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38709933

ABSTRACT

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.


Subject(s)
Breast Neoplasms , Cell Differentiation , Diet, High-Fat , Disease Progression , Gastrointestinal Microbiome , Leucine , Myeloid-Derived Suppressor Cells , Animals , Diet, High-Fat/adverse effects , Leucine/metabolism , Female , Humans , Mice , Myeloid-Derived Suppressor Cells/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/microbiology , Breast Neoplasms/metabolism , Obesity/microbiology , Obesity/metabolism , Obesity/pathology , Cell Line, Tumor
SELECTION OF CITATIONS
SEARCH DETAIL
...