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1.
Cell Metab ; 36(4): 745-761.e5, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38569471

RESUMO

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).


Assuntos
Doenças Cardiovasculares , Resistência à Insulina , Síndrome Metabólica , Obesidade Metabolicamente Benigna , Adulto , Humanos , Obesidade/metabolismo , Triglicerídeos , Síndrome Metabólica/metabolismo , Índice de Massa Corporal , Fatores de Risco
2.
Front Immunol ; 15: 1335651, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38566998

RESUMO

Regulatory T cells (Tregs) residing in visceral adipose tissue (VAT) play a pivotal role in regulating tissue inflammation and metabolic dysfunction associated with obesity. However, the specific phenotypic and functional characteristics of Tregs in obese VAT, as well as the regulatory mechanisms shaping them, remain elusive. This study demonstrates that obesity selectively reduces Tregs in VAT, characterized by restrained proliferation, heightened PD-1 expression, and diminished ST2 expression. Additionally, obese VAT displays distinctive maturation of dendritic cells (DCs), marked by elevated expressions of MHC-II, CD86, and PD-L1, which are inversely correlated with VAT Tregs. In an in vitro co-culture experiment, only obese VAT DCs, not macrophages or DCs from subcutaneous adipose tissue (SAT) and spleen, result in decreased Treg differentiation and proliferation. Furthermore, Tregs differentiated by obese VAT DCs exhibit distinct characteristics resembling those of Tregs in obese VAT, such as reduced ST2 and IL-10 expression. Mechanistically, obesity lowers IL-33 production in VAT DCs, contributing to the diminished Treg differentiation. These findings collectively underscore the critical role of VAT DCs in modulating Treg generation and shaping Treg phenotype and function during obesity, potentially contributing to the regulation of VAT Treg populations.


Assuntos
Interleucina-33 , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/metabolismo , Interleucina-33/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Obesidade/metabolismo , Células Dendríticas/metabolismo
3.
Sci Rep ; 14(1): 8070, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580672

RESUMO

Obesity is associated with increased ovarian inflammation and the establishment of leptin resistance. We presently investigated the role of impaired leptin signalling on transcriptional regulation in granulosa cells (GCs) collected from genetically obese mice. Furthermore, we characterised the association between ovarian leptin signalling, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and macrophage infiltration in obese mice. After phenotype characterisation, ovaries were collected from distinct group of animals for protein and mRNA expression analysis: (i) mice subjected to a diet-induced obesity (DIO) protocol, where one group was fed a high-fat diet (HFD) and another a standard chow diet (CD) for durations of 4 or 16 weeks; (ii) mice genetically deficient in the long isoform of the leptin receptor (ObRb; db/db); (iii) mice genetically deficient in leptin (ob/ob); and (iv) mice rendered pharmacologically hyperleptinemic (LEPT). Next, GCs from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Transcriptional analysis revealed opposing profiles in genes associated with steroidogenesis and prostaglandin action between the genetic models, despite the similarities in body weight. Furthermore, we observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice or in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob and 16-wk HFD-fed mice. We concluded that leptin signalling regulates NLRP3 inflammasome activation and the expression of M1 markers in the ovaries of obese mice in an ObRb-dependent and ObRb-independent manner. Furthermore, we found no changes in the expression of leptin signalling and NLRP3 inflammasome genes in GCs from db/db and ob/ob mice, which was associated with no effects on macrophage infiltration genes, despite the dysregulation of genes associated with steroidogenesis in homozygous obese db/db. Our results suggest that: (i) the crosstalk between leptin signalling, NLRP3 inflammasome and macrophage infiltration takes place in ovarian components other than the GC compartment; and (ii) transcriptional changes in GCs from homozygous obese ob/ob mice suggest structural rearrangement and organisation, whereas in db/db mice the impairment in steroidogenesis and secretory activity.


Assuntos
Inflamassomos , Leptina , Feminino , Camundongos , Animais , Leptina/metabolismo , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Camundongos Obesos , Proteínas NLR , Obesidade/metabolismo , Células da Granulosa/metabolismo , RNA Mensageiro , Camundongos Endogâmicos C57BL , Receptores para Leptina/genética
4.
Nutr Diabetes ; 14(1): 12, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570479

RESUMO

BACKGROUND & AIMS: Some studies have reported links between 25-hydroxyvitamin D levels and the presence of obesity and some genetic variants. The aim of our design was to evaluate the effects of rs2282679 genetic variant of CG gene on 25-hydroxyvitamin D levels, weight loss and metabolic parameters after a robotic sleeve gastrectomy in premenopausal females with obesity. METHODS: 76 participants were enrolled. 25-hydroxyvitamin D levels, biochemical evaluation and anthropometric parameters were registered before surgery and after 3, 6 and 12 months follow up. Genotype of rs2282679 CG gene was evaluated. RESULTS: The improvements in anthropometric parameters, blood pressure and lipid profile were similar in both genotypes (TT vs TG + GG). Basal insulin levels and HOMA-IR were greater in G allele carriers than non-carriers (Delta: 6.7 ± 1.2 mUI/L; p = 0.01) and (Delta: 1.3 ± 0.1 units; p = 0.02). 25-hydroxyvitamin D levels were lower in G allele carriers than non-carriers (Delta: 8.1 ± 1.1 ng/dl; p = 0.03). The levels of insulin and HOMA-IR remained greater in G allele carriers than non-carriers throughout all the visits. The levels of 25-hydroxyvitamin D remained lower in G allele carriers than non-G allele. The average level of 25-hydroxyvitamin D at 12 months in non-G allele carriers were above 30 ng/dl (36.0 ± 3.1 ng/dl) and the level in G allele carriers were below (24.9 ± 4.9 ng/dl). CONCLUSIONS: rs 2282679 (GC) was related with low 25 hydroxyvitamin D levels and insulin resistance. In addition, the presence of G allele produced a decrease in the improvement of 25-hydroxyvitamin D levels and insulin resistance after weight loss during 12 months.


Assuntos
Resistência à Insulina , Vitamina D/análogos & derivados , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Obesidade/metabolismo , Insulina , Redução de Peso
5.
Cell Metab ; 36(4): 857-876.e10, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38569472

RESUMO

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.


Assuntos
Leptina , Obesidade , Animais , Camundongos , Desacetilase 6 de Histona , Leptina/metabolismo , Obesidade/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Aumento de Peso , Redução de Peso
6.
Sci Rep ; 14(1): 7844, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570726

RESUMO

Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.


Assuntos
Doenças Metabólicas , Receptores de Glucocorticoides , Camundongos , Animais , Humanos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Proteína Relacionada com Agouti/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo
7.
Front Endocrinol (Lausanne) ; 15: 1344262, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38559696

RESUMO

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.


Assuntos
Hippophae , Morus , Ratos , Animais , PPAR gama/genética , PPAR gama/metabolismo , Hippophae/metabolismo , Morus/metabolismo , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Transdução de Sinais , Redução de Peso
8.
Front Endocrinol (Lausanne) ; 15: 1348853, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562410

RESUMO

Introduction: Obesity, prevalent in approximately 80% of Qatar's adult population, increases the risk of complications like type 2 diabetes and cardiovascular diseases. Predictive biomarkers are crucial for preventive strategies. Salivary α-amylase activity (sAAa) inversely correlates with obesity and insulin resistance in adults and children. However, the connection between sAAa and cardiometabolic risk factors or chronic low-grade inflammation markers remains unclear. This study explores the association between serum sAAa and adiposity markers related to cardiovascular diseases, as well as markers indicative of chronic low-grade inflammation. Methods: Serum samples and clinical data of 1500 adult, non-diabetic, Overweight/Obese participants were obtained from Qatar Biobank (QBB). We quantified sAAa and C reactive protein (CRP) levels with an autoanalyzer. Cytokines, adipokines, and adiponectin of a subset of 228 samples were quantified using a bead-based multiplex assay. The associations between the sAAa and the adiposity indices and low-grade inflammatory protein CRP and multiple cytokines were assessed using Pearson's correlation and adjusted linear regression. Results: The mean age of the participants was 36 ± 10 years for both sexes of which 76.6% are women. Our analysis revealed a significant linear association between sAAa and adiposity-associated biomarkers, including body mass index ß -0.032 [95% CI -0.049 to -0.05], waist circumference ß -0.05 [95% CI -0.09 to -0.02], hip circumference ß -0.052 [95% CI -0.087 to -0.017], and HDL ß 0.002 [95% CI 0.001 to 0.004], albeit only in women. Additionally, sAAa demonstrated a significant positive association with adiponectin ß 0.007 [95% CI 0.001 to 0.01]while concurrently displaying significant negative associations with CRP ß -0.02 [95% CI -0.044 to -0.0001], TNF-α ß -0.105 [95% CI -0.207 to -0.004], IL-6 ß [95% CI -0.39 -0.75 to -0.04], and ghrelin ß -5.95 [95% CI -11.71 to -0.20], specifically within the female population. Conclusion: Our findings delineate significant associations between sAAa and markers indicative of cardiovascular disease risk and inflammation among overweight/obese adult Qatari females. Subsequent investigations are warranted to elucidate the nuances of these gender-specific associations comprehensively.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , alfa-Amilases Salivares , Masculino , Adulto , Criança , Humanos , Feminino , Pessoa de Meia-Idade , Sobrepeso , Adiponectina , Diabetes Mellitus Tipo 2/complicações , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações , Obesidade/metabolismo , Biomarcadores , Inflamação/metabolismo , Citocinas
9.
Physiol Rep ; 12(7): e15995, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38561245

RESUMO

Exercise has different effects on different tissues in the body, the sum of which may determine the response to exercise and the health benefits. In the present study, we aimed to investigate whether physical training regulates transcriptional network communites common to both skeletal muscle (SM) and subcutaneous adipose tissue (SAT). Eight such shared transcriptional communities were found in both tissues. Eighteen young overweight adults voluntarily participated in 7 weeks of combined strength and endurance training (five training sessions per week). Biopsies were taken from SM and SAT before and after training. Five of the network communities were regulated by training in SM but showed no change in SAT. One community involved in insulin- AMPK signaling and glucose utilization was upregulated in SM but downregulated in SAT. This diverging exercise regulation was confirmed in two independent studies and was also associated with BMI and diabetes in an independent cohort. Thus, the current finding is consistent with the differential responses of different tissues and suggests that body composition may influence the observed individual whole-body metabolic response to exercise training and help explain the observed attenuated whole-body insulin sensitivity after exercise training, even if it has significant effects on the exercising muscle.


Assuntos
Resistência à Insulina , Obesidade , Adulto , Humanos , Obesidade/metabolismo , Músculo Esquelético/metabolismo , Exercício Físico/fisiologia , Gordura Subcutânea/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Expressão Gênica , Tecido Adiposo/metabolismo
10.
Physiol Rep ; 12(7): e15987, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38561248

RESUMO

Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.4 ± 2.5 years, 37.8 ± 1.5 kg/m2, ~1200 kcal/d) or LCD + INT (n = 11, 47.6 ± 4.3 years, 37.9 ± 2.3 kg/m2; 60 min/d supervised INT of 3 min 90% & 50% HRpeak). TCAi and amino acids (AA) were measured at 0 min of a 75 g OGTT, while glucose, insulin, and FFA were obtained at 0, 30, 60, 90, 120, and 180 min to assess total area under the curve (tAUC180min) and insulin resistance (IR; tAUC180min of Glucose × Insulin). Fuel use (indirect calorimetry) was also collected at 0, 60, 120, and 180 min as was fitness (VO2peak) and body composition (BodPod). Treatments reduced weight (p < 0.001), fasting RER (p = 0.01), and IR (p = 0.03), although LCD + INT increased VO2peak (p = 0.02) and maintained RER tAUC180min (p = 0.05) versus LCD. Treatments increased FFA tAUC180min (p = 0.005), cis-aconitate, isocitrate, and succinate (p ≤ 0.02), as well as reduced phenylalanine and tryptophan, cysteine (p ≤ 0.005). However, LCD + INT increased malate, citrate, α-ketoglutarate, and alanine more than LCD (p ≤ 0.04). Thus, INT enhanced LCD effects on some TCAi in women with obesity independent of IR.


Assuntos
Resistência à Insulina , Humanos , Feminino , Restrição Calórica , Obesidade/metabolismo , Glucose/metabolismo , Insulina
11.
Nat Commun ; 15(1): 2825, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561362

RESUMO

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.


Assuntos
Dioxigenases , Leptina , Animais , Humanos , Masculino , Camundongos , Adipócitos/metabolismo , Peso Corporal , Dioxigenases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Retroalimentação , Leptina/metabolismo , Mamíferos/metabolismo , Obesidade/genética , Obesidade/metabolismo
12.
JCI Insight ; 9(7)2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38587078

RESUMO

Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Ácidos e Sais Biliares , Colesterol/metabolismo , Glucose , Obesidade/metabolismo
13.
Proc Natl Acad Sci U S A ; 121(16): e2318935121, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38588421

RESUMO

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.


Assuntos
Tecido Adiposo Marrom , Glucose , Camundongos , Humanos , Animais , Glucose/metabolismo , Tecido Adiposo Marrom/metabolismo , Acetilação , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Obesidade/genética , Obesidade/metabolismo , Termogênese/genética , Camundongos Endogâmicos C57BL , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo
14.
Front Endocrinol (Lausanne) ; 15: 1333778, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38596222

RESUMO

There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Adolescente , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/complicações , Qualidade de Vida , Obesidade/metabolismo
15.
Cell Signal ; 118: 111140, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38492625

RESUMO

The gut microbiome, a crucial component of the human system, is a diverse collection of microbes that belong to the gut of human beings as well as other animals. These microbial communities continue to coexist harmoniously with their host organisms and perform various functions that affect the host's general health. Each person's gut microbiota has a unique makeup. The gut microbiota is well acknowledged to have a part in the local as well as systemic inflammation that underlies a number of inflammatory disorders (e.g., atherosclerosis, diabetes mellitus, obesity, and inflammatory bowel disease).The gut microbiota's metabolic products, such as short-chain fatty acids (butyrate, propionate, and acetate) inhibit inflammation by preventing immune system cells like macrophages and neutrophils from producing pro-inflammatory factors, which are triggered by the structural elements of bacteria (like lipopolysaccharide). The review's primary goal is to provide comprehensive and compiled data regarding the contribution of gut microbiota to inflammation and the associated signalling pathways.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Humanos , Inflamação/metabolismo , Sistema Imunitário , Obesidade/metabolismo
16.
Vopr Pitan ; 93(1): 44-60, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38555609

RESUMO

Interest to the tissue-specific intestinal isoenzyme of alkaline phosphatase (IAP) has increased in recent years due to eating disorders that have led to widespread obesity and diet-related diseases. Obesity is considered as an inflammation of low intensity, which is accompanied by the manifestation of various metabolic complications and a disturbance of intestinal homeostasis. IAP is one of the participants in the mechanism of the macroorganism protection against inflammatory and infectious processes, carrying out enzymatic detoxification of bacterial lipopolysaccharide (the trigger of the inflammatory process). Deficiency of IAP activity contributes to the risk of obesity, inflammatory diseases. The objective of the research was to summarize the current understanding of the role of IAP involved in the molecular mechanism of diet-induced obesity and to evaluate the impact of dietary components - fats and dietary fiber on IAP activity. Material and methods. A literature search on the role of IAP in the development of obesity was carried out using PubMed, Scopus, Web of Science, Google Scholar, ResearchGate, RSCI databases. Results. IAP prevents the development of the inflammatory process by participating in the detoxification of toxic bacterial products, limiting the translocation of pathogenic bacteria from the intestine to various tissues and organs of the macroorganism. The enzyme maintains the integrity of the intestinal barrier, influencing the synthesis and proper localization of tight junction's proteins between intestinal epithelial cells, promotes changes in the composition of the microbiota, decreasing pathogenic bacteria and increasing the population of the community of beneficial microorganisms. IAP is involved in the regulation of fatty acid absorption and influences on the adipogenesis. Monitoring the activity of IAP present in human stool can predict the early development of such complications associated with obesity as metabolic syndrome and diabetes mellitus, Some nutrients modulate IAP activity. Depending on the amount, type, composition of fats and the duration of their consumption, either an increase or decrease in the IAP activity are observed, while dietary fibers stimulate the activity of the enzyme. Conclusion. IAP activity can be considered as an early predictor of the risk of obesity. Deficiency of IAP activity contributes to the development of obesity caused by high-fat diet. The high activity of the enzyme contributes to the support of intestinal homeostasis and limits transepithelial movement of bacteria, weakening the inflammatory process induced by lipopolysaccharides, the excess concentration of which is detected in obesity. Stimulating enzyme activity through dietary intervention reduces the risk of obesity and metabolic complications.


Assuntos
Fosfatase Alcalina , Dieta Hiperlipídica , Humanos , Intestinos/microbiologia , Obesidade/metabolismo , Gorduras na Dieta , Isoenzimas/fisiologia , Fibras na Dieta
17.
Sci Rep ; 14(1): 7571, 2024 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-38555310

RESUMO

Obesity is a growing concern in human and equine populations, predisposing to metabolic pathologies and reproductive disturbances. Cellular lipid accumulation and mitochondrial dysfunction play an important role in the pathologic consequences of obesity, which may be mitigated by dietary interventions targeting these processes. We hypothesized that obesity in the mare promotes follicular lipid accumulation and altered mitochondrial function of oocytes and granulosa cells, potentially contributing to impaired fertility in this population. We also predicted that these effects could be mitigated by dietary supplementation with a combination of targeted nutrients to improve follicular cell metabolism. Twenty mares were grouped as: Normal Weight [NW, n = 6, body condition score (BCS) 5.7 ± 0.3], Obese (OB, n = 7, BCS 7.7 ± 0.2), and Obese Diet Supplemented (OBD, n = 7, BCS 7.7 ± 0.2), and fed specific feed regimens for ≥ 6 weeks before sampling. Granulosa cells, follicular fluid, and cumulus-oocyte complexes were collected from follicles ≥ 35 mm during estrus and after induction of maturation. Obesity promoted several mitochondrial metabolic disturbances in granulosa cells, reduced L-carnitine availability in the follicle, promoted lipid accumulation in cumulus cells and oocytes, and increased basal oocyte metabolism. Diet supplementation of a complex nutrient mixture mitigated most of the metabolic changes in the follicles of obese mares, resulting in parameters similar to NW mares. In conclusion, obesity disturbs the equine ovarian follicle by promoting lipid accumulation and altering mitochondrial function. These effects may be partially mitigated with targeted nutritional intervention, thereby potentially improving fertility outcomes in the obese female.


Assuntos
Oócitos , Folículo Ovariano , Humanos , Cavalos , Animais , Feminino , Folículo Ovariano/metabolismo , Oócitos/metabolismo , Líquido Folicular , Obesidade/metabolismo , Lipídeos , Suplementos Nutricionais
18.
Biomed Pharmacother ; 173: 116341, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428309

RESUMO

Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.


Assuntos
Dieta Hiperlipídica , Fígado , Masculino , Feminino , Camundongos , Animais , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Aumento de Peso , Obesidade/metabolismo , Inflamação/metabolismo , Camundongos Knockout
19.
Mol Metab ; 82: 101913, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38458567

RESUMO

OBJECTIVE: Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis. METHODS: To explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and 14C-malonyl CoA allowed us to measure de novo lipogenic activity in adipose tissue of these mice. In vitro cell culture models were used to elucidate the mechanism of cellular responses to PexRAP deletion. RESULTS: Adipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance. CONCLUSIONS: These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.


Assuntos
Resistência à Insulina , Lipogênese , Animais , Camundongos , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Tecido Adiposo/metabolismo , Colesterol/metabolismo , Gorduras na Dieta/metabolismo , Lipogênese/genética , Receptores X do Fígado/metabolismo , Camundongos Knockout , Obesidade/metabolismo
20.
J Diabetes Complications ; 38(4): 108706, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38490125

RESUMO

BACKGROUND: Adiponectin is one of the most important adipokines in human beings. Obesity and sarcopenia are associated with a low-level chronic inflammatory status, and adiponectin plays an anti-inflammatory role. AIMS: The objective of the current work was to study the association between muscle mass, determined via bioelectrical impedance (BIA), and circulating adiponectin levels among obese patients with metabolic syndrome who are older than 60 years of age. METHODS: We performed a cross-sectional study incorporating 651 patients with obesity and metabolic syndrome. Anthropometric data, BIA data (total fat mass (FM), fat-free mass (FFM), fat-free mass index (FFMi), skeletal muscle mass (SMM) and skeletal muscle mass index (SMMi)), arterial pressure, HOMA-IR (homeostasis model assessment of insulin resistance), and biochemical parameters were recorded. RESULTS: The patients were separated into two groups based on their median SMMi (skeletal muscle mass index) levels. The low-SMMi group presented adiponectin levels that were higher than those in the high-SMMi group (delta value: 4.8 + 0.7 ng/dl: p = 0.02). Serum adiponectin values were negatively correlated with fat mass (FM), fat-free mass (FFM), fat-free mass index (FFMi), SMM, and SMMi. Adiponectin presented a negative correlation with HOMA-IR and a positive correlation with HDL-cholesterol. In the final multivariate model using SMMi as a dependent variable, adiponectin levels explained 18 % of the variability (Beta -0.49, CI95% -0.89 to -0.16) after adjusting for age and gender. CONCLUSIONS: Serum adiponectin levels are negatively associated with low skeletal muscle mass among obese subjects with metabolic syndrome who are older than 60 years of age.


Assuntos
Adiponectina , Síndrome Metabólica , Obesidade , Humanos , Adiponectina/sangue , Índice de Massa Corporal , Estudos Transversais , Resistência à Insulina , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Músculo Esquelético/metabolismo , Obesidade/sangue , Obesidade/metabolismo
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