RESUMEN
Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.
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Tejido Adiposo , Macrófagos , Ratones , Humanos , Animales , Adipocitos , Inflamación , ObesidadRESUMEN
Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.
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Adiposidad/genética , Distribución de la Grasa Corporal , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Carácter Cuantitativo Heredable , Alelos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is an important driver of blood pressure (BP), but the association of the RAAS with ambulatory BP (ABP) and ABP monitoring phenotypes among African Americans has not been assessed. METHODS: ABP and ABP monitoring phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analyses were used to analyze the association of aldosterone and PRA with clinic, awake, and asleep systolic BP and diastolic BP (DBP) and ABP monitoring phenotypes, adjusting for important confounders. RESULTS: The mean age of participants was 59±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep systolic BP and DBP (all P<0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all P<0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (odds ratio [OR] 0.59 [95% CI, 0.49-0.71]), nocturnal hypertension (OR, 0.68 [95% CI, 0.58-0.79]), daytime and nocturnal hypertension (OR, 0.59 [95% CI, 0.48-0.71]), sustained hypertension (OR, 0.52 [95% CI, 0.39-0.70]), and masked hypertension (OR 0.75 [95% CI, 0.62-0.90]). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR, 1.38 [95% CI, 1.05-1.81]). Neither PRA nor aldosterone was associated with percent dipping, nondipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to patterns for PRA. CONCLUSIONS: Suppressed renin activity and higher aldosterone:renin ratios were associated with higher systolic BP and DBP in the office and during the awake and asleep periods as evidenced by ABP monitoring. Higher aldosterone levels were associated with higher DBP, but not systolic BP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in African Americans.
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Aldosterona/sangre , Presión Sanguínea/fisiología , Hipertensión/patología , Renina/sangre , Adulto , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Estudios Prospectivos , Sistema Renina-Angiotensina , Factores de Tiempo , Adulto JovenRESUMEN
Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4+ T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII-/-]) were created and metabolically characterized. FITC+ glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII-/- were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet-fed C57BL/6 mice. Unexpectedly, mMHCII-/- mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4+ T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8+ T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclusion, loss of either ATM or adipocyte APC function, but not both, improves systemic glucose metabolism because of maintenance of AT regulatory T cells.
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Adipocitos/inmunología , Tejido Adiposo/inmunología , Presentación de Antígeno , Glucosa/inmunología , Macrófagos/inmunología , Adipocitos/citología , Tejido Adiposo/citología , Animales , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Glucosa/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Macrófagos/citología , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Adipose tissue (AT) inflammation is linked to the development of type 2 diabetes (T2DM) and atherosclerosis in murine models of obesity. Reduced AT regulatory T cells (Tregs), which are anti-inflammatory immune cells, play an important part in this pathogenesis, and we have shown that AT-Tregs are inversely correlated to increasing body-mass-index. The purpose of this study was to evaluate the association between AT-Treg abundance and comorbidity status in patients undergoing bariatric surgery (BS). METHODS: Visceral (intra-abdominal) AT was harvested at that time of primary BS (n = 80) and collagenase digested. AT-Treg abundance (CD4+/CD25+/FOXP3+) was characterized using flow cytometry from the AT stromal vascular fraction. The median AT-Treg abundance (3.03%) was utilized to define high (High-Tregs, n = 39) and low AT-Treg (low-Tregs, n = 38) abundance within this cohort. These two groups were compared in terms of baseline demographic data, preoperative obesity-related comorbidities, glycemic parameters, including insulin resistance (HOMA-IR). RESULTS: Age, excess body weight, and sex were not different between groups. Prevalence of hypertension, hyperlipidemia, or T2DM preoperatively were not different between groups. Compared to High-Tregs, patients with low-Tregs were more likely to have insulin-dependent type 2 diabetes (12.5% vs 2.9%, p = 0.04). Within patients with T2DM, low-Treg patients had higher plasma insulin levels compared to high-Tregs (31.8 (28.4-56.5) vs 15.5 (10.1-23.1), p = 0.04) and trended towards higher insulin resistance (HOMA-IR) (9.0 (5.3-18.3) vs 3.5 (2.2-7.7), p = 0.08). Within those diagnosed with hyperlipidemia, preoperative statin use was higher in Low-Treg patients compared to the control cohort (91% vs 50%, p = 0.056). Low-Treg patients with hypertension were more likely to need 2 + anti-hypertensive agents preoperatively compared to their counterparts (71% vs 44%, p = 0.058). CONCLUSION: Within bariatric candidates, lower visceral AT-Treg abundance was associated with increased baseline medication requirements for type 2 diabetes, hypertension, and hyperlipidemia. This suggests that reduced AT-Tregs may be associated with higher obesity-related comorbidity severity.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Animales , Comorbilidad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Grasa Intraabdominal , Ratones , Linfocitos T ReguladoresRESUMEN
CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining homeostasis and preventing autoimmune diseases. Nonetheless, we and others have previously reported that natural Treg cells are unstable and dysfunctional in the inflamed environment with a high-salt diet, limiting the Treg function in disease control. In this study, we made an innovative observation showing a high degree of heterogeneity within the Treg pool. We identified that CD126, interleukin (IL)-6 receptor alpha chain, contributed to Treg cell instability. Using a series of in vitro and in vivo experimental approaches, we demonstrated that CD126Lo/- Treg cells presented greater function and were more stable than CD126Hi nTreg cells, even in the presence of IL-6 and inflammation. Blockade of programmed death-1 (PD-1) interrupted CD126Lo/- nTreg cell stability. Additionally, CD126Lo/- Treg cells can treat colitis and established collagen-induced arthritis, while the CD126Hi cell population failed to do this. Moreover, we noted that CD126 expression of Treg cells had a positive correlation to rheumatoid arthritis (RA) severity and the stability of Treg cells. Our results strongly suggest that the manipulation of CD126Lo/- nTreg cells could be a novel strategy for the treatment of autoimmune diseases and for other conditions associated with a deficit of Treg cells.
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Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Enfermedades Autoinmunes/terapia , Autoinmunidad , Biomarcadores , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Humanos , Inmunofenotipificación , Inmunoterapia/métodos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Obesity dramatically increases the risk of numerous conditions, including type 2 diabetes mellitus and other components of the metabolic syndrome. Pro-inflammatory changes that occur in adipose tissue are critical to the pathogenesis of these obesity-induced complications. Adipose tissue is one of the body's largest endocrine organs, and the cells that comprise the adipose tissue immunoenvironment secrete multiple factors (including adipokines and cytokines) that impact systemic metabolism. In particular, immunosuppressive regulatory T cells (Tregs) decline in obesity, partly in response to its complex interaction with adipocytes, and this decline contributes to disruption of the typical homeostasis observed in lean adipose tissue. Although the regulation of Treg differentiation, function, and enrichment is incompletely understood, factors including various cell-surface co-stimulatory molecules, certain lipid species, and cytokines such as PPARγ, adiponectin, and leptin are important mediators. It is also clear that there may be depot-specific differences in Tregs, rendering adipose tissue Tregs distinct from lymphoid or circulating Tregs, with implications on maintenance and functionality. While most of these findings are derived from studies in murine models, comparatively little is known about the human adipose tissue Treg signature, which requires further investigation.
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Diabetes Mellitus Tipo 2 , Linfocitos T Reguladores , Adipoquinas , Tejido Adiposo , Animales , Humanos , Inflamación , Ratones , ObesidadRESUMEN
OBJECTIVES: The incidence rates of acute pancreatitis (AP) and the prevalence of class III obesity, and metabolic syndrome (MetS) are increasing in the US. Since class III obesity was associated with adverse clinical outcomes of AP, we sought to understand if the presence of metabolic comorbidities collectively recognized, as MetS were associated with worse clinical outcomes and increased health-care utilization. METHODS: The Nationwide Readmissions Database (NRD) (2010-2014) was reviewed to identify all adult subjects with a principal discharge diagnosis of AP. Inpatient mortality, severe AP (SAP), and 30-day readmissions were the primary outcomes analyzed. Propensity score weighted analyses were used to compare AP subjects with and without MetS and were further stratified by class III obesity status. RESULTS: MetS was associated with 12.91% (139,165/1,078,183) of all admissions with AP. Propensity score weighted analyses showed that MetS was associated with an increased proportion of SAP (OR 1.21, 95% CI 1.17, 1.25), but decreased mortality (OR 0.62, 95% CI 0.54, 0.70) and 30-day readmissions (OR 0.86, 95% CI 0.83, 0.89). Propensity score weighted analyses also revealed that class III obesity was independently associated with increased mortality in AP subjects with (OR 1.92, 95% CI 1.41, 2.61) and without MetS (OR 1.55, 95% CI 1.26, 1.92), and increased SAP in subjects with and without MetS. CONCLUSIONS: Class III obesity appears to be the primary factor associated with adverse clinical outcomes in subjects with MetS admitted with AP. This has significant implications for patient management and future research targeting AP.
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Síndrome Metabólico/complicaciones , Obesidad Mórbida/complicaciones , Pancreatitis/complicaciones , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Comorbilidad , Bases de Datos Factuales , Femenino , Costos de Hospital , Mortalidad Hospitalaria , Humanos , Masculino , Síndrome Metabólico/mortalidad , Persona de Mediana Edad , Obesidad Mórbida/mortalidad , Pancreatitis/mortalidad , Readmisión del Paciente/estadística & datos numéricos , Puntaje de Propensión , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits. DESIGN/PATIENTS/MEASUREMENTS: In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD. RESULTS: Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (ß = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (ß = .22, P < .0001) and legs (ß = .17, P = .001) in women and pelvis (ß = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes. CONCLUSION: Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass.
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Densidad Ósea/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Absorciometría de Fotón , Adulto , Antropometría , Glucemia/metabolismo , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Homeostasis , Humanos , Insulina/metabolismo , Masculino , Análisis Multivariante , Adulto JovenRESUMEN
The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of ß-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating ß-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.
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Catecolaminas/metabolismo , Metabolismo Energético , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Temperatura Corporal , Células Cultivadas , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Grasas de la Dieta/farmacología , Metabolismo Energético/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Resistencia a la Insulina , Americanos Mexicanos/genética , Ratones , Obesidad/inducido químicamente , Obesidad/genética , Obesidad/metabolismo , Fosforilación , Proteínas RGS/biosíntesis , Proteínas RGS/genética , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/química , Factores de Transcripción/deficiencia , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).
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Anticolesterolemiantes/uso terapéutico , Atorvastatina/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Ezetimiba/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Simvastatina/uso terapéutico , Anciano , Glucemia/metabolismo , Presión Sanguínea , Proteína C-Reactiva/metabolismo , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/patología , Enfermedad Coronaria/sangre , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/patología , Método Doble Ciego , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipercolesterolemia/patología , Resistencia a la Insulina , Lipoproteínas HDL/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/complicaciones , Síndrome Metabólico/patología , Persona de Mediana Edad , Obesidad Abdominal/sangre , Obesidad Abdominal/complicaciones , Obesidad Abdominal/patología , Factores de Riesgo , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
In heart failure mitochondrial dysfunction is thought to be responsible for energy depletion and contractile dysfunction. The difficulties in procuring fresh left ventricular (LV) myocardium from humans for assessment of mitochondrial function have resulted in the reliance on surrogate markers of mitochondrial function and limited our understanding of cardiac energetics. We isolated mitochondria from fresh LV wall tissue of patients with heart failure and reduced systolic function undergoing heart transplant or left ventricular assist device placement, and compared their function to mitochondria isolated from the non-failing LV (NFLV) wall tissue with normal systolic function from patients with pulmonary hypertension undergoing heart-lung transplant. We performed detailed mitochondrial functional analyses using 4 substrates: glutamate-malate (GM), pyruvate-malate (PM) palmitoyl carnitine-malate (PC) and succinate. NFLV mitochondria showed preserved respiratory control ratios and electron chain integrity with only few differences for the 4 substrates. In contrast, HF mitochondria had greater respiration with GM, PM and PC substrates and higher electron chain capacity for PM than for PC. Surprisingly, HF mitochondria had greater respiratory control ratios and lower ADP-independent state 4 rates than NFLV mitochondria for GM, PM and PC substrates demonstrating that HF mitochondria are capable of coupled respiration ex vivo. Gene expression studies revealed decreased expression of key genes in pathways for oxidation of both fatty acids and glucose. Our results suggest that mitochondria from the failing LV myocardium are capable of tightly coupled respiration when isolated and supplied with ample substrates. Thus energy starvation in the failing heart may be the result of dysregulation of metabolic pathways, impaired substrate supply or reduced mitochondrial number but not the result of reduced mitochondrial electron transport capacity.
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Insuficiencia Cardíaca/metabolismo , Mitocondrias Cardíacas/metabolismo , Adulto , Antígenos CD36/genética , Antígenos CD36/metabolismo , Estudios de Casos y Controles , Respiración de la Célula , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Femenino , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Oxígeno/metabolismo , Transcriptoma , Adulto JovenRESUMEN
Obesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9 ΔIEC mice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9 ΔIEC mice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9 ΔIEC mice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9 ΔIEC . Transplantation of fecal materials from Sox9 ΔIEC mice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.
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Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic ß-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr-/-) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to ß-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on ß-cell identity and function. LDLr-/- mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin-glucagon colocalization, islet size and %ß-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %ß and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin-glucagon colocalization, and reduction in ß-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to ß-cell identity in LDLr-/- mice and offers intriguing clinical implications for countering metabolic syndrome.
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Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Células Secretoras de Insulina , Islotes Pancreáticos , Síndrome Metabólico , Animales , Ratones , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Glucagón/metabolismo , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Lipoproteínas LDL , Síndrome Metabólico/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Osteocalcina/metabolismo , Proinsulina/metabolismo , Aumento de PesoRESUMEN
Obesity is a global health crisis that contributes to morbidity and mortality worldwide. Obesity's comorbid association with a variety of diseases, from metabolic syndrome to neurodegenerative disease, underscores the critical need to better understand the pathobiology of obesity. Adipose tissue, once seen as an inert storage depot, is now recognized as an active endocrine organ, regulating metabolic and systemic homeostasis. Recent studies spotlight the theranostic utility of extracellular vesicles (EVs) as novel biomarkers and drivers of disease, including obesity-related complications. Adipose-derived EVs (ADEVs) have garnered increased interest for their roles in diverse diseases, however robust isolation and characterization protocols for human, cell-specific EV subsets are limited. Herein, we directly address this technical challenge by establishing a multiparametric analysis framework that leverages bulk and single EV characterization, mRNA phenotyping and proteomics of human ADEVs directly from paired visceral adipose tissue, cultured mature adipocyte conditioned media, and plasma from obese subjects undergoing bariatric surgery. Importantly, rigorous EV phenotyping at the tissue and cell-specific level identified top 'adipose liquid biopsy' candidates that were validated in circulating plasma EVs from the same patient. In summary, our study paves the way toward a tissue and cell-specific, multiparametric framework for studying tissue and circulating adipose EVs in obesity-driven disease.
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BACKGROUND: In the absence of a gold-standard diagnostic modality for cellulitis, sterile inflammatory disorders may be misdiagnosed as cellulitis. OBJECTIVE: To determine the utility of skin biopsy and tissue culture for the diagnosis and management of patients admitted with a diagnosis of presumed cellulitis. DESIGN: Pilot single-blind parallel group randomized controlled clinical trial in 56 patients with a primary diagnosis of presumed cellulitis. In the intervention group only, skin biopsy and tissue culture results were made available to the primary care team to guide diagnosis and management. Length of hospital stay and antibiotic use were evaluated as outcome measures. RESULTS: Length of stay showed the greatest opportunity for further study as a primary outcome (intervention: 4, IQR (2-6) vs. control: 5 IQR (3-8) days; p = 0.124). LIMITATIONS: The COVID-19 pandemic placed limitations on participant enrollment and study duration; in addition, data was collected from a single medical center. CONCLUSION: This study demonstrates that length of stay and anti-pseudomonal antibiotic de-escalation are endpoints that may be influenced by biopsy and tissue culture results in presumed cellulitis patients; these outcomes warrant further study.
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Antibacterianos , COVID-19 , Celulitis (Flemón) , Tiempo de Internación , Humanos , Celulitis (Flemón)/diagnóstico , Celulitis (Flemón)/tratamiento farmacológico , Celulitis (Flemón)/patología , Femenino , Masculino , Persona de Mediana Edad , Tiempo de Internación/estadística & datos numéricos , Biopsia , Proyectos Piloto , Antibacterianos/uso terapéutico , Método Simple Ciego , Adulto , Anciano , Piel/patología , Piel/microbiología , Técnicas de Cultivo de Tejidos , SARS-CoV-2 , Pacientes Internos/estadística & datos numéricosRESUMEN
T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.
Asunto(s)
Tejido Adiposo , Linfocitos T , Ratones , Animales , Linfocitos T/metabolismo , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Inflamación/patología , Células Madre/metabolismoRESUMEN
Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.
Asunto(s)
Dieta Alta en Grasa , Inflamación , Grasa Intraabdominal , Neutrófilos , Obesidad , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Animales , Obesidad/microbiología , Obesidad/inmunología , Humanos , Neutrófilos/inmunología , Dieta Alta en Grasa/efectos adversos , Ratones , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Microbioma Gastrointestinal/inmunología , Masculino , Ratones Endogámicos C57BL , Femenino , Heces/microbiología , Microbiota/inmunología , Células TH1/inmunología , Infiltración NeutrófilaRESUMEN
Circadian clocks in adipose tissue are known to regulate adipocyte biology. Although circadian dysregulation is associated with development of obesity, the underlying mechanism has not been established. Here we report that disruption of the clock gene, brain and muscle Arnt-like 1 (Bmal1), in mice led to increased adipogenesis, adipocyte hypertrophy, and obesity, compared to wild-type (WT) mice. This is due to its cell-autonomous effect, as Bmal1 deficiency in embryonic fibroblasts, as well as stable shRNA knockdown (KD) in 3T3-L1 preadipocyte and C3H10T1/2 mesenchymal stem cells, promoted adipogenic differentiation. We demonstrate that attenuation of Bmal1 function resulted in down-regulation of genes in the canonical Wnt pathway, known to suppress adipogenesis. Promoters of these genes (Wnt10a, ß-catenin, Dishevelled2, TCF3) displayed Bmal1 occupancy, indicating direct circadian regulation by Bmal1. As a result, Wnt signaling activity was attenuated by Bmal1 KD and augmented by its overexpression. Furthermore, stabilizing ß-catenin through Wnt ligand or GSK-3ß inhibition achieved partial restoration of blunted Wnt activity and suppression of increased adipogenesis induced by Bmal1 KD. Taken together, our study demonstrates that Bmal1 is a critical negative regulator of adipocyte development through transcriptional control of components of the canonical Wnt signaling cascade, and provides a mechanistic link between circadian disruption and obesity.