RESUMEN
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose transcription activity is regulated by small compounds provided by diet, xenobiotics, and metabolism. It has been proven to be involved in energy homeostasis and inflammation in most recent years. Epidemiologically, exposure to xenobiotic AHR ligands contributes to obesity and type 2 diabetes (T2D). AHR is also the critical transcription factor determining the lineage commitment of pro-inflammatory Th17 and Th22 cells from naïve CD4+ T lymphocytes. It has been well-illustrated in animal models that IL-22, the major effector cytokine of Th17 and Th22 cells, played a major role in the interaction of metabolism and gut microbiota. But there were still missing links between gut microbiota, IL-22, and metabolism in humans. Our previous findings indicated that elevated circulating levels of IL-22 and frequencies of Th22 cells were associated with insulin resistance in both patients with obesity and T2D. Additionally, the hyperactive Th17 and Th22 cells phenotype also correlate with islets ß-cell dysfunction in T2D. In this study, we made efforts to determine AHR expressions in peripheral blood mononuclear cells (PBMCs) from patients with T2D and metabolically healthy obesity (MHO). Correlation analyses were conducted to assess the possible link between AHR and the metabolic and inflammatory context. We revealed that mRNA expression of AHR was up-regulated and correlated with the percentage of Th17, Th22 as well as Th1 cells. Elevated plasma levels of IL-22 and IL-17 also correlated with increased AHR transcripts in PBMCs from both MHO and T2D patients. The transcription factor AHR may thus have a plausible role in the interaction between metabolism and pro-inflammatory status of patients in the development of obesity and T2D.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Ácidos Nucleicos Libres de Células/sangre , Diabetes Mellitus Tipo 2/sangre , Obesidad Metabólica Benigna/sangre , ARN Mensajero/sangre , Receptores de Hidrocarburo de Aril/sangre , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inmunología , Femenino , Humanos , Mediadores de Inflamación/sangre , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Interleucina-17/sangre , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Obesidad Metabólica Benigna/genética , Obesidad Metabólica Benigna/inmunología , Fenotipo , ARN Mensajero/genética , Receptores de Hidrocarburo de Aril/genética , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Regulación hacia Arriba , Interleucina-22RESUMEN
Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.
Asunto(s)
Inflamación/inmunología , Macrófagos/fisiología , MicroARNs/fisiología , Obesidad Metabólica Benigna/inmunología , Receptor fas/análisis , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Aorta , Enfermedades de la Aorta/etiología , Aterosclerosis/etiología , Antígeno B7-2/análisis , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Inflamación/complicaciones , Molécula 1 de Adhesión Intercelular/biosíntesis , Macrófagos/química , Macrófagos/clasificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Obesidad Metabólica Benigna/metabolismo , Obesidad Metabólica Benigna/patología , Vasculitis/etiologíaRESUMEN
Background: Obesity is associated with macrophage infiltration in adipose tissue that induces insulin resistance and contributes to the development of metabolic syndrome (MS). The aim of this study was to investigate whether circulating monocyte subsets (macrophage precursors) differ among obese subjects with MS [metabolically unhealthy obese (MUO)], obese subjects without MS [metabolically healthy obese (MHO)], and metabolically healthy lean (MHL) individuals. Methods: Fifty-eight obese (33 MUO, 25 MHO) and 25 MHL individuals participated in the study. Absolute blood counts of classical (Mon1A), intermediate (Mon2A), and nonclassical (Mon3A) monocyte subsets were measured by flow cytometry. Results: Increased proinflammatory monocyte counts (Mon2A, Mon3A) were observed in obese compared with MHL individuals (P = 0.001 and P = 0.017 respectively). Mon2A count in MHO was lower compared with that in MUO subjects (P = 0.036) but higher compared with MHL controls (P = 0.032). Mon2A was positively associated with serum triglyceride levels (r = 0.328, P = 0.023) and mean blood pressure (BP) (r = 0.457, P = 0.001) in obese subjects. Among MS components, only the presence of elevated BP (≥130/85 mmHg) was independently associated with increased Mon2A in obese subjects (P < 0.001). Conclusions: Absolute counts of proinflammatory monocytes were lower in metabolically healthy compared with MUO individuals, but higher compared with healthy lean controls. The presence of low-grade inflammation suggests that "metabolically healthy" obesity is not a benign condition. ClinicalTrials.gov identifier: NCT03241394.
Asunto(s)
Inflamación/inmunología , Monocitos/inmunología , Obesidad Metabólica Benigna/inmunología , Adulto , Biomarcadores/sangre , Presión Sanguínea , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Estudios Transversales , Femenino , Citometría de Flujo , Estado de Salud , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/fisiopatología , Mediadores de Inflamación/sangre , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Obesidad Metabólica Benigna/sangre , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/fisiopatología , Fenotipo , Pronóstico , Triglicéridos/sangreRESUMEN
The contribution of adiposopathy to glucose-insulin homeostasis remains unclear. This longitudinal study examined the potential relationship between the adiponectin/leptin ratio (A/L, a marker of adiposopathy) and insulin resistance (IR: homeostasis model assessment (HOMA)), insulin sensitivity (IS: Matsuda), and insulin response to an oral glucose tolerance test before and after a 16-week walking program, in 29 physically inactive pre- and postmenopausal women with obesity (BMI, 29-35 kg/m2; age, 47-54 years). Anthropometry, body composition, VO2max, and fasting lipid-lipoprotein and inflammatory profiles were assessed. A/L was unchanged after training (p = 0.15), despite decreased leptin levels (p < 0.05). While the Matsuda index tended to increase (p = 0.07), HOMA decreased (p < 0.05) and fasting insulin was reduced (p < 0.01) but insulin area under the curve (AUC) remained unchanged (p = 0.18) after training. Body fatness and VO2max were improved (p < 0.05) while triacylglycerols increased and HDL-CHOL levels decreased after training (p < 0.05). At baseline, A/L was positively associated with VO2max, HDL-CHOL levels, and Matsuda (0.37 < ρ < 0.56; p < 0.05) but negatively with body fatness, HOMA, insulin AUC, IL-6, and hs-CRP levels (− 0.41 < ρ < − 0.66; p < 0.05). After training, associations with fitness, HOMA, and inflammation were lost. Multiple regression analysis revealed A/L as an independent predictor of IR and IS, before training (partial R2 = 0.10 and 0.22), although A/L did not predict the insulin AUC pre- or post-intervention. A significant correlation was found between training-induced changes to A/L and IS (r = 0.38; p < 0.05) but not with IR or insulin AUC. Although changes in the A/L ratio could not explain improvements to glucose-insulin homeostasis indices following training, a relationship with insulin sensitivity was revealed in healthy women with obesity
Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Adiponectina/sangre , Adiposidad , Resistencia a la Insulina , Leptina/sangre , Obesidad Metabólica Benigna/terapia , Acondicionamiento Físico Humano , Salud Urbana , Biomarcadores/sangre , Índice de Masa Corporal , Prueba de Tolerancia a la Glucosa , Estudios Longitudinales , Obesidad Metabólica Benigna/sangre , Obesidad Metabólica Benigna/inmunología , Obesidad Metabólica Benigna/metabolismoRESUMEN
The contribution of adiposopathy to glucose-insulin homeostasis remains unclear. This longitudinal study examined the potential relationship between the adiponectin/leptin ratio (A/L, a marker of adiposopathy) and insulin resistance (IR: homeostasis model assessment (HOMA)), insulin sensitivity (IS: Matsuda), and insulin response to an oral glucose tolerance test before and after a 16-week walking program, in 29 physically inactive pre- and postmenopausal women with obesity (BMI, 29-35 kg/m2; age, 47-54 years). Anthropometry, body composition, VO2max, and fasting lipid-lipoprotein and inflammatory profiles were assessed. A/L was unchanged after training (p = 0.15), despite decreased leptin levels (p < 0.05). While the Matsuda index tended to increase (p = 0.07), HOMA decreased (p < 0.05) and fasting insulin was reduced (p < 0.01) but insulin area under the curve (AUC) remained unchanged (p = 0.18) after training. Body fatness and VO2max were improved (p < 0.05) while triacylglycerols increased and HDL-CHOL levels decreased after training (p < 0.05). At baseline, A/L was positively associated with VO2max, HDL-CHOL levels, and Matsuda (0.37 < ρ < 0.56; p < 0.05) but negatively with body fatness, HOMA, insulin AUC, IL-6, and hs-CRP levels (- 0.41 < ρ < - 0.66; p < 0.05). After training, associations with fitness, HOMA, and inflammation were lost. Multiple regression analysis revealed A/L as an independent predictor of IR and IS, before training (partial R2 = 0.10 and 0.22), although A/L did not predict the insulin AUC pre- or post-intervention. A significant correlation was found between training-induced changes to A/L and IS (r = 0.38; p < 0.05) but not with IR or insulin AUC. Although changes in the A/L ratio could not explain improvements to glucose-insulin homeostasis indices following training, a relationship with insulin sensitivity was revealed in healthy women with obesity.
Asunto(s)
Adiponectina/sangre , Adiposidad , Resistencia a la Insulina , Leptina/sangre , Obesidad Metabólica Benigna/terapia , Acondicionamiento Físico Humano , Salud Urbana , Biomarcadores/sangre , Índice de Masa Corporal , Capacidad Cardiovascular , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Obesidad Metabólica Benigna/sangre , Obesidad Metabólica Benigna/inmunología , Obesidad Metabólica Benigna/metabolismo , Consumo de Oxígeno , Posmenopausia , Premenopausia , Quebec , CaminataRESUMEN
Objective To investigate the proportion of circulating invariant natural killer T (iNKT) cells in four body health types. Methods In this cross-sectional study, participants were classified into four body health types according to the body mass index and metabolic status: metabolically healthy and normal weight (MHNW), metabolically unhealthy but normal weight (MUNW), metabolically healthy but obese (MHO), or metabolically unhealthy and obese (MUO). Demographic and clinical characteristics were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) and visceral adiposity index (VAI) were calculated. The proportion of circulating iNKT cells was also evaluated by flow cytometry. Results The study enrolled 41 MHNW, 37 MUNW, 30 MHO, and 43 MUO participants. Compared with the MHNW group, the MUNW, MHO, and MUO groups had significantly lower iNKT cell proportions. The iNKT cell proportion was significantly higher in the MHO group than the MUNW and MUO groups. The iNKT cell proportion was inversely correlated with high-sensitivity C-reactive protein, HOMA-IR, and VAI values. Conclusion The proportion of iNKT cells was lower in people (lean or obese) with excessive visceral fat accumulation, suggesting that iNKT cell deficiency may be involved in the pathophysiology of obesity-related metabolic disorders.