RESUMEN
Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Inmunidad Innata/efectos de los fármacos , Obesidad/inmunología , Sepsis/inmunología , Animales , Bacterias , Citocinas/genética , Citocinas/inmunología , Diabetes Mellitus Experimental/microbiología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Monocitos/patología , Neutrófilos/inmunología , Neutrófilos/patología , Obesidad/microbiología , Fagocitosis , Sepsis/tratamiento farmacológico , Sepsis/microbiologíaRESUMEN
Dysfunctional adipose tissue plays a central role in the pathogenesis of the obesity-related metabolic disease, including type 2 diabetes. Targeting adipose tissue using biopolymer implants is a novel therapeutic approach for metabolic disease. We transplanted porous poly(lactide-co-glycolide) (PLG) implants coated with human interleukin-4 (hIL-4)-expressing lentivirus into epididymal white adipose tissue (eWAT) of mice fed a high-fat diet. Tissue and systemic inflammation and metabolism were studied with flow cytometry, immunohistochemistry, quantitative real-time polymerase chain reaction, adipose tissue histology, and in vivo glucose tolerance testing at 2 and 10 weeks of a high-fat diet. PLG implants carrying hIL-4-expressing lentivirus implanted into epididymal white adipose tissue of mice-regulated adipose tissue inflammation, including increased CD3+ CD4+ T-cell frequency, increased eWAT adipocyte hypertrophy, and decreased FASN and ATGL expression, along with reduced fasting blood glucose levels. These effects were observed in early obesity but were not maintained in established obesity. Local delivery of bioimplants loaded with cytokine-expressing lentivirus vectors to adipose tissue influences tissue inflammation and systemic metabolism in early obesity. Further study will be required to show more durable metabolic effects. These data demonstrate that polymer biomaterials implanted into adipose tissue have the potential to modulate local tissue and systemic inflammation and metabolism.
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Tejido Adiposo/metabolismo , Implantes Experimentales , Interleucina-4 , Lentivirus , Obesidad/metabolismo , Transducción Genética , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Inflamación/metabolismo , Interleucina-4/biosíntesis , Interleucina-4/genética , Masculino , Ratones , Obesidad/genéticaRESUMEN
BACKGROUND: The utility of serum biomarkers related to inflammation and adiposity as predictors of metabolic disease prevalence and outcomes after bariatric surgery are not well-defined. METHODS: Associations between pre- and post-operative serum levels of four biomarkers (C-reactive protein (CRP), cystatin C (CC), leptin, and ghrelin) with baseline measures of adiposity and metabolic disease prevalence (asthma, diabetes, sleep apnea), and weight loss and metabolic disease remission after bariatric surgery were studied in the Longitudinal Assessment of Bariatric Surgery (LABS) cohort. RESULTS: Baseline CRP levels were positively associated with the odds of asthma but not diabetes or sleep apnea; baseline CC levels were positively associated with asthma, diabetes, and sleep apnea; baseline leptin levels were positively associated with asthma and negatively associated with diabetes and sleep apnea; baseline ghrelin levels were negatively associated with diabetes and sleep apnea. Increased weight loss was associated with increased baseline levels of leptin and CRP and decreased baseline levels of CC. Remission of diabetes and asthma was not associated with baseline levels of any biomarker. A higher likelihood of asthma remission was associated with a greater decrease in leptin levels, and a higher likelihood of diabetes remission was predicted by a lesser decrease in CC. Bariatric surgery was associated with decreased post-operative CC, CRP, and leptin levels, and increased post-operative ghrelin levels. CONCLUSION: This is the largest study to date of serum biomarkers of inflammation and adiposity in a bariatric surgery cohort. Biomarker levels correlate with metabolic disease prevalence prior to bariatric surgery, and with weight loss but not metabolic disease remission after surgery. Bariatric surgery regulates serum biomarker levels in a manner consistent with anti-inflammatory and compensatory orexigenic effects. These data contribute to our understanding of the mechanisms underlying the biologic effects of bariatric surgery.
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Cirugía Bariátrica/estadística & datos numéricos , Inflamación , Enfermedades Metabólicas , Obesidad , Adiposidad/fisiología , Adulto , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Femenino , Ghrelina/sangre , Humanos , Inflamación/sangre , Inflamación/epidemiología , Leptina/sangre , Estudios Longitudinales , Masculino , Enfermedades Metabólicas/sangre , Enfermedades Metabólicas/epidemiología , Persona de Mediana Edad , Obesidad/sangre , Obesidad/epidemiología , Obesidad/cirugía , Resultado del TratamientoRESUMEN
Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+ cells overlaps with other leukocytes and that CD45+CD64+ is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c+CD64- cells (ATDC), whereas core macrophage genes were enriched in CD45+CD64+ cells (ATM). CD11c+CD64- ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4+ T cell proliferation as ATMs. ATDCs were predominantly CD11b+ conventional dendritic cells and made up the bulk of CD11c+ cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2-/- mice demonstrated that high-fat diet-induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7-/- mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ ATM and CD45+CD64-CD11c+ ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity.
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Tejido Adiposo/inmunología , Células Dendríticas/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Animales , Células Cultivadas , Dieta Alta en Grasa , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Resistencia a la Insulina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR2/genética , Receptores CCR7/genética , Receptores de IgG/metabolismoRESUMEN
IMPORTANCE: Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. OBJECTIVE: To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. INTERVENTIONS: One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. MAIN OUTCOMES AND MEASURES: The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. RESULTS: In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. CONCLUSION AND RELEVANCE: Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01327976.
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Bloqueo Nervioso/métodos , Obesidad Mórbida/terapia , Nervio Vago , Dolor Abdominal/etiología , Adulto , Método Doble Ciego , Dispepsia/etiología , Electrodos , Femenino , Pirosis/etiología , Humanos , Masculino , Persona de Mediana Edad , Bloqueo Nervioso/efectos adversos , Nervio Vago/fisiopatología , Pérdida de PesoRESUMEN
OBJECTIVE: Optimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity. RESEARCH DESIGN AND METHODS: Weight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED. RESULTS: Postprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass. CONCLUSION: These data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss.
RESUMEN
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.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Ácidos y Sales Biliares , Colesterol/metabolismo , Glucosa , Obesidad/metabolismoRESUMEN
White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte ß adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6 -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.
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Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Adrenérgicos , Lipólisis/fisiología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Obesidad/metabolismo , ARN/metabolismoRESUMEN
Alterations of the extracellular matrix contribute to adipose tissue dysfunction in metabolic disease. We studied the role of matrix density in regulating human adipocyte phenotype in a tunable hydrogel culture system. Lipid accumulation was maximal in intermediate hydrogel density of 5 weight %, relative to 3% and 10%. Adipogenesis and lipid and oxidative metabolic gene pathways were enriched in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways were enriched in 3% hydrogels. These data demonstrate that the intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. These observations contribute to a growing literature describing the role of matrix density in regulating adipose tissue function.
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Adipocitos , Tejido Adiposo , Humanos , Adipocitos/metabolismo , Adipogénesis/genética , Hidrogeles/metabolismo , Fenotipo , LípidosRESUMEN
Increased adipose tissue macrophages (ATMs) correlate with metabolic dysfunction in humans and are causal in development of insulin resistance in mice. Recent bulk and single-cell transcriptomics studies reveal a wide spectrum of gene expression signatures possible for macrophages that depends on context, but the signatures of human ATM subtypes are not well defined in obesity and diabetes. We profiled 3 prominent ATM subtypes from human adipose tissue in obesity and determined their relationship to type 2 diabetes. Visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) samples were collected from diabetic and nondiabetic obese participants to evaluate cellular content and gene expression. VAT CD206+CD11c- ATMs were increased in diabetic participants, were scavenger receptor-rich with low intracellular lipids, secreted proinflammatory cytokines, and diverged significantly from 2 CD11c+ ATM subtypes, which were lipid-laden, were lipid antigen presenting, and overlapped with monocyte signatures. Furthermore, diabetic VAT was enriched for CD206+CD11c- ATM and inflammatory signatures, scavenger receptors, and MHC II antigen presentation genes. VAT immunostaining found CD206+CD11c- ATMs concentrated in vascularized lymphoid clusters adjacent to CD206-CD11c+ ATMs, while CD206+CD11c+ were distributed between adipocytes. Our results show ATM subtype-specific profiles that uniquely contribute to the phenotypic variation in obesity.
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Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulación de la Expresión Génica , Resistencia a la Insulina/genética , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Obesidad/genética , Receptores Inmunológicos/genética , Adipocitos/metabolismo , Tejido Adiposo/patología , Adulto , Anciano , Anciano de 80 o más Años , ADN/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Estudios de Seguimiento , Humanos , Macrófagos/patología , Masculino , Glicoproteínas de Membrana/biosíntesis , Persona de Mediana Edad , Obesidad/metabolismo , Obesidad/patología , Receptores Inmunológicos/biosíntesis , Factores de Tiempo , Adulto JovenRESUMEN
Obesity-associated type 2 diabetes (DM) leads to adipose tissue dysfunction. Lumican is a proteoglycan implicated in obesity, insulin resistance (IR), and adipocyte dysfunction. Using human visceral adipose tissue (VAT) from subjects with and without DM, we studied lumican effects on adipocyte function. Lumican was increased in VAT and adipocytes in DM. Lumican knockdown in adipocytes decreased lipolysis and improved adipogenesis and insulin sensitivity in VAT adipocytes in DM, while treatment with human recombinant lumican increased lipolysis and impaired insulin-sensitivity in an ERK-dependent manner. We demonstrate that lumican impairs adipocyte metabolism, partially via ERK signalling, and is a potential target for developing adipose tissue-targeted therapeutics in DM.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Lumican/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Adipocitos/metabolismo , Lipólisis , Obesidad/complicaciones , Obesidad/metabolismo , Tejido Adiposo/metabolismoRESUMEN
Increased morbidity and mortality from coronavirus disease 2019 (COVID-19) in people with obesity have illuminated the intersection of obesity with impaired responses to infections. Although data on mechanisms by which COVID-19 impacts health are being rapidly generated, there is a critical need to better understand the pulmonary, vascular, metabolic, and immunologic aspects that drive the increased risk for complications from COVID-19 in people with obesity. This review provides a broad overview of the intersection between COVID-19 and the physiology of obesity in order to highlight potential mechanisms by which COVID-19 disease severity is increased by obesity and identify areas for future investigation toward developing tailored therapy for people with obesity who develop COVID-19.
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COVID-19/patología , Obesidad/complicaciones , Humanos , Morbilidad , Obesidad/virologíaRESUMEN
OBJECTIVE: Spigelian hernia is an uncommon congenital or acquired defect in the transversus abdominis aponeurosis with non-specific symptoms posing a diagnostic challenge. There is a paucity of radiology literature on imaging findings of Spigelian hernia. The objective of this study is to explore the role of MDCT in evaluating Spigelian hernia along with clinical and surgical implications. MATERIALS AND METHODS: In this IRB approved, HIPAA compliant retrospective observational analysis MDCT imaging findings of 43 Spigelian hernias were evaluated by two fellowship-trained radiologists. Imaging features evaluated were: presence of Spigelian hernia, laterality, relation to "hernia belt" (between 0 and 6 cm cranial to an imaginary axial line between both anterior superior iliac spines), the hernia neck and sac sizes, hernia content, and other coexistent hernias (umbilical, incisional, inguinal). Patient's demographics (age, gender, BMI, conditions with increased intra-abdominal pressure) were also recorded for any correlation. RESULTS: 60% (26/43) of Spigelian hernias were located below the hernia belt while 33% (14/43) within the hernia belt and 7% (3/43) above the hernia belt. The most common subtype of Spigelian hernia encountered was interparietal (84%). The mean hernia neck diameter was 3.4 cm, mean hernia sac volume was 329 cc. Hernia content included: fat (43/43) bowel (23/43), fluid (3/43). 3 patients had no clinical history provided, the remaining 37 patients' clinical presentation was asymptomatic in 73% (27/37), acute abdominal pain in 5% (2/37) and chronic abdominal pain in 22% (8/37). None of the hernia were incarcerated and none of the patients underwent emergent surgery. No significant correlation was noted between Spigelian hernia and causes of increased intra-abdominal pressure. 90% of our patients had other abdominal hernias. 30.9 was the mean BMI (20.8-69.1). CONCLUSION: Most of the Spigelian hernia occurred below the traditionally described hernia belt and the majority are of interparietal subtype that can be best diagnosed with MDCT in contrast to physical examination.
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Hernia Ventral , Músculos Abdominales , Dolor Abdominal , Hernia Ventral/diagnóstico por imagen , Hernia Ventral/cirugía , Humanos , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Dysfunctional visceral adipose tissue (VAT) in obesity is associated with type 2 diabetes (DM) but underlying mechanisms remain unclear. Our objective in this discovery analysis was to identify genes and proteins regulated by DM to elucidate aberrant cellular metabolic and signaling mediators. We performed label-free proteomics and RNA-sequencing analysis of VAT from female bariatric surgery subjects with DM and without DM (NDM). We quantified 1965 protein groups, 23 proteins, and 372 genes that were differently abundant in DM vs. NDM VAT. Proteins downregulated in DM were related to fatty acid synthesis and mitochondrial function (fatty acid synthase, FASN; dihydrolipoyl dehydrogenase, mitochondrial, E3 component, DLD; succinate dehydrogenase-α, SDHA) while proteins upregulated in DM were associated with innate immunity and transcriptional regulation (vitronectin, VTN; endothelial protein C receptor, EPCR; signal transducer and activator of transcription 5B, STAT5B). Transcriptome indicated defects in innate inflammation, lipid metabolism, and extracellular matrix (ECM) function, and components of complement classical and alternative cascades. The VAT proteome and transcriptome shared 13 biological processes impacted by DM, related to complement activation, cell proliferation and migration, ECM organization, lipid metabolism, and gluconeogenesis. Our data revealed a marked effect of DM in downregulating FASN. We also demonstrate enrichment of complement factor B (CFB), coagulation factor XIII A chain (F13A1), thrombospondin 1 (THBS1), and integrins at mRNA and protein levels, albeit with lower q-values and lack of Western blot or PCR confirmation. Our findings suggest putative mechanisms of VAT dysfunction in DM.
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Diabetes Mellitus Tipo 2/patología , Grasa Intraabdominal/metabolismo , Obesidad/patología , Proteoma/metabolismo , Transcriptoma , Cirugía Bariátrica , Diabetes Mellitus Tipo 2/complicaciones , Regulación hacia Abajo , Matriz Extracelular/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos/genética , Mitocondrias/genética , Obesidad/complicaciones , Análisis de Componente Principal , Regulación hacia ArribaRESUMEN
Subcutaneous (SAT) and visceral (VAT) adipose tissues have distinct metabolic phenotypes. We hypothesized that the extracellular matrix (ECM) regulates depot-specific differences in adipocyte metabolic function in murine obesity. VAT and SAT preadipocytes from lean or obese mice were subject to adipogenic differentiation in standard 2D culture on plastic tissue culture plates or in 3D culture in ECM, followed by metabolic profiling. Adipocytes from VAT relative to SAT manifested impaired insulin-stimulated glucose uptake and decreased adipogenic capacity. In 3D-ECM-adipocyte culture, ECM regulated adipocyte metabolism in a depot-specific manner, with SAT ECM rescuing defects in glucose uptake and adipogenic gene expression in VAT adipocytes, while VAT ECM impaired adipogenic gene expression in SAT adipocytes. These findings demonstrate that ECM-adipocyte crosstalk regulates depot-specific differences in adipocyte metabolic dysfunction in murine obesity.
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Adipocitos/metabolismo , Matriz Extracelular/metabolismo , Obesidad/metabolismo , Animales , Células Cultivadas , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue.
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Diabetes Mellitus Tipo 2/diagnóstico por imagen , Grasa Intraabdominal/fisiopatología , Microscopía de Fuerza Atómica/métodos , Obesidad/diagnóstico por imagen , Adulto , Fenómenos Biomecánicos , Diabetes Mellitus Tipo 2/metabolismo , Módulo de Elasticidad , Matriz Extracelular/metabolismo , Femenino , Humanos , Hidroxiprolina/metabolismo , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/metabolismo , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatologíaRESUMEN
BACKGROUND: Obesity-induced chronic inflammation and fibrosis in adipose tissue contributes to the progression of type 2 diabetes mellitus (DM). While fibrosis is known to induce mechanical stiffening of numerous tissue types, it is unknown whether DM is associated with alterations in adipose tissue mechanical properties. OBJECTIVE: The purpose of this study was to investigate whether DM is associated with differences in bulk viscoelastic properties of adipose tissue from diabetic (DM) and non-diabetic (NDM) obese subjects. METHODS: Bulk shear rheology was performed on visceral (VAT) and subcutaneous (SAT) adipose tissue, collected from obese subjects undergoing elective bariatric surgery. Rheology was also performed on the remaining extracellular matrix (ECM) from decellularized VAT (VAT ECM). Linear mixed models were used to assess whether correlations existed between adipose tissue mechanical properties and DM status, sex, age, and body mass index (BMI). RESULTS: DM was not associated with significant differences in adipose tissue viscoelastic properties for any of the tissue types investigated. Tissue type dependent differences were however detected, with VAT having significantly lower shear storage and loss moduli than SAT and VAT ECM independent of DM status. CONCLUSION: Although DM is typically associated with adipose tissue fibrosis, it is not associated with differences in macroscopic adipose tissue mechanical properties.
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Tejido Adiposo , Diabetes Mellitus Tipo 2 , Obesidad , Tejido Adiposo/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Grasa Intraabdominal , Masculino , Grasa SubcutáneaRESUMEN
Obesity is a major health crisis, and diabetes is one of its most serious sequelae. Obesity is associated with a state of chronic systemic inflammation that is a primary etiologic factor in the development of insulin resistance and diabetes. This inflammatory state is based in adipose tissue and mediated in large part by tissue macrophages and their cytokine and adipokine products. Recent research has identified specific molecular mediators of the link between inflammation and insulin resistance in obesity. Study of these mediators and the specific mechanisms underlying inflammation and insulin resistance in obesity holds the promise for novel pharmacotherapy for obesity-related metabolic disease.