RESUMO
PURPOSE: We developed a comprehensive sleeve gastrectomy (SG) weight loss study cohort and biorepository to uncover mechanisms, biomarkers and predictive factors of weight loss, weight maintenance and amelioration of obesity-related comorbidities. For this purpose, we collected psychosocial, anthropometric, clinical data and a variety of samples pre-surgery, intraoperatively and 1.5, 3, 12 and 24 months post-surgery. For longer-term assessment, the collection of psychosocial and anthropometric data was extended to 10 years. Here, we present in-depth characterisation of the cohort and detailed overview of study procedures as a foundation for future analyses. PARTICIPANTS: We consented 647 participants between June 2017 and March 2020 from two bariatric surgery clinics in New York City-one major urban hospital and one private hospital. Of 355 participants who provided baseline data, 300 underwent SG. Of these, 79% are females with an average age of 38 years, 68% are Hispanic, 20% are non-Hispanic Black and 11% are non-Hispanic White. FINDINGS TO DATE: We collected intraoperative adipose and stomach tissues from 282 patients and biosamples (blood, urine, saliva, stool) from 245 patients at 1.5 months, 238 at 3 month, 218 at 12 months and 180 at 24 months post-surgery. We are currently collecting anthropometric and psychosocial data annually until 10 years post-surgery. Data analysis is currently underway. FUTURE PLANS: Our future research will explore the variability in weight loss outcomes observed in our cohort, particularly among Black and Hispanic patients in comparison to their White counterparts. We will identify social determinants of health, metabolic factors and other variables that may predict weight loss success, weight maintenance and remission of obesity-related comorbidities. Additionally, we plan to leverage our biorepository for collaborative research studies. We will complete long-term follow-up data by December 2031. We plan to apply for funding to expand biosample collection through year 10 to provide insights into the mechanisms of long-term weight maintenance.
Assuntos
Gastrectomia , Obesidade Mórbida , Redução de Peso , Humanos , Feminino , Adulto , Gastrectomia/métodos , Masculino , Obesidade Mórbida/cirurgia , Estudos Longitudinais , Pessoa de Meia-Idade , Cirurgia Bariátrica/métodos , Estados Unidos , Projetos de Pesquisa , Estudos de CoortesRESUMO
Lipedema and lymphedema are physically similar yet distinct diseases that are commonly misdiagnosed. We previously reported that lipedema and lymphedema are associated with increased risk for venous thromboembolism (VTE). The underlying etiology of the prothrombotic profile observed in lipedema and lymphedema is unclear, but may be related to alterations in platelets. Our objective was to analyze the platelet transcriptome to identify biological pathways that may provide insight into platelet activation and thrombosis. The platelet transcriptome was evaluated in patients with lymphedema and lipedema, then compared to control subjects with obesity. Patients with lipedema were found to have a divergent transcriptome from patients with lymphedema. The platelet transcriptome and impacted biological pathways in lipedema were surprisingly similar to weight-matched comparators, yet different when compared to overweight individuals with a lower body mass index (BMI). Differences in the platelet transcriptome for patients with lipedema and lymphedema were found in biological pathways required for protein synthesis and degradation, as well as metabolism. Key differences in the platelet transcriptome for patients with lipedema compared to BMI-matched subjects involved metabolism and glycosaminoglycan processing. These inherent differences in the platelet transcriptome warrant further investigation, and may contribute to the increased risk of thrombosis in patients with lipedema and lymphedema.
Assuntos
Plaquetas , Lipedema , Linfedema , Transcriptoma , Humanos , Linfedema/genética , Lipedema/genética , Feminino , Pessoa de Meia-Idade , Plaquetas/metabolismo , Plaquetas/patologia , Masculino , Adulto , Índice de Massa Corporal , Ativação Plaquetária/genética , Obesidade/genética , Obesidade/complicações , Estudos de Casos e ControlesRESUMO
The prevalence of diabetes is estimated to reach almost 630 million cases worldwide by the year 2045; of current and projected cases, over 90% are type 2 diabetes. Air pollution exposure has been implicated in the onset and progression of diabetes. Increased exposure to fine particulate matter air pollution (PM2.5) is associated with increases in blood glucose and glycated hemoglobin (HbA1c) across the glycemic spectrum, including normoglycemia, prediabetes, and all forms of diabetes. Air pollution exposure is a driver of cardiovascular disease onset and exacerbation and can increase cardiovascular risk among those with diabetes. In this review, we summarize the literature describing the relationships between air pollution exposure, diabetes and cardiovascular disease, highlighting how airborne pollutants can disrupt glucose homeostasis. We discuss how air pollution and diabetes, via shared mechanisms leading to endothelial dysfunction, drive increased cardiovascular disease risk. We identify portable air cleaners as potentially useful tools to prevent adverse cardiovascular outcomes due to air pollution exposure across the diabetes spectrum, while emphasizing the need for further study in this particular population. Given the enormity of the health and financial impacts of air pollution exposure on patients with diabetes, a greater understanding of the interventions to reduce cardiovascular risk in this population is needed.
Assuntos
Poluição do Ar , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Poluição do Ar/efeitos adversos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Exposição Ambiental/efeitos adversos , Material Particulado/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Fatores de Risco , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Fatores de Risco de Doenças Cardíacas , Glicemia/metabolismoRESUMO
Obesity is a growing epidemic in the United States and worldwide and is associated with insulin resistance and cardiovascular disease, among other comorbidities. Understanding of the pathology that links overnutrition to these disease processes is ongoing. Adipose tissue is a heterogeneous organ comprised of multiple different cell types and it is likely that dysregulated metabolism within these cell populations disrupts both inter- and intracellular interactions and is a key driver of human disease. In recent years, metabolic flux analysis, which offers a precise quantification of metabolic pathway fluxes in biological systems, has emerged as a candidate strategy for uncovering the metabolic changes that stoke these disease processes. In this mini review, we discuss metabolic flux analysis as an experimental tool, with a specific emphasis on mass spectrometry with isotope tracing as this is the technique most frequently used for metabolic flux analysis in adipocytes. Furthermore, we examine existing literature that uses metabolic flux analysis to further our understanding of adipose tissue biology. Our group has a specific interest in understanding the role of white adipose tissue inflammation in the progression of cardiometabolic disease, as we know that in obesity the accumulation of pro-inflammatory adipose tissue macrophages is associated with significant morbidity, so we use this as a paradigm throughout our review for framing the application of these experimental techniques. However, there are many other biological applications to which they can be applied to further understanding of not only adipose tissue biology but also systemic homeostasis.
RESUMO
Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic ß-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent ß-cell dysfunction and the potential residual risk of diabetes complications.
RESUMO
OBJECTIVES: This study evaluated whether a range of demographic, social and geographic factors had an influence on glycaemic control longitudinally after an initial diagnosis of diabetes. DESIGN, SETTING AND PARTICIPANTS: We used the US Veterans Administration Diabetes Risk national cohort to track glycaemic control among patients 20-79-year old with a new diagnosis of type 2 diabetes. PRIMARY OUTCOME AND METHODS: We modelled associations between glycaemic control at follow-up clinical assessments and geographic factors including neighbourhood race/ethnicity, socioeconomic, land use and food environment measures. We also adjusted for individual demographics, comorbidities, haemoglobin A1c (HbA1c) at diagnosis and duration of follow-up. These factors were analysed within strata of community type: high-density urban, low-density urban, suburban/small town and rural areas. RESULTS: We analysed 246 079 Veterans who developed a new type 2 diabetes diagnosis in 2008-2018 and had at least 2 years of follow-up data available. Across all community types, we found that lower baseline HbA1c and female sex were strongly associated with a higher likelihood of within-range HbA1c at follow-up. Surprisingly, patients who were older or had more documented comorbidities were more likely to have within-range follow-up HbA1c results. While there was variation by community type, none of the geographic measures analysed consistently demonstrated significant associations with glycaemic control across all community types.
Assuntos
Diabetes Mellitus Tipo 2 , Veteranos , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobinas Glicadas , Glicemia , Estudos Retrospectivos , Controle Glicêmico , Etnicidade , GeografiaRESUMO
Cardiovascular disease risk is known to be influenced by both the severity of a risk factor and the duration of exposure (eg, LDL [low-density lipoprotein] cholesterol, tobacco smoke). However, this concept has been largely neglected within the obesity literature. While obesity severity has been closely linked with cardiometabolic diseases, the risk of developing these conditions among those with obesity may be augmented by greater obesity duration over the life span. Few longitudinal or contemporary studies have investigated the influence of both factors in combination-cumulative obesity exposure-instead generally focusing on obesity severity, often at a single time point, given ease of use and lack of established methods to encapsulate duration. Our review focuses on what is known about the influence of the duration of exposure to excess adiposity within the obesity-associated cardiometabolic disease risk equation by means of summarizing the hypothesized mechanisms for and evidence surrounding the relationships of obesity duration with diverse cardiovascular and metabolic disease. Through the synthesis of the currently available data, we aim to highlight the importance of a better understanding of the influence of obesity duration in cardiovascular and metabolic disease pathogenesis. We underscore the clinical importance of aggressive early attention to obesity identification and intervention to prevent the development of chronic diseases that arise from exposure to excess body weight.
Assuntos
Doenças Cardiovasculares , Síndrome Metabólica , Humanos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Fatores de Risco , Adiposidade , Síndrome Metabólica/complicaçõesRESUMO
As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN-designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity-focused investigators and next-step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.
Assuntos
American Heart Association , Sobrepeso , Animais , Humanos , Sobrepeso/epidemiologia , Sobrepeso/terapia , Obesidade/epidemiologia , Obesidade/terapia , Causalidade , New YorkRESUMO
Recent studies implicate macrophages in regulation of thermogenic, sympathetic neuron-mediated norepinephrine (NE) signaling in adipose tissues, but understanding of such non-classical macrophage activities is incomplete. Here we show that male mice lacking the allograft inflammatory factor-1 (AIF1) protein resist high fat diet (HFD)-induced obesity and hyperglycemia. We link this phenotype to higher adipose NE levels that stem from decreased monoamine oxidase A (MAOA) expression and NE clearance by AIF1-deficient macrophages, and find through reciprocal bone marrow transplantation that donor Aif1-/- vs WT genotype confers the obesity phenotype in mice. Interestingly, human sequence variants near the AIF1 locus associate with obesity and diabetes; in adipose samples from participants with obesity, we observe direct correlation of AIF1 and MAOA transcript levels. These findings identify AIF1 as a regulator of MAOA expression in macrophages and catecholamine activity in adipose tissues - limiting energy expenditure and promoting energy storage - and suggest how it might contribute to human obesity.
Assuntos
Tecido Adiposo , Catecolaminas , Obesidade , Animais , Humanos , Masculino , Camundongos , Tecido Adiposo/metabolismo , Adiposidade , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Catecolaminas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Norepinefrina/metabolismo , Obesidade/genética , Obesidade/metabolismoRESUMO
Obesity has reached epidemic proportions in the United States, but little is known about the mechanisms of weight gain and weight loss. Integration of omics data is becoming a popular tool to increase understanding in such complex phenotypes. Biomarkers come in abundance, but small sample size remains a serious limitation in clinical trials. In the present study, we developed a strategy to screen predictors from a multiomics, high-dimensional, and longitudinal dataset from a small cohort of 10 women with obesity who were provided an identical very-low calorie diet. Our proposal explores the combinatorial space of potential predictors from transcriptomics, microbiome, metabolome, fecal bile acids, and clinical data with the application of the first-order Spearman partial correlation coefficient. Two statistics are proposed for screening predictors, the partial association score, and the persistent significance. We applied our strategy to predict rates of weight loss in our sample of participants in a hospital metabolic facility. Our method reduced an initial set of 42,000 biomarker candidates to 61 robust predictors. The results show baseline fecal bile acids and regulation in RT-polymerase chain reaction as the most predictive data sources in forecasting the rate of weight-loss. In summary, the present study proposes a strategy based on nonparametric statistics for ranking and screening predictors of weight loss from a multiomics study. The proposed biomarker screening strategy warrants further translational clinical investigation in obesity and other complex clinical phenotypes.
Assuntos
Multiômica , Redução de Peso , Feminino , Humanos , Obesidade/genética , Fezes , Ácidos e Sais BiliaresRESUMO
Lipid accumulation in nonadipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human neutral lipid storage disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl KO mice a low- or high-fat diet, we found that heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double KO mice also deficient in either cardiac lipoprotein lipase or cluster of differentiation 36, which is involved in an lipoprotein lipase-independent pathway for FA uptake in the heart. We show that neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined that non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo FA synthesis. Thus, we conclude that pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.
Assuntos
Aciltransferases , Cardiomiopatias , Lipase Lipoproteica , Animais , Humanos , Camundongos , Tecido Adiposo/metabolismo , Cardiomiopatias/metabolismo , Lipase/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos Knockout , Miocárdio/metabolismo , Triglicerídeos/metabolismo , Aciltransferases/deficiência , Aciltransferases/genéticaRESUMO
INTRODUCTION: Lifestyle improvements are key modifiable risk factors for Type 2 diabetes mellitus (DM) however specific influences of biologically active dietary metabolites remain unclear. Our objective was to compare non-targeted plasma metabolomic profiles of women with versus without confirmed incident DM. We focused on three lipid classes (fatty acyls, prenol lipids, polyketides). MATERIALS AND METHODS: Fifty DM cases and 100 individually matched control participants (80% with human immunodeficiency virus [HIV]) were enrolled in a case-control study nested within the Women's Interagency HIV Study. Stored blood samples (1-2 years prior to DM diagnosis among cases; at the corresponding timepoint among matched controls) were assayed in triplicate for metabolomics. Time-of-flight liquid chromatography mass spectrometry with dual electrospray ionization modes was utilized. We considered 743 metabolomic features in a two-stage feature selection approach with conditional logistic regression models that accounted for matching strata. RESULTS: Seven features differed by DM case status (all false discovery rate-adjusted q<0.05). Three flavonoids (two flavanones, one isoflavone) were respectively associated with lower odds of DM (all q<0.05), and sorbic acid was associated with greater odds of DM (all q<0.05). CONCLUSION: Flavonoids were associated with lower odds of incident DM while sorbic acid was associated with greater odds of incident DM.
Assuntos
Diabetes Mellitus Tipo 2 , Infecções por HIV , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Flavonoides , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Fatores de Risco , Ácido SórbicoRESUMO
Background: Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives: We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods: Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results: Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions: This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.
Assuntos
Gerenciamento Clínico , Obesidade/epidemiologia , Pandemias , Feminino , Saúde Global , Humanos , Masculino , Morbidade/tendências , Obesidade/terapiaRESUMO
BACKGROUND: Bariatric procedures are safe and effective treatments for obesity, inducing rapid and sustained loss of excess body weight. Laparoscopic adjustable gastric banding (LAGB) is unique among bariatric interventions in that it is a reversible procedure in which normal gastrointestinal anatomy is maintained. Knowledge regarding how LAGB effects change at the metabolite level is limited. OBJECTIVES: To delineate the impact of LAGB on fasting and postprandial metabolite responses using targeted metabolomics. SETTING: Individuals undergoing LAGB at NYU Langone Medical Center were recruited for a prospective cohort study. METHODS: We prospectively analyzed serum samples from 18 subjects at baseline and 2 months after LAGB under fasting conditions and after a 1-hour mixed meal challenge. Plasma samples were analyzed on a reverse-phase liquid chromatography time-of-flight mass spectrometry metabolomics platform. The main outcome measure was their serum metabolite profile. RESULTS: We quantitatively detected over 4,000 metabolites and lipids. Metabolite levels were altered in response to surgical and prandial stimuli, and metabolites within the same biochemical class tended to behave similarly in response to either stimulus. Plasma levels of lipid species and ketone bodies were statistically decreased after surgery whereas amino acid levels were affected more by prandial status than surgical condition. CONCLUSIONS: Changes in lipid species and ketone bodies postoperatively suggest improvements in the rate and efficiency of fatty acid oxidation and glucose handling after LAGB. Further investigation is necessary to understand how these findings relate to surgical response, including long term weight maintenance, and obesity-related comorbidities such as dysglycemia and cardiovascular disease.
RESUMO
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans. METHODS: We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30-40 mg/kg/m2). Each arm provided 75 grams of either fructose or glucose added to subjects' individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites. RESULTS: Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention. CONCLUSIONS: In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.
RESUMO
Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.
Assuntos
Aorta/metabolismo , Quilomícrons/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Gotículas Lipídicas/metabolismo , Triglicerídeos/metabolismo , Xantomatose/metabolismo , Animais , Aorta/patologia , Quilomícrons/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Gotículas Lipídicas/patologia , Lipase Lipoproteica/deficiência , Lipase Lipoproteica/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Triglicerídeos/genética , Xantomatose/genética , Xantomatose/patologiaRESUMO
OBJECTIVE: Obesity is a major public health challenge, and the US military veteran population is disproportionately affected. Using deidentified records from a local weight management clinic and a national clinical data repository, obesity pharmacotherapy use and effectiveness for weight loss and obesity comorbidities in this vulnerable population were assessed. METHODS: During the initial year of the local clinic, 43 records with monthly follow-up of MOVE! lifestyle intervention augmented by obesity pharmacotherapy were found. Nationally, more than 2 million records of prescribed obesity pharmacotherapy compared with metformin as control were identified. Records with detailed documentation of weight trends from 1 year before to 1 year after the prescription date for further analysis were selected for review. RESULTS: The most commonly prescribed medications in the local clinic were metformin, liraglutide, and combination phentermine/topiramate. On average, weight loss of -4.0 ± 2.1 kg over the initial 6-month intervention was observed. In the national cohort, 577,491 records with an obesity or control metformin prescription and adequate weight documentation were identified. The most effective pharmacotherapy in the national cohort was phentermine/topiramate (-0.0931 ± 0.0198 kg/wk difference), followed by liraglutide, lorcaserin, and orlistat. CONCLUSIONS: Obesity pharmacotherapy is effective in achieving clinically meaningful weight loss in veterans as part of an integrated care approach.