13 results on '"O'Rourke, Robert A."'
Search Results
2. Obesity and Cancer
- Author
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O’Rourke, Robert W., Kurian, Marina, editor, Wolfe, Bruce M., editor, and Ikramuddin, Sayeed, editor
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- 2016
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3. Matrix density regulates adipocyte phenotype.
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Ky, Alexander, McCoy, Atticus J., Flesher, Carmen G., Friend, Nicole E., Li, Jie, Akinleye, Kore, Patsalis, Christopher, Lumeng, Carey N., Putnam, Andrew J., and O'Rourke, Robert W.
- Subjects
DENSITY matrices ,FAT cells ,ADIPOSE tissues ,HUMAN phenotype ,AEROBIC metabolism - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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4. The Pathophysiology of Obesity and Obesity-Related Diseases
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O’Rourke, Robert W., Nguyen, Ninh T., editor, Blackstone, Robin P., editor, Morton, John M., editor, Ponce, Jaime, editor, and Rosenthal, Raul J., editor
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- 2015
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5. Adipose METTL14‐Elicited N6‐Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing β Adrenergic Signaling and Lipolysis.
- Author
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Kang, Qianqian, Zhu, Xiaorong, Ren, Decheng, Ky, Alexander, MacDougald, Ormond A., O'Rourke, Robert W., and Rui, Liangyou
- Subjects
LIPOLYSIS ,INSULIN resistance ,NON-alcoholic fatty liver disease ,HIGH-fat diet ,WHITE adipose tissue ,SYMPATHETIC nervous system - Abstract
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 β 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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6. Lumican modulates adipocyte function in obesity-associated type 2 diabetes.
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Strieder-Barboza, Flesher, Carmen G., Geletka, Lynn M., Eichler, Tad, Akinleye, Olukemi, Ky, Alexander, Ehlers, Anne P., Lumeng, Carey N., and O'Rourke, Robert W.
- Subjects
TYPE 2 diabetes ,FAT cells ,ADIPOSE tissues ,INSULIN sensitivity ,INSULIN resistance - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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7. Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin‐4.
- Author
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Youngblood, Richard, Flesher, Carmen G., Delproposto, Jennifer, Baker, Nicki A., Neeley, Christopher K., Li, Fanghua, Lumeng, Carey N., Shea, Lonnie D., and O'Rourke, Robert W.
- Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Depot-specific adipocyte-extracellular matrix metabolic crosstalk in murine obesity.
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Strieder-Barboza, Clarissa, Baker, Nicki A., Flesher, Carmen G., Karmakar, Monita, Patel, Ayush, Lumeng, Carey N., and O'Rourke, Robert W.
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ADIPOSE tissues ,TISSUE culture ,METABOLIC disorders ,OBESITY ,EXTRACELLULAR matrix - Abstract
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 inmurine 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 SATmanifested 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. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity
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Muir, Lindsey A., Neeley, Christopher K., Meyer, Kevin A., Baker, Nicki A., Brosius, Alice M., Washabaugh, Alexandra R., Varban, Oliver A., Finks, Jonathan F., Zamarron, Brian F., Flesher, Carmen G., Chang, Joshua S., DelProposto, Jennifer B., Geletka, Lynn, Martinez-Santibanez, Gabriel, Kaciroti, Niko, Lumeng, Carey N., and O'Rourke, Robert W.
- Subjects
Male ,Hyperplasia ,Subcutaneous Fat ,Bariatric Surgery ,Hypertrophy ,Middle Aged ,Fibrosis ,Article ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Adipocytes ,Humans ,Female ,Obesity - Abstract
The relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in the context of obesity and the correlation of these tissue-based phenomena with systemic metabolic disease are poorly defined. The goal of this study was to clarify the relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in human obesity and determine the correlation of these adipose-tissue based phenomena with diabetes.Visceral and subcutaneous adipose tissues from humans with obesity collected during bariatric surgery were studied with QRTPCR, immunohistochemistry, and flow cytometry for expression of collagens and fibrosis-related proteins, adipocyte size, and preadipocyte frequency. Results were correlated with clinical characteristics including diabetes status.Fibrosis was decreased, hypertrophy was increased, and preadipocyte frequency and fibrotic gene expression were decreased in adipose tissues from diabetic subjects compared to non-diabetic subjects. These differences were greater in visceral compared to subcutaneous adipose tissue.These data are consistent with the hypothesis that adipose tissue fibrosis in the context of human obesity limits adipocyte hypertrophy and is associated with a reciprocal increase in adipocyte hyperplasia, with beneficial effects on systemic metabolism. These findings suggest adipose tissue fibrosis as a potential target for manipulation of adipocyte metabolism.
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- 2015
10. Adipose tissue and the physiologic underpinnings of metabolic disease.
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O'Rourke, Robert W.
- Abstract
Abstract Adipose tissue dysfunction underlies the pathogenesis of metabolic disease. The metrics used to quantify adiposity and its association with metabolic disease, including body mass index, have limitations with important clinical implications. An understanding of the molecular and cellular mechanisms by which adipose tissue regulates systemic metabolism and contributes to metabolic disease will lead to next-generation adipose tissue–based therapy. [ABSTRACT FROM AUTHOR]
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- 2018
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11. Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice.
- Author
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Frikke-Schmidt, Henriette, Zamarron, Brian F., O'Rourke, Robert W., Sandoval, Darleen A., Lumeng, Carey N., and Seeley, Randy J.
- Abstract
Objective: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. Methods: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. Results: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c
− macrophages, increased frequencies of T cells (CD4+ , CD8+ , and CD4− /CD8− T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. Conclusions: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
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12. Adipocyte hypertrophy-hyperplasia balance contributes to weight loss after bariatric surgery.
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Muir, Lindsey A., Baker, Nicki A., Washabaugh, Alexandra R., Neeley, Christopher K., Flesher, Carmen G., DelProposto, Jennifer B., Geletka, Lynn M., Ghaferi, Amir A., Finks, Jonathan F., Singer, Kanakadurga, Varban, Oliver A., Lumeng, Carey N., and O'Rourke, Robert W.
- Abstract
Predictors of weight loss responses are not well-defined. We hypothesized that adipose tissue phenotypic features related to remodeling would be associated with bariatric surgery weight loss responses. Visceral and subcutaneous adipose tissues collected from patients during bariatric surgery were studied with flow cytometry, immunohistochemistry, and QRTPCR, and results correlated with weight loss outcomes. Age, male sex, and a diagnosis of type 2 diabetes were associated with less weight loss. Adipocyte size was increased and preadipocyte frequency was decreased in visceral adipose tissue from diabetic subjects. Decreased adipose tissue preadipocyte frequency was associated with less weight loss in women but not men. These data suggest that phenotypic features of adipose tissue remodeling may predict responses to weight loss interventions. [ABSTRACT FROM PUBLISHER]
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- 2017
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13. Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose tissue inflammation in obesity and diabetes.
- Author
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Russo, Lucia, Muir, Lindsey, Geletka, Lynn, Delproposto, Jennifer, Baker, Nicki, Flesher, Carmen, O'Rourke, Robert, and Lumeng, Carey N.
- Abstract
Expansion of visceral adipose tissue (VAT) and metabolic inflammation are consequences of obesity and associated with type 2 diabetes (T2DM). Metabolically activated adipose tissue macrophages (ATMs) undergo qualitative and quantitative changes that influence their inflammatory responses. How these cells contribute to insulin resistance (IR) in humans is not well understood. Cholesterol 25-Hydroxylase (CH25H) converts cholesterol into 25-Hydroxycholesterol (25-HC), an oxysterol that modulates immune responses. Using human and murine models, we investigated the role of CH25H in metabolic inflammation. We performed transcriptomic (RNASeq) analysis on the human whole AT biopsies and sorted ATMs from obese non-diabetic (NDM) and obese diabetic (DM) subjects to inquire if CH25H was increased in DM. We challenged mice lacking Ch25h with a high-fat diet (HFD) to characterize their metabolic and immunologic profiling. Ch25h KO mice and human adipose tissue biopsies from NDM and DM subjects were analyzed. LC-MS was conducted to measure 25-HC level in AT. In vitro analysis permitted us to investigate the effect of 25-HC on cytokine expression. In our RNASeq analysis of human visceral and subcutaneous biopsies, gene pathways related to inflammation were increased in obese DM vs. non-DM subjects that included CH25H. CH25H was enriched in the stromal vascular fraction of human adipose tissue and highly expressed in CD206
+ human ATMs by flow cytometry analysis. We measured the levels of the oxysterols, 25-HC and 7α25diHC, in human visceral adipose tissue samples and showed a correlation between BMI and 25-HC. Using mouse models of diet-induced obesity (DIO), we found that HFD-induced Ch25h expression in eWAT and increased levels of 25-HC in AT. On HFD, Ch25h KO mice became obese but exhibited reduced plasma insulin levels, improved insulin action, and decreased ectopic lipid deposit. Improved insulin sensitivity in Ch25h KO mice was due to attenuation of CD11c+ adipose tissue macrophage infiltration in eWAT. Finally, by testing AT explants, bone marrow-derived macrophages (BMDMs) and SVF cells from Ch25h deficient mice, we observed that 25-HC is required for the expression of pro-inflammatory genes. 25-HC was also able to induce inflammatory genes in preadipocytes. Our data suggest a critical role for CH25H/25-HC in the progression of meta-inflammation and insulin resistance in obese humans and mouse models of obesity. In response to obesogenic stimuli, CH25H/25-HC could exert a pro-inflammatory role. • CH25H upregulation in visceral adipose tissue is associated with diabetes in humans. • ATMs are the primary site of CH25H expression in humans and mice. • DIO in mice activates Ch25h expression and 25-HC production in visceral adipose tissue. • Obese Ch25h KO mice have improved insulin sensitivity due to attenuated adipose tissue inflammation. • In response to inflammatory stimuli, Ch25h/25-HC potentiates myeloid activation. [ABSTRACT FROM AUTHOR]- Published
- 2020
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