SRC-3/AIB-1 may Enhance Hepatic NFATC1 Transcription and Mediate Inflammation in a Tissue-Specific Manner in Morbid Obesity

2020 ◽  
Vol 20 (2) ◽  
pp. 242-255
Author(s):  
Athina Chasapi ◽  
Konstantinos Balampanis ◽  
Anna Tanoglidi ◽  
Eleni Kourea ◽  
George I. Lambrou ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Drug Targets ◽  
Energy Homeostasis ◽  
Steroid Receptor ◽  
Inflammatory Biomarkers ◽  
Morbidly Obese ◽  
Low Grade ◽  
Tissue Specific ◽  
Global Epidemic ◽  
Future Drug

Background: Obesity is a global epidemic which is associated with several cardiometabolic comorbidities and is characterized by chronic, low grade systemic inflammation. Numerous biomarkers have been implicated in the pathophysiology of the disease, including transcription factors and coregulators. Steroid Receptor Coactivator (SRC)-family represent the master regulators of metabolic pathways and their dysregulation is strongly associated with numerous metabolic disorders. Methods: 50 morbidly obese patients participated in the present study. Biopsies were collected from visceral adipose tissue, subcutaneous adipose tissue, skeletal muscle, extra-myocellular adipose tissue and liver. We evaluated the differential protein expression of NFATc1, SRC-2/TIF-2, SRC-3/AIB-1 and inflammatory biomarkers CD68 and CD3 by immunohistochemistry. The current study was designed to determine any correlations between the transcription factor NFATc1 and the SRC coregulators, as well as any associations with the inflammatory biomarkers. Results: We identified SRC-3 as a hepatic NFATc1 coactivator and we demonstrated its possible role in energy homeostasis and lipid metabolism. Moreover, we revealed a complex and extensive intraand inter-tissue network among the three main investigated proteins and the inflammatory biomarkers, suggesting their potential participation in the obesity-induced inflammatory cascade. Conclusions: Steroid receptor coactivators are critical regulators of human metabolism with pleiotropic and tissue-specific actions. We believe that our study will contribute to the better understanding of the complex multi-tissue interactions that are disrupted in obesity and can therefore lead to numerous cardiometabolic diseases. Further on, our present findings suggest that SRC-3/AIB-1 could constitute possible future drug targets.

scholarly journals Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8308
Author(s):  
Ming-Ling Chang ◽  
Zinger Yang ◽  
Sien-Sing Yang
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Low Grade ◽  
Colon Polyps ◽  
Alcoholic Fatty Liver ◽  
Global Epidemic ◽  
Markers Of Inflammation ◽  
Digestive Diseases ◽  
Digestive Cancers

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

scholarly journals Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1350-1357 ◽  
Author(s):  
Florian W. Kiefer ◽  
Maximilian Zeyda ◽  
Jelena Todoric ◽  
Joakim Huber ◽  
René Geyeregger ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Plasma Concentrations ◽  
Morbidly Obese ◽  
Low Grade ◽  
Obese Patients ◽  
Multifunctional Protein ◽  
Inflammatory Processes ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (<2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

scholarly journals Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Jolanda H. M. van Bilsen ◽  
Willem van den Brink ◽  
Anita M. van den Hoek ◽  
Remon Dulos ◽  
Martien P. M. Caspers ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Strong Correlation ◽  
In Silico ◽  
Metabolic Disorders ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Hepatic Inflammation ◽  
Tissue Specific ◽  
Tissue Inflammation ◽  
Low Grade Inflammation

Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding of the inflammatory dynamics and to monitor them on the individual level. To this end, blood-based biomarkers reflecting the tissue-specific inflammatory dynamics would be of great value. Here, we describe an in silico approach to select candidate biomarkers for tissue-specific inflammation by using a priori mechanistic knowledge from pathways and tissue-derived molecules. The workflow resulted in a list of candidate markers, in part consisting of literature confirmed biomarkers as well as a set of novel, more innovative biomarkers that reflect inflammation in the liver and adipose tissue. The first step of biomarker verification was on murine tissue gene-level by inducing hepatic inflammation and adipose tissue inflammation through a high-fat diet. Our data showed that in silico predicted hepatic markers had a strong correlation to hepatic inflammation in the absence of a relation to adipose tissue inflammation, while others had a strong correlation to adipose tissue inflammation in the absence of a relation to liver inflammation. Secondly, we evaluated the human translational value by performing a curation step in the literature using studies that describe the regulation of the markers in human, which identified 9 hepatic (such as Serum Amyloid A, Haptoglobin, and Interleukin 18 Binding Protein) and 2 adipose (Resistin and MMP-9) inflammatory biomarkers at the highest level of confirmation. Here, we identified and pre-clinically verified a set of in silico predicted biomarkers for liver and adipose tissue inflammation which can be of great value to study future development of therapeutic/lifestyle interventions to combat metabolic inflammatory complications.

Mini-Review: Fight against fibrosis in adipose tissue remodeling

2021 ◽  
Author(s):  
Siqi Li ◽  
Hongxia Gao ◽  
Yutaka Hasegawa ◽  
Xiaodan Lu
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Caloric Intake ◽  
Clinical Manifestations ◽  
Tissue Remodeling ◽  
Low Grade ◽  
Tissue Fibrosis ◽  
Ecm Remodeling ◽  
Glucose And Lipid Homeostasis ◽  
Adipose Tissue Remodeling

Adipose is a key tissue regulating energy homeostasis. In states of obesity, caloric intake exceeds energy expenditure, thereby accelerating lipid accumulation with ongoing extracellular matrix (ECM) remodeling. Excess deposition of lipids and expansion of adipocytes potentially decrease ECM flexibility with local hypoxia and inflammation. Hypoxia and chronic low-grade inflammation accelerate the development of adipose tissue fibrosis and related metabolic dysfunctions. Adipose tissue remodeling impacts localized adipose tissue metabolism, which including adipogenesis, angiogenesis, insulin sensitivity, cytokine secretion profile, and in turn alters systemic glucose and lipid homeostasis. The activation and maintenance of beige adipocyte is a potential therapeutic strategy for combating HFD-induced adipose tissue fibrosis and insulin resistance. In this review, we focused on the regulatory mechanisms and mediators in remodeling of adipose tissue fibrosis, along with their relevance to clinical manifestations.

Getting the message across: mechanisms of physiological cross talk by adipose tissue

2009 ◽  
Vol 296 (6) ◽  
pp. E1210-E1229 ◽  
Author(s):  
Do-Eun Lee ◽  
Sylvia Kehlenbrink ◽  
Hanna Lee ◽  
Meredith Hawkins ◽  
John S. Yudkin
Keyword(s):  
Adipose Tissue ◽  
Cross Talk ◽  
Energy Homeostasis ◽  
Cellular Level ◽  
The Body ◽  
Low Grade ◽  
Storage Site ◽  
Integrative Physiology ◽  
Energy Excess ◽  
Low Grade Inflammation

Obesity is associated with resistance of skeletal muscle to insulin-mediated glucose uptake, as well as resistance of different organs and tissues to other metabolic and vascular actions of insulin. In addition, the body is exquisitely sensitive to nutrient imbalance, with energy excess or a high-fat diet rapidly increasing insulin resistance, even before noticeable changes occur in fat mass. There is a growing acceptance of the fact that, as well as acting as a storage site for surplus energy, adipose tissue is an important source of signals relevant to, inter alia, energy homeostasis, fertility, and bone turnover. It has also been widely recognized that obesity is a state of low-grade inflammation, with adipose tissue generating substantial quantities of proinflammatory molecules. At a cellular level, the understanding of the signaling pathways responsible for such alterations has been intensively investigated. What is less clear, however, is how alterations of physiology, and of signaling, within one cell or one tissue are communicated to other parts of the body. The concepts of cell signals being disseminated systemically through a circulating “endocrine” signal have been complemented by the view that local signaling may similarly occur through autocrine or paracrine mechanisms. Yet, while much elegant work has focused on the alterations in signaling that are found in obesity or energy excess, there has been less attention paid to ways in which such signals may propagate to remote organs. This review of the integrative physiology of obesity critically appraises the data and outlines a series of hypotheses as to how interorgan cross talk takes place. The hypotheses presented include the “fatty acid hypothesis,”, the “portal hypothesis,”, the “endocrine hypothesis,”, the “inflammatory hypothesis,”, the “overflow hypothesis,”, a novel “vasocrine hypothesis,” and a “neural hypothesis,” and the strengths and weaknesses of each hypothesis are discussed.

scholarly journals Subacute Endotoxemia Induces Adipose Inflammation and Changes in Lipid and Lipoprotein Metabolism in Cats

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 804-815 ◽  
Author(s):  
M. Osto ◽  
E. Zini ◽  
M. Franchini ◽  
C. Wolfrum ◽  
F. Guscetti ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Whole Body ◽  
Low Grade ◽  
Model Assessment ◽  
Insulin Metabolism ◽  
Tissue Specific ◽  
Markers Of Inflammation ◽  
Adipose Tissue Dysfunction

Acute inflammation in humans is associated with transient insulin resistance (IR) and dyslipidemia. Chronic low-grade inflammation is a pathogenic component of IR and adipose tissue dysfunction in obesity-induced type 2 diabetes. Because feline diabetes closely resembles human type 2 diabetes, we studied whether lipopolysaccharide (LPS)-induced subacute inflammation, in the absence of obesity, is the potential primary cause of IR and metabolic disorders. Cats received increasing iv doses (10–1000 ng/kg−1 · h−1) of LPS (n = 5) or saline (n = 5) for 10 d. Body temperature, proinflammatory and metabolic markers, and insulin sensitivity were measured daily. Tissue mRNA and protein expression were quantified on d 10. LPS infusion increased circulating and tissue markers of inflammation. Based on the homeostasis model assessment, endotoxemia induced transient IR and β-cell dysfunction. At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-γ1 and -2, and muscle insulin receptor substrate-1. In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. Prolonged LPS-induced inflammation caused acute IR, followed by long-lasting tissue-specific dysfunctions of lipid-, glucose-, and insulin metabolism-related targets; this ultimately resulted in dyslipidemia but not whole-body IR. Endotoxemia in cats may provide a promising model to study the cross talk between metabolic and inflammatory responses in the development of adipose tissue dysfunction and IR.

scholarly journals Pro-inflammatory effects of DEHP in SGBS-derived adipocytes and THP-1 macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristina Schaedlich ◽  
Laura-Sophie Beier ◽  
Judith Kolbe ◽  
Martin Wabitsch ◽  
Jana Ernst
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Overweight And Obesity ◽  
Environmental Chemicals ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Secreted Factors ◽  
The Impact ◽  
Dehp Exposure

AbstractIn the member countries of the Organization for Economic Co-operation and Development (OECD), overweight and obesity affect the majority of the population. The use of environmental chemicals, such as the plasticizer DEHP, has largely increased simultaneously with this development. DEHP is an "obesogen" that interferes with normal adipocyte differentiation and energy homeostasis. Obesity in turn is accompanied by chronic low-grade adipose tissue inflammation, leading to metabolic disorders such as type II diabetes. The main actors in adipose tissue inflammation are adipocytes and macrophages. However, the impact of DEHP on adipose tissue inflammation and the crosstalk between adipocytes and macrophages are unknown and the subjects of the current study. The influence of DEHP on inflammation was investigated in human Simpson–Golabi–Behmel syndrome (SGBS)-derived adipocytes and human THP-1 macrophages. The proinflammatory markers IL8, MCP1, IL1β, TNFα and others were measured (qRT-PCR, ELISA) in SGBS-derived adipocytes treated with DEHP [day 0 (d0)–d4; 50 µg/ml] and THP-1 macrophages cultured with conditioned medium (CM) from DEHP-treated adipocytes (SGBS-CM) (from d4 and d8). DEHP exposure led to a proinflammatory state in SGBS-derived adipocytes (e.g., increased secretion of IL8 and MCP1). Surprisingly, exposure of THP-1 macrophages to SGBS-CM did not show DEHP-induced effects. However, we demonstrated that medium containing (pre)adipocyte-secreted factors had a significant impact on the expression and secretion of macrophage and inflammatory markers in THP-1 macrophages in general and led to the significantly increased accumulation of intracellular lipid droplets.

scholarly journals The regulation of stearoyl-CoA desaturase gene expression is tissue specific in chickens

2007 ◽  
Vol 192 (1) ◽  
pp. 229-236 ◽  
Author(s):  
Sami Dridi ◽  
Mohammed Taouis ◽  
Arieh Gertler ◽  
Eddy Decuypere ◽  
Johan Buyse
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Food Deprivation ◽  
Broiler Chickens ◽  
Energy Homeostasis ◽  
Mrna Levels ◽  
Related Factors ◽  
Tissue Specific ◽  
Stearoyl Coa Desaturase ◽  
And Gender

Emerging evidence suggests a potential role of stearoyl-CoA desaturase (SCD)-1 in the control of body weight and energy homeostasis. The present study was conducted to investigate the effects of several energy balance-related factors (leptin, cerulenin, food deprivation, genotype, and gender) on SCD gene expression in chickens. In experiment 1, 6-week-old female and male broiler chickens were used. In experiment 2, two groups of 3-week-old broiler chickens were continuously infused with recombinant chicken leptin (8 μg/kg/h) or vehicle for 6 h. In experiment 3, two groups of 2-week-old broiler chickens received i.v. injections of cerulenin (15 mg/kg) or vehicle. In experiment 4, two broiler chicken lines (fat and lean) were submitted to two nutritional states (food deprivation for 16 or 24 h and feeding ad libitum). At the end of each experiment, tissues were collected for analyzing SCD gene expression. Data from experiment 1 showed that SCD is ubiquitously expressed in chicken tissues with highest levels in the proventriculus followed by the ovary, hypothalamus, kidney, liver, and adipose tissue in female, and hypothalamus, leg muscle, pancreas, liver, and adipose tissue in male. Female chickens exhibited significantly higher SCD mRNA levels in kidney, breast muscle, proventriculus, and intestine than male chickens. However, hypothalamic SCD gene expression was higher in male than in female (P < 0.05). Leptin increased SCD gene expression in chicken liver (P < 0.05), whereas cerulenin decreased SCD mRNA levels in muscle. Both leptin and cerulenin significantly reduced food intake (P < 0.05). Food deprivation for either 16 or 24 h decreased the hepatic SCD gene expression in fat line and lean line chickens compared with their fed counterparts (P < 0.05). The hypothalamic SCD mRNA levels were decreased in both lines only after 24 h of food deprivation (P < 0.05). In conclusion, SCD is ubiquitously expressed in chickens and it is regulated by leptin, cerulenin, nutritional state, and gender in a tissue-specific manner.

scholarly journals In Vivo Knockdown of Adipocyte Erythropoietin Receptor Does Not Alter Glucose or Energy Homeostasis

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3652-3659 ◽  
Author(s):  
Cynthia T. Luk ◽  
Sally Yu Shi ◽  
Diana Choi ◽  
Erica P. Cai ◽  
Stephanie A. Schroer ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Physiological Role ◽  
Tissue Expansion ◽  
Erythropoietin Receptor ◽  
Tissue Specific ◽  
Epo Receptor ◽  
Beneficial Effects ◽  
Obesity And Diabetes

The growing prevalence of obesity and diabetes necessitate a better understanding of the role of adipocyte biology in metabolism. Increasingly, erythropoietin (EPO) has been shown to have extraerythropoietic and cytoprotective roles. Exogenous administration has recently been shown to have beneficial effects on obesity and diabetes in mouse models and EPO can modulate adipogenesis and insulin signaling in 3T3-L1 adipocytes. However, its physiological role in adipocytes has not been identified. Using male and female mice with adipose tissue-specific knockdown of the EPO receptor, we determine that adipocyte EPO signaling is not essential for the maintenance of energy homeostasis or glucose metabolism. Adipose tissue-specific disruption of EPO receptor did not alter adipose tissue expansion, adipocyte morphology, insulin resistance, inflammation, or angiogenesis in vivo. In contrast to the pharmacological effects of EPO, we demonstrate that EPO signaling at physiological levels is not essential for adipose tissue regulation of metabolism.

scholarly journals Role of toll-like receptors and their ligands in adipocyte secretion

2021 ◽  
Vol 5 (1) ◽  
pp. 001-007
Author(s):  
Mishra A ◽  
Shestopalov AV ◽  
Gaponov AM ◽  
Alexandrov IA ◽  
Roumiantsev SA
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Low Grade ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Whole Body Metabolism ◽  
Significant Expression ◽  
Adipose Tissue Remodeling

Background: Adipose tissue is one of the main sites of energy homeostasis that regulates whole body metabolism with the help of adipokines. Disruption in its proper functioning results in adipose tissue remodeling (primarily hypertrophy and hyperplasia) which directly influences the secretion of said adipokines. Obesity characterized as chronic low-grade inflammation of the adipose tissue is one such condition that has far reaching effects on whole body metabolism. Inflammation in turn results in immune cells infiltrating into the tissue and further promoting adipocyte dysfunction. Purpose: In our study we explored this adipose tissue-innate immunity axis by differentiating adipose tissue derived stem cells (ADSCs) into white and beige adipocytes. We further stimulated our cultures with lipopolysaccharide (LPS), flagellin, or meteorin-like, glial cell differentiation regulator (METRNL) to trigger an inflammatory response. We then evaluated Toll-like receptor (TLR) mRNA expression and secretion of interleukin (IL-6), interleukin-8 (IL-8), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in these cultures. Results: We found that TLR2 is the highest expressed receptor in adipocytes. Further, LPS and METRNL are strong activators of TLR2 in white and beigeBMP7(-) adipocytes. TLR4 was not significantly expressed in any of our cultures despite LPS stimulation. TLR9 expression is upregulated in ADSCs upon LPS and METRNL stimulation. IL-6 and IL-8 secretion is increased upon LPS stimulation in white adipocytes. METRNL activates both IL-6 and IL-8 expression in adipocyte cultures. Lastly, BDNF and NGF is secreted by all adipocyte cultures with beigeBMP7(-) and beigeBMP7(+) secreting slightly higher amounts in comparison to white adipocytes. Conclusion: ADSCs and adipocytes alike are capable of expressing TLRs, but white adipocytes remain the highest expressing in both control and stimulated cultures. TLR2 is highly expressed in white and beige adipocytes whereas TLR4 showed no significant expression. LPS and METRNL trigger IL-6 and IL-8 secretion in adipocytes. Products of white adipocyte “browning” are capable of secreting higher amounts of BDNF and NGF in comparison to white adipocytes.

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