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

2021 ◽  
Vol 5 (1) ◽  
pp. 001-007
Mishra A ◽  
Shestopalov AV ◽  
Gaponov AM ◽  
Alexandrov IA ◽  
Roumiantsev SA

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.

2017 ◽  
Vol 114 (20) ◽  
pp. 5265-5270 ◽  
Delphine Duteil ◽  
Milica Tosic ◽  
Dominica Willmann ◽  
Anastasia Georgiadi ◽  
Toufike Kanouni ◽  

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.

2020 ◽  
Vol 21 (21) ◽  
pp. 8308
Ming-Ling Chang ◽  
Zinger Yang ◽  
Sien-Sing Yang

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.

Epigenomes ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 3
Ravikanth Nanduri

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

2020 ◽  
Vol 21 (13) ◽  
pp. 4773
Alana Deutsch ◽  
Daorong Feng ◽  
Jeffrey E. Pessin ◽  
Kosaku Shinoda

Adipose tissue is an important regulator of whole-body metabolism and energy homeostasis. The unprecedented growth of obesity and metabolic disease worldwide has required paralleled advancements in research on this dynamic endocrine organ system. Single-cell RNA sequencing (scRNA-seq), a highly meticulous methodology used to dissect tissue heterogeneity through the transcriptional characterization of individual cells, is responsible for facilitating critical advancements in this area. The unique investigative capabilities achieved by the combination of nanotechnology, molecular biology, and informatics are expanding our understanding of adipose tissue’s composition and compartmentalized functional specialization, which underlie physiologic and pathogenic states, including adaptive thermogenesis, adipose tissue aging, and obesity. In this review, we will summarize the use of scRNA-seq and single-nuclei RNA-seq (snRNA-seq) in adipocyte biology and their applications to obesity and diabetes research in the hopes of increasing awareness of the capabilities of this technology and acting as a catalyst for its expanded use in further investigation.

Siqi Li ◽  
Hongxia Gao ◽  
Yutaka Hasegawa ◽  
Xiaodan Lu

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.

2020 ◽  
Emmanouela Tsagkaraki ◽  
Sarah Nicoloro ◽  
Tiffany De Souza ◽  
Javier Solivan-Rivera ◽  
Anand Desai ◽  

AbstractObesity and type 2 diabetes (T2D) are associated with poor tissue responses to insulin1,2, disturbances in glucose and lipid fluxes3–5 and comorbidities including steatohepatitis6 and cardiovascular disease7,8. Despite extensive efforts at prevention and treatment9,10, diabetes afflicts over 400 million people worldwide11. Whole body metabolism is regulated by adipose tissue depots12–14, which include both lipid-storing white adipocytes and less abundant “brown” and “brite/beige” adipocytes that express thermogenic uncoupling protein UCP1 and secrete factors favorable to metabolic health15–18. Application of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing19,20 to enhance “browning” of white adipose tissue is an attractive therapeutic approach to T2D. However, the problems of cell-selective delivery, immunogenicity of CRISPR reagents and long term stability of the modified adipocytes are formidable. To overcome these issues, we developed methods that deliver complexes of SpyCas9 protein and sgRNA ex vivo to disrupt the thermogenesis suppressor gene NRIP121,22 with near 100% efficiency in human or mouse adipocytes. NRIP1 gene disruption at discrete loci strongly ablated NRIP1 protein and upregulated expression of UCP1 and beneficial secreted factors, while residual Cas9 protein and sgRNA were rapidly degraded. Implantation of the CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreased adiposity and liver triglycerides while enhancing glucose tolerance compared to mice implanted with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic modification of human adipocytes without exposure of the recipient to immunogenic Cas9 or delivery vectors.

Francesca Favaretto ◽  
Silvia Bettini ◽  
Luca Busetto ◽  
Gabriella Milan ◽  
Roberto Vettor

AbstractIn physiological conditions, the adipose organ resides in well-defined areas, where it acts providing an energy supply and as an endocrine organ involved in the control of whole-body energy metabolism. Adipose tissue adipokines connect the body’s nutritional status to the regulation of energy balance. When it surrounds organs, it provides also for mechanical protection. Adipose tissue has a complex and heterogenous cellular composition that includes adipocytes, adipose tissue-derived stromal and stem cells (ASCs) which are mesenchymal stromal cells, and endothelial and immune cells, which signal to each other and to other tissues to maintain homeostasis. In obesity and in other nutrition related diseases, as well as in age-related diseases, biological and functional changes of adipose tissue give rise to several complications. Obesity triggers alterations of ASCs, impairing adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance and other metabolic disorders. Adipose tissue grows by hyperplasia recruiting new ASCs and by hypertrophy, up to its expandability limit. To overcome this limitation and to store the excess of nutrients, adipose tissue develops ectopically, involving organs such as muscle, bone marrow and the heart. The origin of ectopic adipose organ is not clearly elucidated, and a possible explanation lies in the stimulation of the adipogenic differentiation of mesenchymal precursor cells which normally differentiate toward a lineage specific for the organ in which they reside. The chronic exposition of these newly-formed adipose depots to the pathological environment, will confer to them all the phenotypic characteristics of a dysfunctional adipose tissue, perpetuating the organ alterations. Visceral fat, but also ectopic fat, either in the liver, muscle or heart, can increase the risk of developing insulin resistance, type 2 diabetes, and cardiovascular diseases. Being able to prevent and to target dysfunctional adipose tissue will avoid the progression towards the complications of obesity and other nutrition-related diseases. The aim of this review is to summarize some of the knowledge regarding the presence of adipose tissue in particular tissues (where it is not usually present), describing the composition of its adipogenic precursors, and the interactions responsible for the development of organ pathologies.

Érique Castro ◽  
Tiago E. Oliveira Silva ◽  
William T. Festuccia

AbstractBeige (or brite, “brown in white”) adipocytes are uncoupling protein 1 (UCP1)-positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism.

2020 ◽  
Francisco Javier Ruiz-Ojeda ◽  
Jiefu Wang ◽  
Theresa Bäcker ◽  
Martin Krueger ◽  
Samira Zamani ◽  

AbstractReorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre), we demonstrate here that active β1 and β3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.

2021 ◽  
Vol 12 (1) ◽  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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