scholarly journals Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance: From Innate to Adaptive Immunity

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yanjing Li ◽  
Shaojingya Gao ◽  
Sirong Shi ◽  
Dexuan Xiao ◽  
Shuanglin Peng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Nucleic Acid ◽  
Adaptive Immunity ◽  
Water Solubility ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Tetrahedral Framework ◽  
Tissue Inflammation ◽  
Prepared Nanoparticles ◽  
Immunomodulatory Capacity

AbstractObesity-induced insulin resistance is the hallmark of metabolic syndrome, and chronic, low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Current therapeutic approaches lack efficacy and immunomodulatory capacity. Thus, a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance. Here, we synthesized a tetrahedral framework nucleic acid (tFNA) nanoparticle that carried resveratrol (RSV) to inhibit tissue inflammation and improve insulin sensitivity in obese mice. The prepared nanoparticles, namely tFNAs-RSV, possessed the characteristics of simple synthesis, stable properties, good water solubility, and superior biocompatibility. The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy. In high-fat diet (HFD)-fed mice, the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status. tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages. As for adaptive immunity, the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg, leading to the alleviation of insulin resistance. Furthermore, this study is the first to demonstrate that tFNAs, a nucleic acid material, possess immunomodulatory capacity. Collectively, our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice, suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

scholarly journals Correction to: Tetrahedral Framework Nucleic Acid‑Based Delivery of Resveratrol Alleviates Insulin Resistance: From Innate to Adaptive Immunity

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yanjing Li ◽  
Shaojingya Gao ◽  
Sirong Shi ◽  
Dexuan Xiao ◽  
Shuanglin Peng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Nucleic Acid ◽  
Adaptive Immunity ◽  
Tetrahedral Framework

scholarly journals Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1004
Author(s):  
Sonia Kiran ◽  
Vijay Kumar ◽  
Santosh Kumar ◽  
Robert L Price ◽  
Udai P. Singh
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Metabolic Diseases ◽  
Liver Disorder ◽  
Low Grade ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Cytokines And Chemokines

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.

scholarly journals Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Charmaine S. Tam ◽  
Leanne M. Redman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

2017 ◽  
Vol 312 (4) ◽  
pp. E309-E325 ◽  
Author(s):  
Pia S. Petersen ◽  
Xia Lei ◽  
Risa M. Wolf ◽  
Susana Rodriguez ◽  
Stefanie Y. Tan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Resistance Index ◽  
Activity Level ◽  
Low Grade ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Metabolic Role ◽  
Obesity And Diabetes

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

scholarly journals The Role of the Immune System in Obesity and Insulin Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Payal S. Patel ◽  
Eric D. Buras ◽  
Ashok Balasubramanyam
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune System ◽  
Stress Responses ◽  
Innate Immune System ◽  
Metabolic Diseases ◽  
Innate Immune ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation

The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKKβpathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance.

scholarly journals Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance

2012 ◽  
Vol 71 (4) ◽  
pp. 622-633 ◽  
Author(s):  
Orla M. Finucane ◽  
Clare M. Reynolds ◽  
Fiona C. McGillicuddy ◽  
Helen M. Roche
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Metabolic Diseases ◽  
Inhibitory Factor ◽  
Low Grade ◽  
Macrophage Migration ◽  
Pharmacological Agents

High-fat diet (HFD)-induced obesity has emerged as a state of chronic low-grade inflammation characterised by a progressive infiltration of immune cells, particularly macrophages, into obese adipose tissue. Adipose tissue macrophages (ATM) present immense plasticity. In early obesity, M2 anti-inflammatory macrophages acquire an M1 pro-inflammatory phenotype. Pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β produced by M1 ATM exacerbate local inflammation promoting insulin resistance (IR), which consequently, can lead to type-2 diabetes mellitus (T2DM). However, the triggers responsible for ATM recruitment and activation are not fully understood. Adipose tissue-derived chemokines are significant players in driving ATM recruitment during obesity. Macrophage migration inhibitory factor (MIF), a chemokine-like inflammatory regulator, is enhanced during obesity and is directly associated with the degree of peripheral IR. This review focuses on the functional role of macrophages in obesity-induced IR and highlights the importance of the unique inflammatory cytokine MIF in propagating obesity-induced inflammation and IR. Given MIF chemotactic properties, MIF may be a primary candidate promoting ATM recruitment during obesity. Manipulating MIF inflammatory activities in obesity, using pharmacological agents or functional foods, may be therapeutically beneficial for the treatment and prevention of obesity-related metabolic diseases.

scholarly journals Nutritional approaches for managing obesity-associated metabolic diseases

2017 ◽  
Vol 233 (3) ◽  
pp. R145-R171 ◽  
Author(s):  
Rachel Botchlett ◽  
Shih-Lung Woo ◽  
Mengyang Liu ◽  
Ya Pei ◽  
Xin Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Metabolic Pathways ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Fat Deposition ◽  
Low Grade ◽  
Metabolic Homeostasis ◽  
Peripheral Tissues ◽  
Metabolic Dysregulation

Obesity is an ongoing pandemic and serves as a causal factor of a wide spectrum of metabolic diseases including diabetes, fatty liver disease, and cardiovascular disease. Much evidence has demonstrated that nutrient overload/overnutrition initiates or exacerbates inflammatory responses in tissues/organs involved in the regulation of systemic metabolic homeostasis. This obesity-associated inflammation is usually at a low-grade and viewed as metabolic inflammation. When it exists continuously, inflammation inappropriately alters metabolic pathways and impairs insulin signaling cascades in peripheral tissues/organs such as adipose tissue, the liver and skeletal muscles, resulting in local fat deposition and insulin resistance and systemic metabolic dysregulation. In addition, inflammatory mediators, e.g., proinflammatory cytokines, and excessive nutrients, e.g., glucose and fatty acids, act together to aggravate local insulin resistance and form a vicious cycle to further disturb the local metabolic pathways and exacerbate systemic metabolic dysregulation. Owing to the critical role of nutrient metabolism in controlling the initiation and progression of inflammation and insulin resistance, nutritional approaches have been implicated as effective tools for managing obesity and obesity-associated metabolic diseases. Based on the mounting evidence generated from both basic and clinical research, nutritional approaches are commonly used for suppressing inflammation, improving insulin sensitivity, and/or decreasing fat deposition. Consequently, the combined effects are responsible for improvement of systemic insulin sensitivity and metabolic homeostasis.

scholarly journals Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders

2021 ◽  
Vol 18 (2) ◽  
pp. 511
Author(s):  
Kaiser Wani ◽  
Hind AlHarthi ◽  
Amani Alghamdi ◽  
Shaun Sabico ◽  
Nasser M. Al-Daghri
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Nlrp3 Inflammasome Activation ◽  
Specific Inhibitors

NLRP3 inflammasome is one of the multimeric protein complexes of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing pyrin and HIN domain family (PYHIN). When activated, NLRP3 inflammasome triggers the release of pro-inflammatory interleukins (IL)-1β and IL-18, an essential step in innate immune response; however, defective checkpoints in inflammasome activation may lead to autoimmune, autoinflammatory, and metabolic disorders. Among the consequences of NLRP3 inflammasome activation is systemic chronic low-grade inflammation, a cardinal feature of obesity and insulin resistance. Understanding the mechanisms involved in the regulation of NLRP3 inflammasome in adipose tissue may help in the development of specific inhibitors for the treatment and prevention of obesity-mediated metabolic diseases. In this narrative review, the current understanding of NLRP3 inflammasome activation and regulation is highlighted, including its putative roles in adipose tissue dysfunction and insulin resistance. Specific inhibitors of NLRP3 inflammasome activation which can potentially be used to treat metabolic disorders are also discussed.

Supplementation of a propionate-producing consortium improves markers of insulin resistance in an in vitro model of gut-liver axis

2020 ◽  
Vol 318 (5) ◽  
pp. E742-E749 ◽  
Author(s):  
Racha El Hage ◽  
Emma Hernandez-Sanabria ◽  
Marta Calatayud Arroyo ◽  
Tom Van de Wiele
Keyword(s):  
Insulin Resistance ◽  
Cross Talk ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Glycogen Synthesis ◽  
Short Chain Fatty Acids ◽  
Glycogen Storage ◽  
Cellular Level ◽  
Low Grade

Gut-liver cross talk is an important determinant of human health with profound effects on energy homeostasis. While gut microbes produce a huge range of metabolites, specific compounds such as short-chain fatty acids (SCFAs) can enter the portal circulation and reach the liver (Brandl K, Schnabl B. Curr Opin Gastroenterol 33: 128–133, 2017), a central organ involved in glucose homeostasis and diabetes control. Propionate is a major SCFA involved in activation of intestinal gluconeogenesis (IGN), thereby regulating food intake, enhancing insulin sensitivity, and leading to metabolic homeostasis. Although microbiome-modulating strategies may target the increased microbial production of propionate, it is not clear whether such an effect spreads through to the hepatic cellular level. Here, we designed a propionate-producing consortium using a selection of commensal gut bacteria, and we investigated how their delivered metabolites impact an in vitro enterohepatic model of insulin resistance. Glycogen storage on hepatocyte-like cells and inflammatory markers associated with insulin resistance were evaluated to understand the role of gut metabolites on gut-liver cross talk in a simulated scenario of insulin resistance. The metabolites produced by our consortium increased glycogen synthesis by ~57% and decreased proinflammatory markers such as IL-8 by 12%, thus elucidating the positive effect of our consortium on metabolic function and low-grade inflammation. Our results suggest that microbiota-derived products can be a promising multipurpose strategy to modulate energy homeostasis, with the potential ability to assist in managing metabolic diseases due to their adaptability.

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