scholarly journals Organ Crosstalk and the Modulation of Insulin Signaling

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2082
Author(s):  
Alejandra Romero ◽  
Juergen Eckel
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Current Knowledge ◽  
Secreted Proteins ◽  
Additional Component ◽  
Organ Crosstalk ◽  
Potential Impact

A highly complex network of organ communication plays a key role in regulating metabolic homeostasis, specifically due to the modulation of the insulin signaling machinery. As a paradigm, the role of adipose tissue in organ crosstalk has been extensively investigated, but tissues such as muscles and the liver are equally important players in this scenario. Perturbation of organ crosstalk is a hallmark of insulin resistance, emphasizing the importance of crosstalk molecules in the modulation of insulin signaling, potentially leading to defects in insulin action. Classically secreted proteins are major crosstalk molecules and are able to affect insulin signaling in both directions. In this review, we aim to focus on some crosstalk mediators with an impact on the early steps of insulin signaling. In addition, we also summarize the current knowledge on the role of extracellular vesicles in relation to insulin signaling, a more recently discovered additional component of organ crosstalk. Finally, an attempt will be made to identify inter-connections between these two pathways of organ crosstalk and the potential impact on the insulin signaling network.

MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets

2019 ◽  
Vol 133 (1) ◽  
pp. 23-40 ◽  
Author(s):  
Silvia Lorente-Cebrián ◽  
Pedro González-Muniesa ◽  
Fermín I. Milagro ◽  
J. Alfredo Martínez
Keyword(s):  
Adipose Tissue ◽  
Current Knowledge ◽  
Metabolic Effects ◽  
Protein Coding ◽  
Non Coding Rnas ◽  
Potential Impact ◽  
Dietary Strategies ◽  
Potential Use

AbstractObesity is a metabolic condition usually accompanied by insulin resistance (IR), type 2 diabetes (T2D), and dyslipidaemia, which is characterised by excessive fat accumulation and related to white adipose tissue (WAT) dysfunction. Enlargement of WAT is associated with a transcriptional alteration of coding and non-coding RNAs (ncRNAs). For many years, big efforts have focused on understanding protein-coding RNAs and their involvement in the regulation of adipocyte physiology and subsequent role in obesity. However, diverse findings have suggested that a dysfunctional adipocyte phenotype in obesity might be also dependent on specific alterations in the expression pattern of ncRNAs, such as miRNAs. The aim of this review is to update current knowledge on the physiological roles of miRNAs and other ncRNAs in adipose tissue function and their potential impact on obesity. Therefore, we examined their regulatory role on specific WAT features: adipogenesis, adipokine secretion, inflammation, glucose metabolism, lipolysis, lipogenesis, hypoxia and WAT browning. MiRNAs can be released to body fluids and can be transported (free or inside microvesicles) to other organs, where they might trigger metabolic effects in distant tissues, thus opening new possibilities to a potential use of miRNAs as biomarkers for diagnosis, prognosis, and personalisation of obesity treatment. Understanding the role of miRNAs also opens the possibility of using these molecules on individualised dietary strategies for precision weight management. MiRNAs should be envisaged as a future therapeutic approach given that miRNA levels could be modulated by synthetic molecules (f.i. miRNA mimics and inhibitors) and/or specific nutrients or bioactive compounds.

scholarly journals Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

2020 ◽  
Author(s):  
Yujeong Kim ◽  
Ok-Kyung Kim
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Metabolic Disorders ◽  
Extracellular Vesicle ◽  
Extracellular Mirnas

ABSTRACT Recently, extracellular microRNAs (miRNAs) from adipose tissue have been shown to be involved in the development of insulin resistance. Here, we summarize several mechanisms explaining the pathogenesis of obesity-induced insulin resistance and associated changes in the expression of obesity-associated extracellular miRNAs. We discuss how miRNAs, particularly miR-27a, miR-34a, miR-141-3p, miR-155, miR210, and miR-222, in extracellular vesicles secreted from the adipose tissue can affect the insulin signaling pathway in metabolic tissue. Understanding the role of these miRNAs will further support the development of therapeutics for obesity and metabolic disorders such as type 2 diabetes.

scholarly journals Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jie Li ◽  
Ran An ◽  
Simin Liu ◽  
Haiyan Xu
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Knockout Model ◽  
Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

scholarly journals Obesity: The role of desynchronosis and genetic factors in mechanisms of its development

2017 ◽  
Vol 8 (1) ◽  
pp. 23-29
Author(s):  
M. O. Ryznychuk ◽  
V. P. Pishak
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Genetic Factors ◽  
Hormone Secretion ◽  
Insulin Receptors ◽  
Secretory Activity ◽  
Membrane Receptors ◽  
Brown Adipose

The article highlights the role of desynchronosis and certain genetic factors in the development of obesity. Some pathogenetic links of obesity and the influence of melatonin on them are analyzed.Desynchronosis is one of the causes of obesity as a result of dysregulatory changes in the chronoperiodic system – between suprachiasmatic nuclei of the hypothalamus and secretory activity of the pineal gland.In obesity there are some changes in circadian patterns of important physiological parameters. These include acrophases of blood pressure; rhythm of hormone secretion, including insulin; electrolytes; sleep-wake cycle displaced for a period of a day, which is a deviation from the normal course. Phase discrepancies of established circadian oscillations of physiological processes arise. Preconditions of fat metabolism imbalance, particularly visfatin, apelin and vaspin – components of atherosclerotic lesions, gradually emerge.There is abundant evidence for close relationships between metabolism and circadian mechanisms. It is proved, that there is a strong direct impact of endogenous circadian rhythms on the metabolic pathways that do not depend on food intake or sleep. A potential low molecular weight of biomarkers of human circadian phases has been identified. A number of key metabolic enzymes in tissues such as the liver, adipose tissue or the pancreas are chronodependent. Desynchronosis phenomena caused by genetic or environmental factors can lead to serious metabolic disorders, including obesity, insulin resistance and metabolic syndrome.Genesis of pineal removal-induced insulin resistance and reduced glucose tolerance in cells is related to the consequences of melatonin absence, which leads to abnormalities in insulin signaling pathways and reduced GLUT4 gene expression and protein content.Insulin-sensitive tissues (white and brown adipose tissue, skeletal and heart muscles) after pineal removal are characterized by a significant reduction of GLUT4 mRNA and the content of microsomal and membrane proteins, which are compensated during treatment by melatonin. Functional synergy exists between melatonin and insulin. Melatonin is able through the membrane receptors MT1 to cause rapid tyrosine phosphorylation, activate tyrosine kinase of beta subunits of insulin receptors and mobilize several intracellular stages of insulin-signaling pathway transduction.Thus, the protective effect of melatonin in cases of disturbance to the carbohydrate metabolism is manifested in the formation of circadian periodicity by modulating the expression of time genes.

scholarly journals The role of obesity and adipose tissue dysfunction in gestational diabetes mellitus

2018 ◽  
Vol 238 (2) ◽  
pp. R63-R77 ◽  
Author(s):  
Patrik Šimják ◽  
Anna Cinkajzlová ◽  
Kateřina Anderlová ◽  
Antonín Pařízek ◽  
Miloš Mráz ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Current Knowledge ◽  
Peripheral Insulin Resistance ◽  
Adipose Tissue Dysfunction ◽  
History Of

Gestational diabetes mellitus is defined as diabetes diagnosed in the second or third trimester of pregnancy in patients with no history of diabetes prior to gestation. It is the most common complication of pregnancy. The underlying pathophysiology shares some common features with type 2 diabetes mellitus (T2DM) combining relatively insufficient insulin secretion with increased peripheral insulin resistance. While a certain degree of insulin resistance is the physiological characteristics of the second half of pregnancy, it is significantly more pronounced in patients with gestational diabetes. Adipose tissue dysfunction and subclinical inflammation in obesity are well-described causes of increased insulin resistance in non-pregnant subjects and are often observed in individuals with T2DM. Emerging evidence of altered adipokine expression and local inflammation in adipose tissue in patients with gestational diabetes suggests an important involvement of adipose tissue in its etiopathogenesis. This review aims to summarize current knowledge of adipose tissue dysfunction and its role in the development of gestational diabetes. We specifically focus on the significance of alterations of adipokines and immunocompetent cells number and phenotype in fat. Detailed understanding of the role of adipose tissue in gestational diabetes may provide new insights into its pathophysiology and open new possibilities of its prevention and treatment.

scholarly journals Inflammatory Mediators and Insulin Resistance in Obesity: Role of Nuclear Receptor Signaling in Macrophages

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Lucía Fuentes ◽  
Tamás Rőszer ◽  
Mercedes Ricote
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Liver Steatosis ◽  
Visceral Obesity ◽  
M2 Macrophage ◽  
Low Grade ◽  
The Impact

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.

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 Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

Abstract 461: Role of Physical Training Intensity in Metabolic and Cardiovascular Dysfunctions in a Fructose Overload Model

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jacqueline F Machi ◽  
Nathalia Bernardes ◽  
Danielle S Dias ◽  
Cristiano Mostarda ◽  
Edson Moreira ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Maximum Speed ◽  
Normal Range ◽  
Maximal Exercise Test ◽  
Baroreceptor Sensitivity ◽  
Chronic Effects ◽  
Male Wistar Rats

This study evaluated the chronic effects of the run and walk in the metabolic and cardiovascular parameters of a metabolic syndrome experimental model. Male Wistar rats were divided into 4 groups(n=8): Control (C),Sedentary Fructose (SF), Fructose Run (FR) and Fructose Walk (FW, n= 8). Metabolic syndrome (MS) induction was performed with D-fructose in drinking water for 18 weeks. The exercise training was initiated after the nineth week of treatment with fructose and was held for 8 weeks (60 minutes/day, 5 times / week). The FW and FR were performed on a treadmill (1 h/day; 5 days/wk for 8 wk), with ∼20% and 60% intensities respectively of the maximum speed in a maximal exercise test. Plasma glucose, triglycerides, insulin resistance, adipose tissue, blood pressure, heart rate, baroreceptor sensitivity and sympathetic and parasympathetic tone, were evaluated at the end of protocol. The results showed that run and walking decreased the adipose tissue (FR: 2.97±0.2; FW: 4.26±0.9; SF: 6.49±0.6; C: 3.23±0.2 g). The glycemia values remained within the normal range,(FR: 86.7±2.3; WF: 91.0±1.4; SF: 70.2±1.9; C: 84±2.3 mg/dl), however only the FR group decreased the triglycerides levels (FR: 133±8.8; FW: 159±10.2; SF: 220±6.3; C: 96± 4.2 mg/dl), and the insulin resistance (FR: 4.37±0.1; FW: 3.55±0.2; SF: 2.79±0.3; C: 4.86±0.3 %/min). The FR group showed a reduction in mean arterial pressure (FR: 111±4.5, FW: 125±4.1; SF: 137±2.6, C: 113±1.5 mmHg) and increased of bradycardic (FR 1.76±0.08; FW 1.31±0.10; SF 1.37±0.10; C 1.72±0.14 bpm/mmHg) and tachycardic response to BP changes (FR 4.02±0.32; FW 2.56±0.16; SF 1.97±0.15; C (and C 3.25±0.37 bpm/mmHg). Finally we observed that only the FR group showed an increase of the vagal tone (FR: 72.3±8.1, FW: 47.3±6.7; FS: 40.3±4.6, C: 60.7±6.5 bpm). In conclusion, our results suggest that training walk (FW), a practice widely recommended, is especially effective for the treatment of metabolic disorders, whereas controlled exercise (FR) seems to encompass hemodynamic and metabolic aspects. This application is easy and within reach of the majority of the population, indicating that this practice should be encouraged and may be effective in managing cardiovascular risk in MS as start therapeutic. Sources of Funding:FAPESP.

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