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 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 Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation

2020 ◽  
Vol 247 (1) ◽  
pp. 39-52
Author(s):  
Iyad H Manaserh ◽  
Emily Maly ◽  
Marziyeh Jahromi ◽  
Lakshmikanth Chikkamenahalli ◽  
Joshua Park ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Body Temperature ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Metabolic Dysregulation ◽  
Brown Adipose ◽  
Novel Target

The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

scholarly journals SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jennifer Wootton Hill ◽  
Iyad H Manaserh
Keyword(s):  
Body Temperature ◽  
Energy Expenditure ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Normal Body Temperature ◽  
Metabolic Dysregulation ◽  
Brown Adipose ◽  
Novel Target ◽  
Thermogenic Response

Abstract The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

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.

Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

2019 ◽  
Vol 854 ◽  
pp. 354-364 ◽  
Author(s):  
Kripa Shankar ◽  
Durgesh Kumar ◽  
Sanchita Gupta ◽  
Salil Varshney ◽  
Sujith Rajan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Fat Diet ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Brown Adipose

Role of brown adipose tissue (BAT) in burn-induced insulin resistance

2013 ◽  
Vol 2 (2) ◽  
pp. 85 ◽  
Author(s):  
Qin Zhang ◽  
BangYi Ma ◽  
Eirka Cyr ◽  
Lacey Mcintosh ◽  
Alan Fischman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Brown Adipose

scholarly journals Hypoxia Inhibits Cavin-1 and Cavin-2 Expression and Down-Regulates Caveolae in Adipocytes

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 789-801 ◽  
Author(s):  
Claire Regazzetti ◽  
Karine Dumas ◽  
Sandra Lacas-Gervais ◽  
Faustine Pastor ◽  
Pascal Peraldi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Hypoxia Inducible Factor ◽  
Insulin Receptors ◽  
Underlying Mechanism ◽  
Epididymal Adipose Tissue ◽  
Diabetic Patients ◽  
Model Assessment ◽  
Hypoxia Inducible Factor 1

Abstract During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.

scholarly journals Adiposity and Insulin Resistance in Humans: The Role of the Different Tissue and Cellular Lipid Depots

2013 ◽  
Vol 34 (4) ◽  
pp. 463-500 ◽  
Author(s):  
Samantha Hocking ◽  
Dorit Samocha-Bonet ◽  
Kerry-Lee Milner ◽  
Jerry R. Greenfield ◽  
Donald J. Chisholm
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Lipolytic Activity ◽  
Liver Lipid ◽  
Subcutaneous Fat ◽  
Abdominal Fat ◽  
Brown Adipose ◽  
Perivascular Fat

Abstract Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount. Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties. Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance. There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear. Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.

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.

scholarly journals Secretory function of adipose tissue

2016 ◽  
Vol 19 (2) ◽  
pp. 441-446 ◽  
Author(s):  
J. Kuryszko ◽  
P. Sławuta ◽  
G. Sapikowski
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Insulin Receptors ◽  
Endocrine Function ◽  
Endocrine Gland ◽  
Main Function ◽  
Secretory Function ◽  
Brown Adipose

Abstract There are two kinds of adipose tissue in mammals: white adipose tissue – WAT and brown adipose tissue – BAT. The main function of WAT is accumulation of triacylglycerols whereas the function of BAT is heat generation. At present, WAT is also considered to be an endocrine gland that produces bioactive adipokines, which take part in glucose and lipid metabolism. Considering its endocrine function, the adipose tissue is not a homogeneous gland but a group of a few glands which act differently. Studies on the secretory function of WAT began in 1994 after discovery of leptin known as the satiation hormone, which regulates body energy homeostasis and maintainence of body mass. Apart from leptin, the following belong to adipokines: adiponectin, resistin, apelin, visfatin and cytokines: TNF and IL 6. Adiponectin is a polypeptide hormone of antidiabetic, anti-inflammatory and anti-atherogenic activity. It plays a key role in carbohydrate and fat metabolism. Resistin exerts a counter effect compared to adiponectin and its physiological role is to maintain fasting glycaemia. Visfatin stimulates insulin secretion and increases insulin sensitivity and glucose uptake by muscle cells and adipocytes. Apelin probably increases the insulin sensitivity of tissues. TNF evokes insulin resistance by blocking insulin receptors and inhibits insulin secretion. Approximately 30% of circulating IL 6 comes from adipose tissue. It causes insulin resistance by decreasing the expression of insulin receptors, decreases adipogenesis and adiponectin and visfatin secretion, and stimulates hepatic gluconeogenesis. In 2004, Bays introduced the notion of adiposopathy, defined as dysfunction of the adipose tissue, whose main feature is insulin and leptin resistance as well as the production of inflammatory cytokines: TNF and IL 6 and monocyte chemoattractant protein. This means that excess of adipose tissue, especially visceral adipose tissue, leads to the development of a chronic subclinical inflammatory condition, which favours the development of insulin resistance and Type 2 diabetes. Obesity is a systemic illness caused by energy transformation homeostasis disorder which results in an increase in the amount of body fat mass. It effects approximately 40% of dogs and 20% of cats. Illnesses which accompany obesity result, to a great extent, from the secretive role of adipose tissue, which is still little known, which should be included when planning treatment of an obese animal.

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